Isoprenyl-thiourea and urea derivatives as new farnesyl diphosphate analogues: Synthesis and in vitro antimicrobial and cytotoxic activities

Article abstract of DOI:10.1016/j.ejmech.2012.10.042

A series of new isoprenyl-thiourea and urea derivatives were synthesized by the reaction of alkyl or aryl isothiocyanate or isocyanate and primary amines. The structures of the compounds were established by ¹H NMR, ¹³C NMR, MS, HRMS

Full text of DOI:10.1016/j.ejmech.2012.10.042

European Journal of Medicinal Chemistry 58 (2012) 591e612
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Isoprenyl-thiourea and urea derivatives as new farnesyl diphosphate analogues:
Synthesis and in vitro antimicrobial and cytotoxic activities
,
a
b
a
José M. Vega-Pérez a , Ignacio Periñán , Montserrat Argandoña , Margarita Vega-Holm ,
*
Carlos Palo-Nieto a, Estefanía Burgos-Morón c, Miguel López-Lázaro c, Carmen Vargas b,
Joaquín J. Nieto b, Fernando Iglesias-Guerra a
,
*
a Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, 41071 Sevilla, Spain
b Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad de Sevilla, 41071 Sevilla, Spain
c Departamento de Farmacología, Facultad de Farmacia, Universidad de Sevilla, 41071 Sevilla, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new isoprenyl-thiourea and urea derivatives were synthesized by the reaction of alkyl or aryl
isothiocyanate or isocyanate and primary amines. The structures of the compounds were established by
1H NMR, 13C NMR, MS, HRMS and elemental analysis. The new compounds were screened for in vitro
antimicrobial activity against seven strains representing different types of gram-positive and gram-
negative bacteria. More than a third of the synthesized compounds showed variable inhibition activi-
ties against the tested strains. Best antimicrobial activities were found for those thiourea analogues with
3-methyl-2-butenyl, isobutyl or isopentyl groups and aromatic rings possessing electron withdrawing
substituents. The new compounds were also subjected to a preliminary screening for antitumoral
activity. The presence of a highly lipophilic group and an electron withdrawing group in the aromatic
rings enhanced anticancer activity of the synthesized compounds, showing in most cases more activity
than that of the controls.
Received 12 March 2012
Received in revised form
22 October 2012
Accepted 24 October 2012
Available online 1 November 2012
Keywords:
Antibacterial
Antifungal
Anticancer
Farnesyl diphosphate analogue
Isoprenyl-thiourea/urea derivative
Structural requirements
Ó 2012 Elsevier Masson SAS. All rights reserved.
1. Introduction
be designed focusing on farnesyl diphosphate synthase inhibi-
tion [1].
Due isoprenoids represent the largest class of small molecules
on earth, many of the enzymes that are involved in isoprenoid
biosynthesis are drug targets [1,2].
Farnesyl diphosphate and its C20 homologue, geranylgeranyl
diphosphate are important isoprenoids involved in a number of
cellular processes including cholesterol biosynthesis, glycoprotein
synthesis, vitamin and cofactor synthesis, and protein prenylation
[3,4]. The design of novel inhibitors of compounds involved in these
cellular processes has attracted considerable attention as these
inhibitors are possible chemotherapeutic agents.
For example, compounds that inhibit squalene synthase are
expected to be effective therapeutic agents for lowering serum
cholesterol levels, an interesting alternative to prevent athero-
sclerosis and subsequent cardiovascular disease [5]. New anti-
parasitic agents that block sterol biosynthesis in protozoa can
Both farnesyl diphosphate and geranylgeranyl diphosphate are
also used in protein prenylation, an important post-translational
modification central to many cellular processes. They are
substrates of farnesyltransferase (FTase) and geranylgeranyl-
transferase (GGTase-I) respectively, which catalize the transfer of
the prenyl group from farnesyl diphosphate or geranylgeranyl
diphosphate to the intracellular protein active, so that the attached
lipid acts as hydrophobic membrane anchor leading to the
membrane localization. In this sense, an active area of research is
the development of protein prenylation inihibitors [6e11]. The
primary force for such efforts came from the finding that Ras
proteins require farnesylation. Oncogenic Ras proteins that are
found in a significant number of cancers contribute to malignancy
and are therefore considered favored targets for direct therapy. The
research is oriented to the preparation of highly potent and selec-
tive compounds that are reversible inhibitors of human FTase.
Inhibitors of Ras FTase have been designed based both on the far-
nesyl moiety of the farnesyl diphosphate susbtrate and the
diphosphate group FDP [12].
* Corresponding authors.
E-mail addresses: vega@us.es (J.M. Vega-Pérez), iglesias@us.es (F. Iglesias-Guerra).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.10.042

592
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
Sesquiterpene/terpene isoprenoid ruler
R= OPP
isostere
OPP
FPP
OPP
fm-1
Scheme 1. Reaction for the synthesis of the isoprenyl-thiourea/urea derivatives
library 3.
O
OPP
OPP
O
fm-2
farnesyl mimics (fm) smaller than farnesyl residue might be less
specific towards squalene synthase and FTase. On the other hand an
ideal diphosphate isostere would be one that shares electronic and
steric similarities with the diphosphate moiety. Such isosteres
include biphosphonic acids, mixed phosphonic/carboxyl acids
and dicarboxyl acid moieties [15]. These farnesyl diphosphate
analogues exhibited promising antimicrobial activities (Fig. 2, fm-1
and fm-2) that were thought to be attributable to inhibition of
squalene synthase. However, the low squalene synthase inhibition
results suggest an alternative site of inhibition, possibly FTase
(Fig. 1).
fm-3
O
OPP
fm-4
O
Additionally and closely related to results presented in this
work, new chemotherapeutics agents have been described with
urea or thiourea functions present in their structures. A survey of
the literature reveals many N-acyl-thiourea derivatives with wide
application as insecticides [16], antitumorals [17,18], antimicrobials
and antifungals [19e24]. Substituted halopyridyl, indolyl and
naphthyl thiourea compounds have been synthesized and evalu-
ated as an efficient new chemical class of anti-allergic [25].
Additionally, urea derivatives have been used for the treatment
of a wide range of solid tumors [26], have also been reported as
protein kinasa inhibitors, and have become an important class of
potential anticancer drugs [27]. For these reasons, the synthesis and
biological evaluation of new functionalized urea derivatives has
acquired a high interest. Indeed, during the preparation of this
manuscript the synthesis of ureido and thioureido derivatives of
peptide conjugated heterocycles has been reported [28]. Our effort
Fig. 1. Molecular hypothesis for isoprenoid specificity.
The emergence of drug resistant pathogenic bacteria continues
to be a serious health problem worldwide [13]. As a result, it has
become critical to identify new structural classes of antibacterial
agents to combat the growing threat of bacterial resistance.
In this line, a recent approach to the design of new antibacterial
compounds is the development of easily synthesizable farnesyl
diphosphate mimetics. A wide range of structurally diverse farnesyl
diphosphate mimetics have been described for antimicrobial
evaluation considering a farnesyl mimic and diphosphate isostere
essential for inhibitory activity [3,14]. According to the ‘‘molecular
ruler’’ hypothesis for isoprenoid substrate specificity where the
depth of the hydrophobic binding cavity acts as a ruler in
discriminating between isoprenoids of different lengths, those
Table 1
Isoprenyl-thiourea derivatives 4e20. R1 ¼ 3-methyl-2-butenyl.
Highly charged
Entry
Compound
O-
P
O-
P
R2
Yield (%)
O-
O
O
1
2
3
4
5
6
7
8
4
5
6
7
8
Methyl
tert-Butyl
Allyl
Phenyl
97
92
87
79
93
97
78
95
85
88
96
92
90
85
79
90
96
O
O
Labile bond
Common motif recognized
4-Nitrophenyl
by several enzymes
9
4-Trifluoromethylphenyl
4-Fluorophenyl
4-Chlorophenyl
4-Cyanophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
3-Pyridyl
2-(1-Piperidino)ethyl
2-(4-Morpholino)ethyl
3-(4-Morpholino)propyl
Ethoxycarbonylmethyl
10
11
12
13
14
15
16
17
18
19
20
X
9
R
N
H
10
11
12
13
14
15
16
17
N
H
H
n
n:
1, 2, 3
X: S, O
R: alkyl, aryl
Fig. 2. General backbone for new isoprenyl-thiourea and urea derivatives.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
593
Table 2
Table 4
Geranyl thiourea derivatives 21e40. R1 ¼ geranyl.
Alkyl thiourea derivatives 59e68.
Entry
Compound
Entry
Compound
R2
Yield (%)
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Methyl
tert-Butyl
Allyl
Phenyl
78
97
98
98
94
90
97
90
95
98
85
90
90
90
84
92
96
80
96
83
1
2
3
4
5
6
7
8
9
10
59
60
61
62
63
64
65
66
67
68
Isobutyl
Isopentyl
Benzyl
Cyclohexyl
1-Dodecyl
1-Dodecyl
1-Dodecyl
1-Dodecyl
1-Dodecyl
4-Morpholino
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
4-Nitrophenyl
3-Nitrophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
4-Nitrophenyl
89
92
96
90
99
82
96
93
86
90
4-Nitrophenyl
3-Nitrophenyl
4-Trifluoromethylphenyl
4-Fluorophenyl
4-Chlorophenyl
4-Cyanophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
3-Pyridyl
2-(1-Piperidino)ethyl
2-(4-Morpholino)ethyl
3-(4-Morpholino)propyl
4-Piperidyl
Ethoxycarbonymethyl
Ethoxycarbonyl
9
10
11
12
13
14
15
16
17
18
19
20
2. Results and discussion
2.1. Design
Our general structure has been designed by an attempt to
generate farnesyl diphosphate analogues by challenges in the FDP
structure illustrated in Fig. 2. We made the following structural
modifications: (1) we have replaced the farnesyl residue by
different unsaturated lipidic moieties, commonly isoprenyl
derived; (2) another aspect taken under consideration is the lability
of the diphosphate bond, which has been replaced in our model
with a more resistant bond, urea or thiourea, thus introducing a less
polar, less charged group; (3) and finally our general backbone
possesses another structural variability point, R substituent, so
different alkyl and aryl substituents can be introduced in order to
evaluate their effects on the biological activity of the compounds.
As several different enzymes in the cell utilize FDP, these
analogues are expected to act as inhibitors, so a part of our current
investigation involved their evaluation, both antimicrobial and
citotoxic.
in this field, taking into consideration the aforementioned biolog-
ical significance of isoprenoids and thiourea and urea functions,
was the development of new chemotherapeutic agents (as a part of
our research focused in the synthesis of new compounds with
potential biological activity [29]) by joining in one single structure
these two important biologically active scaffolds, the thiourea or
urea function and the isoprenyl residue, seeking an improved bio-
logical activity.
The major aim of this report is to present the synthesis, by
a short and high yielded methodology, of small libraries of new
isoprenyl urea/thiourea derivatives. Biological screening and SAR
studies were done in order to identify novel lead molecules.
Table 5
Urea derivatives 69e89.
Table 3
Farnesyl thiourea derivatives 41e58. R1 ¼ farnesyl.
Entry Compound
Entry
Compound
R1
R2
Yield (%)
1
2
3
4
5
6
7
8
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
3-Methyl-2-butenyl Ethyl
3-Methyl-2-butenyl Allyl
3-Methyl-2-butenyl Phenyl
3-Methyl-2-butenyl 4-Nitrophenyl
87
87
63
83
98
97
98
98
94
R2
Yield (%)
1
2
3
4
5
6
7
8
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
Methyl
tert-Butyl
Allyl
Phenyl
4-Nitrophenyl
3-Nitrophenyl
4-Trifluoromethylphenyl
4-Fluorophenyl
4-Chlorophenyl
4-Cyanophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
2-(1-Piperidino)ethyl
2-(4-Morpholino)ethyl
3-(4-Morpholino)propyl
Ethoxycarbonylmethyl
Ethoxycarbonyl
94
79
85
96
97
91
85
97
78
85
91
91
92
85
76
90
96
96
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
1-Dodecyl
Ethyl
tert-Butyl
Allyl
Phenyl
4-Nitrophenyl
9
10
11
12
13
14
15
16
17
18
19
20
21
4-Trifluoromethylphenyl 97
4-Chlorophenyl
4-Cyanophenyl
Ethyl
tert-Butyl
Allyl
Phenyl
4-Nitrophenyl
4-Trifluoromethylphenyl 85
95
95
95
70
95
96
87
9
10
11
12
13
14
15
16
17
18
4-Chlorophenyl
4-Cyanophenyl
4-Nitrophenyl
78
85
93

594
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
2.2. Chemistry
Our procedure started with a preliminary screening prelimi-
nary screening in order to identify those compounds that pre-
sented some antibacterial activity. Once detected, the most
interesting (more active or selective) were chosen and subjected
to a compared analysis of growth in liquid medium versus
commercial substances.
Preliminary in vitro evaluation was carried out by disk diffusion
method using nutrient agar medium. The tests were repeated three
times and the results are reported as means of at least three
determinations. After the incubation time, the radius of the clear
zones showing no bacterial growth was measured around each
well. The zones of inhibition (mm scale) were calculated and reflect
the degree of antibacterial activity. The compounds were dissolved
in dimethylsulfoxide (DMSO). Commercial antibiotics Tobramycine,
Tetracycline and Ketoconazol were used as a positive control and
Our objective was to prepare a small library of new isoprenyl-
thiourea and urea derivatives through a short synthetic method-
ology. By choosing the appropriate precursors, the primary amine
and the alkyl or aryl isothiocyanate or isocyanate derivative, we can
generate the chemical diversity of compounds. Apart from
isoprenyl and farnesyl amines (easily prepared [30]) all cyanate
derivatives and primary amines employed were commercial
reagents.
Scheme 1 outlines the synthesis of the thiourea/urea derived
compounds. The reaction took place at room temperature in
dichloromethane, and was completed in 15e20 min in high yields.
With this method we obtained a structurally varied library
consisting of 63 new isoprenyl-thiourea derivatives (Tables 1e4)
and 21 isoprenylurea derivatives (Table 5).
The general backbone of these compounds (Scheme 1) shows
that both amide function substituents are structural variation
points. R1 (from the amine precursor) are groups with different
degrees of lipophilia, mainly unsaturated, and R2 (from the isocy-
anate reactant) is the position we use to widen the range of
possibilities: alkyl groups of different sizes, aromatic carbocyclic
and heterocyclic groups (with different substituents, possessing
electron withdrawing or electron-releasing groups). That gives us
a pool of compounds that, after screening process, will provide
information about the structureeactivity relationship.
the solvent was used as
concentrations.
a negative control at the same
The observed data (inhibitory zone) for our compounds are
presented in Table 6.
The data generated from this study (Table 6) revealed that
around 40% of the synthesized compounds showed variable inhi-
bition activities against the tested strains. However no activity was
detected against enterobacter strains in any case.
Best activities, highest inhibition zone (17e23 mm), were
detected for those compounds with a small group at R1 position
(such as isoprenyl, isobutyl and isopentyl) and a 4-nitrophenyl
group at R2 (compounds 8, 59, 60, entries 5, 49 and 50). These
three compounds possessed broad-spectrum antibacterial activity
against gram-positive pathogens (Staphylococcus aureus and
Bacillus subtilis) and against gram-negative pathogens (Klebsiella
pneumonia and Pseudomonas aeruginosa).
Tables 1e4 show the new thiourea derivatives grouped by the
type of lipophilic substituent.
In a similar way, employing isocyanate compounds as reactant
we synthesized the urea derivatives 69e89.
All compounds were obtained in high yields (over 80% in almost
all cases).
In compounds with an isoprenyl group, changes in the aromatic
1H NMR spectra of the thioureas and ureas showed the signals of
the isoprenoid chains in all cases. NHCH2 protons appear at around
3.98 ppm, the signals corresponding to the double bonds of the
isoprenyl chains are observed at 5.23 ppm, other signal for geranyl
derivatives corresponding to the second double bond present in the
geranyl chains is observed at 5.02 ppm and farnesyl derivatives
present a signal at 5.06 ppm attributed to the third double bond.
These signals of the alkenyl protons permitted the characterization
of the hydrogens showing similar values for those thioureas and
ureas with the same substituents. For dodecyl derivatives, the
(CH2)10 protons are observed at 1.7e1.2 ppm and the CH3 terminal
as a triplet at 0.87 in all cases.
ring in position R2 (4-trifluoromethylphenyl, 4-fluorophenyl, 4-
chlorophenyl,
4-cyanophenyl,
4-methoxyphenyl,
3-
methoxypheny, 2-methoxyphenyl, 3-pyridyl) brought either
a decrease in activity (compound 9, entry 6) or total loss of activity
(compounds 15 and 16, entries 12 and 13). It should be noted that
some of these compounds have moderate activity (inhibition zone
10e12 mm) against P. aeruginosa, (compounds 9e11, entries 6e8)
or are completely selective (compounds 14 and 17, entries 11 and
14).
Replacing the isoprenyl group with a geranyl group decreased
the activity (compound 25, entry 21 vs compound 8, entry 5).
However, geranyl derivatives with groups other than 4-nitrophenyl
at R2 position have a moderate activity against gram-positive
pathogens (compounds 27e30, 34, 35 and 37, entries 22e25, 28e
29 and 31).
13C NMR spectra of the thioureas and ureas showed the typical
absorptions for the signals for the thiocarbonylic and carbonylic
carbons, in the range of
respectively.
d 181e182 ppm and 155e156 ppm
Most compounds with a farnesyl group in R1 position present no
antibacterial activity (entries 34e43). Only those with 3-
methoxyphenyl, 2-(1-piperidino)ethyl, 2-(4-morpholino)ethyl and
3-(4-morpholino)propyl grops at R2 present a small inhibition zone
against gram-positive pathogens (compounds 52, 54e56, entries
44e47).
Spectral (NMR, mass spectrometry) and analytical data of all the
synthesized compounds were in full agreement with the proposed
structures.
The next step in our research was to subject these compounds to
biological assays [our group have previously described their use of
few of them (7, 8, 21, 40, 45, 69, 73, 81) for the treatment of hepatic
encephalopathy [31].
If, in position R1, the isobutyl or isopentyl alkyl chain is replaced
by a benzyl or cyclohexyl group the resulting compounds present
the same antibacterial spectrum, but a decreased activity (11e
14 mm, compounds 61 and 62, entries 51e52).
2.3. In vitro antimicrobial activity
The results of this preliminary antimicrobial screening lead to
the following assumptions about the structural activity relationship
(SAR), Fig. 3.
Antimicrobial activity of the synthesized compounds was eval-
uated against seven strains representing different types of gram-
positive and gram-negative bacteria, Bacillus subtilis ATCC6633,
Staphylococcus aureus ATCC2595, Klebsiella pneumoniae ATCC10031,
Pseudomonas aeruginosa CECT110, Escherichia coli ATCC25922,
Salmonella enterica ATCC10708, Serratia marcescens ATCC 14756.
Antifungal activity was also evaluated against Candida albicans.
-
The substituent R1 (from the primary amine employed in the
reaction) plays a key role in varying the efficacy of antimicro-
bial activity. Thiourea analogues with 3-methyl-2-butenyl,
isobutyl or isopentyl groups gave best activities.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
595
Table 6
Antimicrobial bioassay screnning.
Entry
Compd
Antimicrobial activitya
Gram-positive
Gram-negative fungi
B. subtilis
S. aureus
K. pneumoniae
P. aeruginosa
E. coli
S. enterica
S. marcenscens
C. albicans
1
2
3
4
5
6
7
8
4
5
6
7
8
9
e
e
e
e
e
20
13
e
e
14
e
e
e
e
e
e
e
e
e
e
e
15
10
8
e
11
e
11
17
9
e
e
e
e
e
10
12
11
e
e
12
e
e
12
e
e
e
e
e
e
e
e
e
e
e
e
e
12
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
23
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
22
21
e
20
e
12
e
e
e
13
18
e
e
e
e
21
e
10
e
e
e
e
e
e
e
e
e
e
e
11
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
18
9
11
e
10
11
12
13
14
15
16
17
18
19
21
22
23
24
25
27
28
29
30
31
32
34
35
36
37
39
40
41
42
43
44
45
47
48
49
50
51
52
54
55
56
58
59
60
61
62
63
65
66
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
e
e
11
e
e
e
e
e
e
e
10
e
e
e
e
e
e
e
e
e
e
e
11
8
13
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
19
20
14
11
9
9
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
e
e
e
e
e
e
e
12
e
e
e
13
e
11
e
9
13
12
e
16
e
e
12
e
e
8
e
e
e
e
e
e
e
e
e
e
e
e
8
11
15
e
11
e
e
e
e
e
e
e
e
e
e
e
11
11
12
10
e
8
9
e
e
20
22
12
13
8
18
18
13
13
e
e
e
e
13
e
e
e
e
e
e
11
e
e
e
e
e
e
e
e
e
7
e
e
e
e
e
e
e
14
e
e
e
e
e
11
e
e
e
e
e
20
e
e
e
e
e
e
e
e
e
e
(continued on next page)

596
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
Table 6 (continued )
Entry
Compd
Antimicrobial activitya
Gram-positive
Gram-negative fungi
B. subtilis
S. aureus
K. pneumoniae
P. aeruginosa
E. coli
S. enterica
S. marcenscens
C. albicans
71
72
73
74
75
76
77
78
79
80
83
84
85
86
87
88
89
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
8
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Tobramycine
Tetracycline
Ketoconazol
41
48
20
28
33
15
21
36
e
34
14
e
23
31
e
30
39
e
23
12
e
25
ꢀ, No activity.
a
Zone of inhibition (radius, mm).
Fig. 3. Structural requirements for antimicrobial activity of thiourea derivatives.
-
According to the nature of R2 substituent most active
compounds were those with 4-nitrophenyl group (the role of
electron withdrawing groups in improving antimicrobial
activities has been reported in the literature [32]).
Antifungal activity evaluation results revealed that most of the
tested compounds were not active. Only a few isoprenyl and ger-
anyl derivatives showed high activity (18e21 mm). From observed
data, for those isoprenyl derivatives, R2 position admitted greater
structural variability, tert-butyl, allyl, 4-nitrophenyl, 2-
methoxyphenyl groups (compounds 5, 6, 8 and 15, entries 2, 3, 5
and 12). Compound 21 with R1 geranyl and R2 methyl showed
similar activity (entry 17), Fig. 4.
Fig. 5. Growth inhibitory effect against P. aeruginosa of selected compounds and
Tobramycine.
Compounds with R1 farnesyl or alkyl group did not exhibit
activity.
Urea derivatives did not exhibit either antibacterian or anti-
fungal activity. Notably, compound 72, R1 geranyl and R2 4-
nitrophenyl, gave high and selective activity against Bacillus sub-
tilis (entry 60).
2.4. Growth inhibitory effect of selected compounds
Those compounds which presented remarkable antimicrobial
activity in the assay and/or were selective against a specific refer-
ence strain using the disc diffusion method were selected to
compare their activity with clinical commercial compounds. For
that purpose, growth of different strains was monitored during
a long period (60e300 h) in absence and presence of different
concentrations of antimicrobial compounds (0, 20, 50, 100, 200 mg/
ml) and compared with the growth in the presence of the minimal
concentration of commercial ones that produce total inhibitory
effect.
Fig. 6. Growth inhibitoryeffect against S. aureus of selected compounds and Tetracycline.
Fig. 4. Structural requirements for antifungal activity of thiourea derivatives.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
597
Table 7
Citotoxic activity data.
Entry Compound
X
S
R1
R2
IC50 (mM)
1
2
3
4
4
6
7
8
3-Methyl Methyl
-2-butenyl
3-Methyl Allyl
-2-butenyl
3-Methyl Phenyl
-2-butenyl
3-Methyl 4-Nitrophenyl
-2-butenyl
89.48 ꢁ 8.59
75.00 ꢁ 20.41
> 100.00
S
S
S
4.79 ꢁ 0.81
5
6
7
8
21
23
24
25
26
27
28
29
30
31
32
33
34
39
40
41
43
44
45
46
47
48
49
50
51
52
53
55
56
57
58
63
64
65
66
67
69
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
O
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Methyl
Allyl
Phenyl
4-Nitrophenyl
3-Nitrophenyl
30.70 ꢁ 6.90
47.07 ꢁ 15.10
13.81 ꢁ 5.33
5.58 ꢁ 1.49
9
15.21 ꢁ 13.81
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
4-Trifluoromethylphenyl 4.28 ꢁ 0.24
4-Fluorophenyl
4-Chlorophenyl
4-Cyanophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
3-Pyridyl
21.86 ꢁ 3.48
27.08 ꢁ 3.89
4.72 ꢁ 0.37
16.96 ꢁ 2.13
27.36 ꢁ 3.58
28.50 ꢁ 2.12
28.50 ꢁ 2.12
30.31 ꢁ 2.40
38.43 ꢁ 1.68
40.17 ꢁ 0.33
15.34 ꢁ 0.08
17.03 ꢁ 4.79
1.48 ꢁ 0.78
1.14 ꢁ 0.36
Fig. 7. Growth inhibitory effect against K. pneumoniae of selected compounds and
Tetracycline.
The Pseudomonas aeruginosa growth was monitored during 70 h
against compounds 9, 10, 11, 14, 17 and 34 and compared with the
growth against Tobramycine in a final concentration of 20 mg/ml.
Only compounds 9, 11 and 34 showed a partial inhibitory effect as
a delayed growth of P. aeruginosa was observed (Fig. 5). However
none of the tested compounds showed higher antimicrobial
activity against P. aeruginosa than the commercial one, Tobramy-
cine (TBR).
Ethoxycarbonylmethyl
Ethoxycarbonyl
Methyl
Allyl
Phenyl
4-Nitrophenyl
3-Nitrophenyl
4-Trifluoromethylphenyl 1.60 ꢁ 1.01
4-Fluorophenyl
3.73 ꢁ 0.09
2.65 ꢁ 0.12
0.36 ꢁ 0.03
8.03 ꢁ 1.48
4.20 ꢁ 0.40
10.97 ꢁ 2.22
5.11 ꢁ 0.26
4-Chlorophenyl
4-Cyanophenyl
4-Methoxyphenyl
3-Methoxyphenyl
2-Methoxyphenyl
2-(4-Morpholino)ethyl
Staphylococcus aureus and Klebsiella pneumoniae were grown in
the presence of 20 mg/ml of compounds 59, 60, 61, 62 and Tetra-
cycline. In the case of S. aureus compounds 59 and 61 showed an
inhibitory effect comparable with Tetracycline and, interestingly,
compounds 60 and 62 were even more effective (Fig. 6). On the
other hand, K. pneumoniae was also sensitive to the effect of
compounds 60, 61, 62 (Fig. 7). Compound 59 presented an inhibi-
tory effect comparable to Tetracycline during 50 h, however it
disappeared after this period allowing K. pneumoniae to grow and
3-(4-Morpholino)propyl 3.13 ꢁ 0.25
Ethoxycarbonylmethyl
Ethoxycarbonyl
19.69 ꢁ 7.08
28.75 ꢁ 1.52
2.50 ꢁ 1.04
4.14 ꢁ 0.38
27.01 ꢁ 15.04
10.28 ꢁ 1.49
8.28 ꢁ 2.51
>100.00
1-Dodecyl 4-Nitrophenyl
1-Dodecyl 3-Nitrophenyl
1-Dodecyl 4-Methoxyphenyl
1-Dodecyl 3-Methoxyphenyl
1-Dodecyl 2-Methoxyphenyl
3-Methyl Ethyl
-2-butenyl
42
43
70
71
O
O
3-Methyl Allyl
-2-butenyl
3-Methyl Phenyl
-2-butenyl
>100.00
>100.00
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
73
75
76
77
78
79
80
81
83
84
85
86
87
88
89
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Geranyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Farnesyl
Ethyl
Allyl
Phenyl
4-Nitrophenyl
71.83 ꢁ 23.00
41.82 ꢁ 18.84
39.19 ꢁ 4.41
3.97 ꢁ 0.42
4-Trifluoromethylphenyl 15.75 ꢁ 5.87
4-Chlorophenyl
4-Cyanophenyl
Ethyl
51.06 ꢁ 23.71
10.43 ꢁ 6.94
30.91 ꢁ 3.16
37.37 ꢁ 8.99
16.89 ꢁ 10.51
1.67 ꢁ 0.60
Allyl
Phenyl
4-Nitrophenyl
4-Trifluoromethylphenyl 2.98 ꢁ 0.56
4-Chlorophenyl
4-Cyanophenyl
76.01 ꢁ 12.07
2.63 ꢁ 0.37
2.73 ꢁ 1.12
4.32 ꢁ 2.15
86.21 ꢁ 13.79
1-Dodecyl 4-Nitrophenyl
5-Fluorouracil
Hydroyurea
Fig. 8. Growth inhibitory effect against C. albicans of selected compounds and
Ketoconazol.

598
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
Fig. 9. Structural requirements for cytotoxic activity of thiourea and urea derivatives.
reach O.D. similar to that without any antimicrobial compound
(Fig. 7) suggesting that compound 59 could be a better antimicro-
bial agent to be use in Gram positive than in Gram-negative
bacteria.
Finally to test the inhibitory effect of selective antifungal
compounds, Candida albicans growth was monitored in the pres-
inhibit the growth of tumor cells. Evidence suggests that the anti-
cancer activity of several anticancer drugs commonly used in clinic
(e.g. cisplatin, doxorubicin, arsenic trioxide, bortezomib, procar-
bazine, etoposide, etc) is mediated, at least in part, by reactive
oxygen species (ROS) such as hydrogen peroxide (H2O2) [33]. For
instance, although it has been known for many years that the
anticancer effect of paclitaxel (taxol) is mediated by its activity on
the microtubule protein tubulin, recent experiments have shown
that H2O2 plays an important role in paclitaxel-induced cancer cell
death [34]. The induction of oxidative stress by pro-oxidant agents
is emerging as an attractive anticancer strategy [33,35,36]. In
addition, our most cytotoxic compounds have a farnesyl radical in
their structure, and recent data indicate that the generation of ROS
is a primary mechanism by which farnesol kills cells [37]. Data also
suggest that nitrobenzene, a radical that is present in several of our
most potent compounds, may also generate ROS [38]. This made us
consider the possible involvement of ROS in the cytotoxic activity of
our compounds. HT-29 cells were treated with the five most active
compounds in the presence or absence of the antioxidants N-ace-
tylcysteine (NAC) or Mn(III) Tetrakis(1-methyl-4-pyridyl)
porphyrin pentachloride (MnTMPyP); NAC and MnTMPyP have
been shown to reduce the cytotoxic activity of drugs that generate
ROS [39]. The five compounds and 5-FU were tested at three
ence of 20 mg/ml of compounds 5, 6, 15 and 21. In this case Keto-
conazol was used as commercial control. As shown in Fig. 8
compounds 5, 6 and 15 presented partial inhibitory effect on
C. albicans growth but only compound 21 presented the best anti-
fungal activity comparable with that of Ketoconazol.
2.5. In vitro citotoxic activity
For each group of analogues, representative compounds were
chosen and they were subjected to a preliminary screening for
antitumoral activity.
In vitro evaluation of the citotoxic activity of these compounds
was carried against HT-29 human colon adenocarcinoma cell line
by sulforhodamine B (SRB) assay. Cell viability was expressed as
percentage in relation to controls. Data were averaged from at least
three independent experiments and are expressed as
means ꢁ standard error of the means (SEM). 5-Fluorouracil, a drug
widely used in the treatment of colon cancers, and hydroxyurea
were used as positive controls.
different concentrations (1, 10 and 100
mM). The antioxidants were
added to the cells at a final concentration of 5 mM (NAC) and 5
mM
(MnTMPyP) 30 min before the compounds. After a 48 h drug
exposure, cell viability was estimated using the SRB assay. Neither
antioxidant significantly modified the cytotoxic activity of any
compound at any of the tested concentrations (results not shown).
Data (IC50) observed for compounds submitted to antitumoral
assay are presented in Table 7.
From data shown in Table 7, we can see that the most active
compounds (IC50 < 2 mM) were those having a highly lipophilic
group, farnesyl, at R1, and an aromatic substituent with electron
withdrawing groups (NO2, CF3, CN) at R2 position (entries 23e25,
28, and 54, compounds 45e47, 50 and 85). The presence of other
electron withdrawing groups (F, Cl) produced a slight increase in
IC50 (<4) being still very active (entries 26e27, compounds 48 and
49).
The cytotoxicity of pyrogallol (100 mM) and curcumin (10 mM) were
significantly reduced by MnTMPyP and NAC, respectively (results
not shown); these two drugs can be taken as positive controls for
the assay. Our results suggested that the cytotoxic activity of these
compounds is not mediated by the formation ROS.
High activity (IC50 < 4) was also found in 1-dodecyl derivatives
with aromatic substituent with electron withdrawing groups
(entries 36e37, compounds 63e64).
3-Methyl-2-butenyl and geranyl derivatives possessing an
aromatic substituent with electron withdrawing groups gave
antitumoral activity (IC50 4e5) (entries 4, 8, 10 and 13, compounds
8, 25, 27 and 30).
3. Conclusions
Based on the design of new farnesyl diphosphate analogues we
have prepared a series of new isoprenyl-thiourea and urea deriv-
atives through an easy, high yielded reaction. We have evaluated
their inhibitory activity on the growth of pathogenic bacteria and
fungi, and we have detected antimicrobial activity in some of them
(40% of the newly synthesized compounds). Higher antibacterial
activity was observed in those thiourea derivatives having small
chains (3-methyl-2-butenyl, isobutyl or isopentyl) and p-nitro-
phenyl group as substituents. Some of our compounds presented
inhibitory activity comparable to that of commercial compounds
against pathogenic strains Staphylococcus aureus and Klebsiella
pneumonia.
In general, urea derivatives provided higher values of IC50 (but
still active) than thiourea analogues.
Based on these data we can suggest that the presence of a highly
lipophilic group (farnesyl or dodecyl) in R1 and an electron with-
drawing group (more variability than that for antimicrobial
activity) in the aromatic ring located at R2 position enhanced
anticancer activity against HT-29 cancer cell line of the synthesized
compounds, showing in most cases more activity than that of the
controls (Fig. 9).
Most of these compounds did not exhibit antifungal activity.
Only a few isoprenyl and geranyl thiourea derivatives possessing
certain structurally varied groups (tert-butyl, allyl, 4-nitrophenyl,
2-methoxyphenyl, methyl) showed high activity.
An addition to these preliminary cell cytotoxicity tests is the
study of the possible mechanism by which the new compounds

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
599
For both purposes (antibacterial and antifungal) urea derivatives
were not active.
18.0 [(CH3)2C
¼
CHCH2N]; HRMS (CI): calcd for C7H15N2S
159.095595; found, 159.095439 [M þ H]þ.
We have also subjected representative compounds to a prelim-
inary screening for antitumoral activity. In this case our most active
compounds possessed phenyl rings with electron withdrawing
group and, unlike those with high antibacterial activity, a highly
lipophilic group (specially farnesyl, but also 1-dodecyl substitu-
ents). In general thiourea derivatives were most active than urea
ones. Our most active farnesyl derivatives presented greater
activity than the standard used in the assay.
4.1.2.2. N-tert-butyl-N0-(3-methyl-2-butenyl) thiourea (5). The solid
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (184 mg, 92% yield). M.p. 68e69 ꢂC; MS
(EI): m/z 200 (40%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 5.92,
5.48 (2s, 2H, 2NH), 5.28 [m, 1H, (CH3)2C ¼ CHCH2N], 4.08 [m, 2H,
(CH3)2C ¼ CHCH2N],1.76,1.71 [2s, 6H, (CH3)2C ¼ CHCH2N],1.42 [9 H,
NC(CH3)3]; 13C NMR (125 MHz, CDCl3,
d ppm): 180.9 (C]S), 137.9
We have described a simple general backbone that allows
(operating to its structural variation points) to improve/modulate
antimicrobial or antitumoral activities, by choosing the appro-
priate reactants (amine and isothiocyanate/isocyanate). For the
two biological activities studied (antimicrobial and cytotoxic) an
aromatic ring with electron withdrawing groups at one position is
required to be active. The presence of a small chain at the other
position improves antibacterial activity, while if a highly lipo-
philic group is present, these compounds are fundamentally
cytotoxic.
[(CH3)2C ¼ CHCH2N], 119.3 [(CH3)2C ¼ CHCH2N], 52.8 [NC(CH3)3],
43.7 [(CH3)2C CHCH2N], 29.6 [NC(CH3)3], 25.6, 18.1
¼
[(CH3)2C ¼ CHCH2N]; HRMS (EI): calcd. for C10H20N2S 200.134721;
found, 200.134344 [M]þ$. Anal. Calcd for C10H20N2S: C, 59.95; H,
10.06; N, 13.98; S, 16.00. Found: C, 60.11; H, 10.25; N, 13.87; S, 15.83.
4.1.2.3. N-allyl-N0-(3-methyl-2-butenyl) thiourea (6). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(5:1) as eluent (160 mg, 87% yield). MS (EI): m/z 184 (45%) [M]þ$
;
1H NMR (500 MHz, CDCl3,
NCH2CH CH2), 5.27e5.17 [m, 3H, (CH3)2C
d
ppm): 6.10e5.80 (m, 3H, 2NH,
CHCH2N,
The results presented in this work encourage us to continue in
this line of research.
¼
¼
NCH2CH ¼ CH2], 4.08 (m, 2H, NCH2CH ¼ CH2), 3.97 [m, 2H,
(CH3)2C
¼
CHCH2N], 1.72, 1.67 [d, 3H, 4J ¼ 1.0 Hz, s, 3H,
4. Experimental section
(CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 181.8 (C]
S), 137.8 [(CH3)2C ¼ CHCH2N], 133.3 (NCH2CH ¼ CH2), 119.0
[(CH3)2C ¼ CHCH2N], 117.3 (NCH2CH ¼ CH2), 46.9 (NCH2CH ¼ CH2),
42.5 [(CH3)2C ¼ CHCH2N], 25.6, 18.0 [(CH3)2C ¼ CHCH2N]; HRMS
4.1. Chemistry
4.1.1. General
(EI): calcd. for C9H16N2S 184.103420; found, 184.103966 [M]þ$
.
All reagents, solvents, and starting materials were obtained
from commercial suppliers and used without further purification.
Evaporations were conducted under reduced pressure. Reactions
were monitored by thin layer chromatography (TLC) using Kieselgel
60 F254 (E. Merck) plates and UV detector for visualization. Flash
column chromatography was performed on Silica Gel 60 (E. Merck).
Yields are of purified products. Melting points were obtained on
a Stuart Melting Point Apparatus SMP 10 and are uncorrected.
Optical rotations were obtained on a Perkin Elmer Polarimeter
Model 341 at 25 ꢂC. Mass spectra were recorded on a Micromass
AUTOSPECQ mass spectrometer: EI at 70 eV and CI at 150 eV, HR
mass measurements with resolutions of 10,000. NMR spectra were
recorded at 25 ꢂC on a Bruker AMX500 spectrometer and on
a Bruker AV500 spectrometer at 500 MHz for 1H and 125 MHz for
4.1.2.4. N-(3-methyl-2-butenyl)-N0-phenyl thiourea (7). The solid
was purified by column chromatography, using hexaneeethyl
acetate (6:1) as eluent (176 mg, 79% yield). M.p. 115e117 ꢂC; MS
(CI): m/z 221 (70%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.01
(s, 1H, NHPh), 7.46e7.16 (m, 5H, Ph), 5.91 (m, 1H, NH), 5.19 [m, 1H,
(CH3)2C ¼ CHCH2N], 4.20 [m, 2H, (CH3)2C ¼ CHCH2N], 1.69, 1.65 [2s,
6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 180.2
(C]S),137.5 [(CH3)2C ¼ CHCH2N],136.2,130.1,127.1,125.0 (Ph),119.0
[(CH3)2C
¼
CHCH2N], 43.7 [(CH3)2C
¼
CHCH2N], 25.6, 18.0
[(CH3)2C ¼ CHCH2N]; HRMS (CI): calcd. for C12H17N2S 221.111245;
found, 221.111332 [M þ H]þ. Anal. Calcd for C12H16N2S: C, 65.41; H,
7.32; N, 12.71; S, 14.55. Found: C, 65.43; H, 7.47; N, 12.59; S, 14.11.
13C. The chemical shifts are reported in ppm on the
d
scale relative
4.1.2.5. N-(3-methyl-2-butenyl)-N0-(4-nitrophenyl) thiourea (8).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (35:10) as eluent (246 mg, 93% yield). MS (CI): m/z 266
to TMS. COSY, DEPT, HSQC, and NOESY experiments were per-
formed to assign the signals in the NMR spectra.
(20%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.39 (s, 1H,
4.1.2. General procedure for synthesis of thiourea/urea derivatives
(4e89)
NHAr), 8.24, 7.43 (2m, 4H, Ar), 6.26 (m, 1H, NH), 5.27 [m, 1H,
(CH3)2C ¼ CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2N], 1.75, 1.71 [2s,
To a solution of the isothiocyanate or isocyanate (1.0 mmol) in
dichloromethane (10 ml), the amine (1.0 mmol) was added. The
reaction was kept at room temperature for 15e20 min (TLC showed
that all the starting material had reacted). The reaction mixture was
evaporated to dryness to obtain the corresponding thiourea/urea
derivative. Column chromatography gave the pure compounds in
high yields.
6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm):
180.2 (C]S), 137.5 [(CH3)2C
¼
CHCH2N], 143.3e122.3 (Ar),
119.0 [(CH3)2C ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2N], 25.6, 18.0
[(CH3)2C
¼
CHCH2N]; HRMS (CI): calcd. for C12H16N3O2S
266.096324; found, 266.095976 [M þ H]þ.
4.1.2.6. N-(4-Trifluoromethyl)phenyl-N0-(3-methyl-2-butenyl) thio-
urea (9). The solid was purified by column chromatography, using
hexaneeethyl acetate (4:1) as eluentþ(2$ 79 mg, 97% yield). M.p.128e
4.1.2.1. N-methyl-N0-(3-methyl-2-butenyl) thiourea (4). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (15:10) as eluent (153 mg, 97% yield). MS (CI): m/z 159
129 ꢂC; MS (EI): m/z 288 (30%) [M]
;
1H NMR (500 MHz, CDCl3,
d
ppm): 8.06 (s, 1H, NHAr), 7.67, 7.34 (2m, 4H, Ar), 6.03 (m, 1H, NH),
(100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 6.08, 5.84 (2m,
5.24 [m, 1H, (CH3)2C ¼ CHCH2N], 4.22 [m, 2H, (CH3)2C ¼ CHCH2N],
2H, 2NH), 5.23 [m, 1H, (CH3)2C
¼
CHCH2N], 3.98 [m, 2H,
1.73, 1.69 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz,
(CH3)2C ¼ CHCH2N], 2.98 [d, 3H, J 3.9 Hz, NCH3], 1.72, 1.67 [d, 3H,
CDCl3,
d ppm): 180.2 (C]S), 139.9, 127.3, 123.9 (Ar), 138.3
4J ¼ 1.0 Hz, s, 3H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz,
[(CH3)2C
¼
CHCH2N], 118.5 [(CH3)2C
¼
CHCH2N], 43.9
CDCl3,
d
ppm): 182.2 (C]S), 137.7 [(CH3)2C ¼ CHCH2N], 119.0
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (EI):
[(CH3)2C ¼ CHCH2N], 42.5 [(CH3)2C ¼ CHCH2N], 30.8 (NCH3), 25.6,
calcd. for C13H15F3N2S 288.090805; found, 288.090886 [M]þ$. Anal.

600
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
Calcd for C13H15F3N2S: C, 54.15; H, 5.24; N, 9.72; S, 11.12. Found: C,
54.26; H, 5.06; N, 9.66; S, 11.40.
4.1.2.12. N-(2-Methoxyphenyl)-N0-(3-methyl-2-butenyl)
thiourea
(15). The syrup was purified by column chromatography, using
hexaneeethyl acetate (4:1) as eluent (230 mg, 92% yield). MS (EI):
4.1.2.7. N-(4-Fluorophenyl)-N0-(3-methyl-2-butenyl) thiourea (10).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (35:10) as eluent (185 mg, 78% yield). MS (CI): m/z 239
m/z 250 (30%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 7.53 (s, 1H,
NHAr), 7.21, 6.97 (2m, 4H, Ar), 6.02 (m, 1H, NH), 5.22 [m, 1H,
(CH3)2C ¼ CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2N], 3.84 (OCH3),
1.71, 1.67 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
(100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.69 (s, 1H,
NHAr), 7.24e7.09 (m, 4H, Ar), 5.69 (m, 1H, NH), 5.18 [m, 1H,
J ¼ 7.0 Hz, (CH3)2C ¼ CHCH2N], 4.19 [m, 2H, (CH3)2C ¼ CHCH2N],
1.70, 1.66 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz,
d ppm): 180.2 (C]S), 152.3, 127.3, 125.5, 124.5, 121.0, 111.9 (Ar),
137.5 [(CH3)2C ¼ CHCH2N], 119.1 [(CH3)2C ¼ CHCH2N], 55.6 (OCH3),
43.7 [(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS
CDCl3,
d
ppm): 180.7 (C]S), 162.4, 160.5, 127.8, 117.0 (Ar), 137.7
(EI): calcd. for C13H18N2OS 250.1140; found, 250.1141 [M]þ$
.
[(CH3)2C
¼
CHCH2N], 118.9 [(CH3)2C
¼
CHCH2N], 43.8
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (CI):
4.1.2.13. N-(3-methyl-2-butenyl)-N0-(3-pyridyl)
thiourea
(16).
calcd. for C12H16FN2S 239.101824; found, 239.102189 [M þ H]þ.
The solid was purified by column chromatography, using hexanee
ethyl acetate (1:1) as eluent (199 mg, 90% yield). M.p. 123e124 ꢂC;
4.1.2.8. N-(4-Chlorophenyl)-N0-(3-methyl-2-butenyl) thiourea (11).
The solid was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (241 mg, 95% yield). M.p. 119e120 ꢂC;
MS (EI): m/z 221 (30%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm):
8.52, 7.65, 7.37 (3m, 4H, Py), 7.72 (s, 1H, NHPy), 5.85 (m, 1H, NH),
5.22 [m, 1H, (CH3)2C ¼ CHCH2N], 4.20 [m, 2H, (CH3)2C ¼ CHCH2N],
1.72, 1.69 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
MS (EI): m/z 254 (30%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm).
8.18 (s, 1H, NHAr), 7.37, 7.16 (2m, 4H, Ar), 5.85 (m, 1H, NH), 5.19 [m,
1H, (CH3)2C ¼ CHCH2N], 4.18 [m, 2H, (CH3)2C ¼ CHCH2N], 1.70, 1.66
d ppm): 180.9 (C]S), 148.0, 146.4, 135.3, 132.5, 124.3 (Py), 138.3
[(CH3)2C
¼
CHCH2N], 118.6 [(CH3)2C
¼
CHCH2N], 43.8
[2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (EI):
calcd. for C11H15N3S 221.098669; found, 221.098908 [M]þ$. Anal.
Calcd for C16H23N3S: C, 59.69; H, 6.83; N, 18.99; S, 14.49. Found: C,
59.86; H, 6.97; N, 18.78; S, 14.29.
180.3 (C]S), 137.8 [(CH3)2C ¼ CHCH2N], 134.9, 132.6, 130.2, 126.3
(Ar),118.8 [(CH3)2C ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2N], 25.6,18.1
[(CH3)2C ¼ CHCH2N]; HRMS (EI): calcd. for C12H15ClN2S 254.064448;
found, 254.064256 [M]þ$. Anal. Calcd for C12H15ClN2S: C, 56.57; H,
5.93; N, 11.00; S, 12.60. Found: C, 56.76; H, 6.10; N, 11.02; S, 12.72.
4.1.2.14. N-(3-methyl-2-butenyl)-N0-(2-piperidinoethyl)
thiourea
(17). The solid was purified by column chromatography, using
hexaneeethyl acetate (1:6) as eluent (2þ16 mg, 85% yield). M.p.148e
149 ꢂC; MS (CI): m/z 256 (60%) [M þ H] ; 1H NMR (500 MHz, CDCl3,
4.1.2.9. N-(4-Cyanophenyl)-N0-(3-methyl-2-butenyl) thiourea (12).
The solid was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (208 mg, 85% yield). M.p. 148e149 ꢂC;
MS (CI): m/z 246 (100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 6.71 (m, 2H, NH), 5.26 [t,1H, J ¼ 6.7 Hz, (CH3)2C ¼ CHCH2N],
4.06 [m, 2H, (CH3)2C ¼ CHCH2N], 3.44 (m, 2H, NCH2CH2N), 2.52 [m,
6H, CH2N(CH2)2], 1.71, 1.68 [2s, 6H, (CH3)2C ¼ CHCH2N], 1.60 (m, 4H,
d
ppm): 8.41 (s, 1H, NHAr), 7.66, 7.39 (2m, 4H, Ar), 6.21 (m, 1H, NH),
5.25 [m, 1H, (CH3)2C ¼ CHCH2N], 4.19 [m, 2H, (CH3)2C ¼ CHCH2N],
2CH2), 1.45 (m, 2H, CH2); 13C NMR (125 MHz, CDCl3,
d ppm): 182.4
1.74, 1.70 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz,
(C]S), 136.2 [(CH3)2C ¼ CHCH2N], 120.1 [(CH3)2C ¼ CHCH2N], 58.8,
54.5 (NCH2CH2N), 43.4 [(CH3)2C ¼ CHCH2N], 42.0, 25.6, 25.5
(piperidine), 23.7, 18.0 [(CH3)2C ¼ CHCH2N]; HRMS (CI): calcd. for
CDCl3,
d ppm): 179.8 (C]S), 141.3, 133.8, 123.1 (Ar), 138.5
[(CH3)2C ¼ CHCH2N], 118.3 [(CH3)2C ¼ CHCH2N], 108.5 (ArCN), 43.7
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (CI):
calcd. for C13H16N3S 246.106494; found, 246.107236 [M þ H]þ. Anal.
Calcd for C13H15N3S: C, 63.64; H, 6.16; N, 17.13; S, 13.07. Found: C,
63.93; H, 6.39; N, 16.83; S, 12.81.
C
C
13H26N3S 256.184745; found, 256.183576 [M þ H]þ. Anal. Calcd for
13H25N3S: C, 61.13; H, 9.87; N, 16.45; S, 12.55. Found: C, 62.96; H,
9.67; N, 16.61; S, 12.43.
4.1.2.15. N-(3-methyl-2-butenyl)-N0-[2-(4-morpholino)ethyl] thio-
urea (18). The syrup was purified by column chromatography,
using hexaneeethyl acetate (1:4) as eluent (203 mg, 79% yield). MS
4.1.2.10. N-(4-Methoxyphenyl)-N0-(3-methyl-2-butenyl)
thiourea
(13). The syrup was purified by column chromatography, using
hexaneeethyl acetate (3:1) as eluent (220 g, 88% yield). MS (CI): m/z
(EI): m/z 257 (20%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 6.61
251 (30%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 7.52 (s, 1H,
(m, 2H, NH), 5.20 [t, 1H, J ¼ 6.8 Hz, (CH3)2C ¼ CHCH2N], 3.97 [m, 2H,
(CH3)2C ¼ CHCH2N], 3.63 (t, 4H, J ¼ 4.4 Hz, CH2OCH2), 3.42 (m,
2H, NCH2CH2N), 2.58e2.40 [m, 6H, CH2N(CH2)2], 1.68, 1.64 [2s,
NHAr), 7.14e6.93 (m, 4H, Ar), 5.65 (m, 1H, NH), 5.16 [m, 1H,
(CH3)2C ¼ CHCH2N], 4.19 [m, 2H, (CH3)2C ¼ CHCH2N], 3.82 (OCH3),
1.69, 1.65 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 181.
d
ppm): 180.9 (C]S), 162.4, 158.9, 127.7, 115.3 (Ar), 137.4
(C]S), 136.6 [(CH3)2C ¼ CHCH2N], 119.6 [(CH3)2C ¼ CHCH2N],
[(CH3)2C ¼ CHCH2N], 119.1 [(CH3)2C ¼ CHCH2N], 55.5 (OCH3), 43.7
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (CI):
calcd. for C13H19N2OS 251.1218; found, 251.1235 [M þ H]þ.
66.4
[(CH3)2C ¼ CHCH2N], 25.5, 17.9 [(CH3)2C ¼ CHCH2N]; HRMS (EI):
calcd. for C12H23N3OS 257.156184; found, 257.155985 [M]þ$
(CH2OCH2),
57.7,
53.4
[NCH2CH2N(CH2)2],
42.7
.
4.1.2.11. N-(3-Methoxyphenyl)-N0-(3-methyl-2-butenyl)
thiourea
4.1.2.16. N-(3-methyl-2-butenyl)-N0-[3-(4-morpholino)propyl] thio-
urea (19). The syrup was purified by column chromatography,
using hexaneeethyl acetate (1:3) as eluent (245 mg, 90% yield). MS
(14). The syrup was purified by column chromatography, using
hexaneeethylacetate (4:1)aseluent(240mg, 96%yield). MS(CI):m/z
251 (55%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 7.80 (s, 1H,
(CI): m/z 272 (5%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.40
NHAr), 7.31, 6.82, 6.77, 6.73 (4m, 4H,Ar), 6.00 (m,1H,NH), 5.20[m,1H,
(CH3)2C ¼ CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2N], 3.80 (OCH3),
1.70, 1.66 [2s, 6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
(m, 2H, NH), 5.23 [m, 1H, (CH3)2C ¼ CHCH2N], 4.00 [m, 2H,
(CH3)2C
¼
CHCH2N], 3.69 (m, 4H, CH2OCH2), 3.49 (m, 2H,
NCH2CH2CH2N), 2.56e2.44 [m, 6H, CH2N(CH2)2], 1.83e1.65 (m, 8H,
d
ppm): 180.2 (C]S), 161.0, 137.6, 130.9, 116.9, 112.7, 110.6 (Ar), 137.3
NCH2CH2CH2N, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
[(CH3)2C ¼ CHCH2N], 119.0 [(CH3)2C ¼ CHCH2N], 55.4 (OCH3), 43.8
[(CH3)2C ¼ CHCH2N], 25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (CI):
calcd. for C13H19N2OS 251.1218; found, 251.1215 [M þ H]þ.
d
ppm): 181.7 (C]S), 136.6 [(CH3)2C
¼
CHCH2N], 119.6
[(CH3)2C
¼
CHCH2N], 66.5 (CH2OCH2), 58.9, 53.8, 23.4
[NCH2CH2CH2N(CH2)2], 47.4 (CH2NCH2), 40.7 [(CH3)2C ¼ CHCH2N],

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
601
25.6, 18.1 [(CH3)2C ¼ CHCH2N]; HRMS (CI): calcd. for C13H26N3OS
272.179660; found, 272.179292 [M þ H]þ.
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.7 [(CH3)2C ¼ CHCH2
CH2C(CH3) CHCH2N], 117.4 (NCH2CH CH2), 47.0
¼
¼
(NCH2CH ¼ CH2), 42.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.4, 26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for
4.1.2.17. N-ethoxycarbonyl-N0-(3-methyl-2-butenyl) thiourea (20).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (286 mg, 96% yield). MS (EI): m/z 230
C
14H25N2S 253.173846; found, 253.174184 [M þ H]þ.
(25%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 6.44 (m, 2H, 2NH),
5.22 [m, 1H, (CH3)2C ¼ CHCH2N], 4.40 [m, 2H, (CH3)C]CHCH2N],
4.30 [d, 2H, J 4.8 Hz, (NCH2CONCH2CH3)], 4.20 (q, 2H, J 7.2 Hz,
NCH2CO2CH2CH3), 1.69, 1.66, [2s, 6H, (CH3)2C ¼ CHCH2N], 1.25 (t,
4.1.2.21. N-geranyl-N0-phenyl thiourea (24). The solid was purified
by column chromatography, using hexaneeethyl acetate (6:1) as
eluent (282 mg, 98% yield). M.p. 108e109 ꢂC; MS (CI): m/z 289
3H, J 7.2 Hz, NCH2CO2CH2CH3); 13C NMR (125 MHz, CDCl3,
d
ppm):
CHCH2N], 117.2
(NCH2CO2CH2CH3), 46.7
CHCH2N], 25.6, 18.24
[(CH3)2C ¼ CHCH2N], 14.0 (NCH2CO2CH2CH3); HRMS (EI): calcd. for
10H18N2O2S 230.10890; found, 230.10901 [M]þ$
(100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.93 (s, 1H,
185.0 (C]S), 171.2 (C]O), 137.6 [(CH3)2C
[(CH3)2C CHCH2N], 61.0
(NCH2COCH2CH3), 39.4 [(CH3)2C
¼
NHPh), 7.44e7.18 (m, 5H, Ph), 5.91 (m, 1H, NH), 5.20 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.02 [m, 1H, (CH3)2C ¼ CH
¼
¼
CH2CH2C(CH3)
¼
CHCH2N], 4.22 [m, 2H, (CH3)2C
¼
CHCH2
CH2C(CH3) ¼ CHCH2N], 2.08e1.96 [m, 4H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 1.65, 1.64, 1.56 [3s, 9H, (CH3)2C ¼ CHCH2
C
.
CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 180.3
4.1.2.18. N-geranyl-N0-methyl thiourea (21). The syrup was purified
by column chromatography, using hexaneeethyl acetate (35:10) as
eluent (180 mg, 78% yield). MS (CI): m/z 227 (100%) [M þ H]þ; 1H
(C]S), 141.0, 136.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 131.8,
130.1, 127.1, 125.0 (Ph), 123.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CH
CH2N], 118.8 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 43.7
NMR (500 MHz, CDCl3,
1H, (CH3)2C CHCH2CH2C(CH3)
(CH3)2C CHCH2CH2C(CH3)
d
ppm): 6.20, 5.96 (2m, 2H, 2NH), 5.21 [m,
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.4, 26.2 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.5 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C17H25N2S 289.173846;
found, 289.173140 [M þ H]þ. Anal. Calcd for C17H24N2S: C, 70.79; H,
8.39; N, 9.71; S, 11.12. Found: C, 70.92; H, 8.37; N, 9.77; S, 11.01.
¼
¼
CHCH2N], 5.02 [m, 1H,
CHCH2N], 3.97 [m, 2H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.97 (d, 3H, J ¼ 4.2 Hz,
NCH3), 2.10e1.95 [m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
1.65, 1.64, 1.57 [3s, 9H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13
C
NMR (125 MHz, CDCl3,
d
ppm): 182.1 (C]S), 141.0, 137.8
4.1.2.22. N-geranyl-N0-(4-nitrophenyl) thiourea (25). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(35:10) as eluent (313 mg, 94% yield). MS (CI): m/z 334 (15%)
[(CH3)2C
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 123.5 [(CH3)2C
CHCH2N], 118.8 [(CH3)2C
CHCH2N], 42.4 [(CH3)2C
¼
¼
¼
¼
¼
CHCH2
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.46 (s, 1H, NHAr),
CH2C(CH3) ¼ CHCH2N], 39.3, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3)
8.22, 7.44 (2m, 4H, Ar), 6.31 (m, 1H, NH), 5.28 [m, 1H, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 5.04 [m, 1H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 4.22 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
¼
CHCH2N], 30.8 (NCH3), 25.5, 17.6, 16.3 [(CH3)2C
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C12H23N2S
227.158196; found, 227.158051 [M þ H]þ.
CHCH2N], 2.12e2.01 [m, 4H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 1.71, 1.65, 1.58 [3s, 9H, (CH3)2C
¼
CHCH2CH2
4.1.2.19. N-tert-butyl-N0-geranyl thiourea (22). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(4:1) as eluent (259 mg, 97% yield). MS (EI): m/z 268 (20%) [M]þ$; 1H
NMR (500 MHz, CDCl3, d ppm): 5.91, 5.49 (2s, 2H, 2NH), 5.29 [t, 1H,
J ¼ 7.0 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06 [m, 1H,
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 179.9 (C]S),
144.4, 132.0 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 143.3, 142.2,
125.5, 122.3 (Ar), 123.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
118.0 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.6 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 39.4, 26.3 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 25.6, 17.7, 16.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N]; HRMS (CI): calcd. for C17H24N3O2S 334.158924; found,
334.160376 [M þ H]þ.
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 4.09 [m, 2H,
CHCH2N], 2.13e2.02 [m, 4H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.70, 1.67, 1.60 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.42 [NC(CH3)3]; 13C NMR
(125 MHz, CDCl3,
[(CH3)2C
d
ppm): 180.9 (C]S), 141.5, 131.9
4.1.2.23. N-geranyl-N0-(3-nitrophenyl) thiourea (26). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(4:1) as eluent (300 mg, 90% yield). MS (CI): m/z 334 (10%)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 123.6 [(CH3)2C
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 119.1 [(CH3)2C ¼ CHCH2CH2
C(CH3)
¼
CHCH2N], 52.8 [NC(CH3)3], 43.6 [(CH3)2C
CHCH2N], 39.4, 26.3 [(CH3)2C
¼
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.14 (s, 1H, NHAr),
CHCH2CH2C(CH3)
¼
¼
C
8.07, 7.65, 7.58 (3m, 4H, Ar), 6.04 (m, 1H, NH), 5.27 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.04 [m, 1H, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.12e2.00 [m, 4H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 1.71, 1.64, 1.58 [3s, 9H, (CH3)2C ¼ CHCH2CH2
HCH2CH2C(CH3) ¼ CHCH2N], 29.5 [NC(CH3)3], 25.7, 17.7, 16.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
C
15H28N2S 268.197321; found, 268.197912 [M]þ$
.
4.1.2.20. N-allyl-N0-geranyl thiourea (23). The syrup was purified
by column chromatography, using hexaneeethyl acetate (5:1) as
eluent (245 mg, 98% yield). MS (CI): m/z 253 (95%) [M þ H]þ; 1H
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 180.5 (C]S),
149.0, 130.1, 120.9, 118.9 (Ar), 142.4, 132.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
C(CH3) ¼ CHCH2N], 118.1 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
43.5 [(CH3)2C CHCH2CH2C(CH3) CHCH2N], 39.4, 26.2
[(CH3)2C CHCH2CH2C(CH3) CHCH2N], 25.6, 17.7, 16.6
¼
CHCH2N], 123.5 [(CH3)2C
¼
CHCH2CH2
NMR (500 MHz, CDCl3,
NCH2CH
d
ppm): 6.10e5.80 (m, 3H, 2NH,
CHCH2CH2
¼
CH2), 5.28e5.18 [m, 3H, (CH3)2C
¼
¼
¼
C(CH3) ¼ CHCH2N, NCH2CH ¼ CH2], 5.04 [m, 1H, (CH3)2C ¼ CH
CH2CH2C(CH3) ¼ CHCH2N], 4.09 (m, 2H, NCH2CH ¼ CH2), 3.98 [m,
2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.11e1.98 [m, 4H,
¼
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for
C
17H24N3O2S 334.1589; found, 334.1608 [M þ H]þ.
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 1.67, 1.57 [2s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
4.1.2.24. N-(4-Trifluoromethyl)phenyl-N0-geranyl
thiourea
(27).
d
ppm): 182.0 (C]S), 141.4, 131.9 [(CH3)2C
¼
CHCH2CH2
CH2), 123.5
The solid was purified by column chromatography, using hexanee
C(CH3)
¼
CHCH2N], 133.3 (NCH2CH
¼
ethyl acetate (4:1) as eluent (345 mg, 97% yield). M.p. 83e84 ꢂC; MS

602
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
(EI): m/z 356 (10%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.47 (s,
d
ppm): 179.7 (C]S), 141.3, 132.0 [(CH3)2C
¼
CHCH2CH2
1H, NHAr), 7.66, 7.35 (2m, 4H, Ar), 6.05 (m, 1H, NH), 5.24 [t, 1H,
J ¼ 6.8 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.03 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.23 [m, 2H, (CH3)2C ¼
C(CH3) CHCH2N], 142.0, 133.8, 123.4, 118.2 (Ar), 123.0
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.0 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 108.7 (ArCN), 43.6 [(CH3)2C ¼ CHCH2
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 2.12e1.98 [m, 4H, (CH3)2C
CHCH2N], 1.68, 1.64, 1.57 [3s, 9H,
¼
CH2C(CH3)
C(CH3)
¼
CHCH2N], 39.4, 26.2 [(CH3)2C
CHCH2N], 25.6, 17.7, 16.5 [(CH3)2C
¼
¼
CHCH2CH2
CHCH2CH2
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C18H23N3S 313.161270;
found, 313.161017 [M]þ$. Anal. Calcd for C18H23N3S: C, 68.97; H,
7.40; N, 13.41; S, 10.23. Found: C, 69.22; H, 7.32; N, 13.44; S, 10.12.
d
ppm): 179.9 (C]S), 147.8, 141.7, [(CH3)2C
¼
CHCH2CH2
C(CH3) ¼ CHCH2N], 139.9, 128.3, 128.1, 123.8 (Ar), 123.5 [(CH3)2C ¼
CHCH2CH2C(CH3) CHCH2N], 118.3 [(CH3)2C CHCH2CH2
¼
¼
C(CH3) ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.4, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.5
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
4.1.2.28. N-geranyl-N0-(4-methoxyphenyl) thiourea (31). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (3:1) as eluent (270 mg, 85% yield). MS (CI): m/z 319
C
C
18H23F3N2S 356.153405; found, 356.153753 [M]þ$. Anal. Calcd for
18H23F3N2S: C, 60.65; H, 6.50; N, 7.86; S, 9.00. Found: C, 60.90; H,
(20%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.47 (s, 1H,
NHAr), 7.17e6.90 (m, 4H, Ar), 5.65 (m, 1H, NH), 5.17 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.02 [m, 1H, (CH3)2C ¼
6.43; N, 7.83; S, 9.31.
CHCH2CH2C(CH3)
¼
CHCH2N], 4.22 [m, 2H, (CH3)2C
¼
4.1.2.25. N-(4-fluorophenyl)-N0-geranyl thiourea (28). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (275 mg, 90% yield). MS (EI): m/z 306
CHCH2CH2C(CH3) ¼ CHCH2N], 3.82 (OCH3), 2.10e1.94 [m, 4H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.64, 1.58, 1.56 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
(15%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 7.71 (s, 1H, NHAr),
d ppm): 180.1 (C]S), 159.0, 128.3, 127.7, 115.3 (Ar), 140.8, 131.8
7.24e7.08 (m, 4H, Ar), 5.70 (m, 1H, NH), 5.19 [t, 1H, J ¼ 6.8 Hz,
[(CH3)2C
CHCH2CH2C(CH3) ¼ CHCH2N], 118.9 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 55.5 (OCH3), 43.7 [(CH3)2C CHCH2CH2C(CH3)
¼ CHCH2N], 39.9, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
25.6, 17.7, 17.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI):
calcd. for C18H27N2OS 319.1844; found, 319.1825 [M þ H]þ.
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 123.6 [(CH3)2C
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.02 [m, 1H, (CH3)2C ¼ CH
CH2CH2C(CH3)
¼
CHCH2N], 4.21 [m, 2H, (CH3)2C
¼
CHCH2
¼
CH2C(CH3) ¼ CHCH2N], 2.09e1.96 [m, 4H, (CH3)2C ¼ CHCH2CH2
C(CH3)
¼
CHCH2N], 1.65, 1.64, 1.57 [3s, 9H, (CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
180.8 (C]S), 162.4, 160.5, 127.7, 117.0 (Ar), 141.2, 131.9
[(CH3)2C
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 123.6 [(CH3)2C
¼
4.1.2.29. N-geranyl-N0-(3-methoxyphenyl) thiourea (32). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (285 mg, 90% yield). MS (CI): m/z 319
¼
CHCH2N], 118.7 [(CH3)2C
¼
CHCH2CH2
C(CH3) ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.4, 26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.7, 16.5
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
(50%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.68 (s, 1H,
NHAr), 7.32, 6.82, 6.77, 6.72 (4m, 4H, Ar), 6.00 (m, 1H, NH), 5.21 [m,
C
17H23FN2S 306.156599; found, 306.156477 [M]þ$
.
1H, (CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 5.03 [m, 1H,
CHCH2N], 4.23 [m, 2H,
¼
CHCH2CH2C(CH3)
¼
4.1.2.26. N-(4-Chlorophenyl)-N0-geranyl thiourea (29). The solid
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (306 mg, 95% yield). M.p. 101e102 ꢂC, MS
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.80 (OCH3), 2.09e1.96
[m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.66, 1.64, 1.60,
1.57 [4s, 9H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR
(EI): m/z 322 (10%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 7.75 (s,
(125 MHz, CDCl3, d ppm): 180.1 (C]S), 160.9, 137.2, 130.9, 116.8,
1H, NHAr), 7.39, 7.16 (2m, 4H, Ar), 5.80 (m, 1H, NH), 5.20 [t, 1H,
J ¼ 7.0 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.02 [m, 1H,
(Ar), 140.8, 131.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.7 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 55.4 (OCH3), 43.8 [(CH3)2C ¼ CHCH2
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.21 [m, 2H,
¼
CHCH2CH2C(CH3)
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.65, 1.57 [3s, 9H,
¼
CHCH2N], 2.10e1.97 [m, 4H,
CH2C(CH3)
C(CH3)
¼
CHCH2N], 39.4, 26.3 [(CH3)2C
¼
¼
CHCH2CH2
¼
CHCH2N], 25.6, 17.7, 16.5 [(CH3)2C
C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C18H27N2OS 319.1844;
CHCH2CH2
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 180.4 (C]S), 141.4, 131.9 [(CH3)2C
¼
CHCH2CH2
found, 319.1840 [M þ H]þ.
C(CH3)
¼
CHCH2N], 134.7, 132.8, 130.3, 126.3 (Ar), 123.6
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.5 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 43.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 39.4, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.7, 16.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI):
calcd. for C17H23ClN2S 322.127048; found, 322.126797 [M]þ$. Anal.
calcd for C17H23ClN2S: C, 63.23; H, 7.18; N, 8.68; S, 9.93. Found: C,
63.50; H, 7.44; N, 8.76; S, 9.81.
4.1.2.30. N-geranyl-N0-(2-methoxyphenyl) thiourea (33). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (285 mg, 90% yield). MS (EI): m/z 318 (15%)
[M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 7.52 (s, 1H, NHAr), 7.21,
6.97 (2m, 4H, Ar), 6.02 (m, 1H, NH), 5.23 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.03 [m, 1H, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 4.23 [m, 2H, (CH3)2C ¼ CHCH2
CH2C(CH3)
¼
CHCH2N], 3.84 (OCH3), 2.10e1.97 [m, 4H,
4.1.2.27. N-(4-cyanophenyl)-N0-geranyl thiourea (30). The solid was
purified by column chromatography, using hexaneeethyl acetate
(5:1) as eluent (306 mg, 98% yield). M.p. 59e60 ꢂC, MS (EI): m/z 313
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.65, 1.57 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz,
CDCl3;
d ppm): 180.2 (C]S), 152.3, 127.3, 125.5, 111.9 (Ar), 141.0,
(10%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.58 (s, 1H, NHAr),
131.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6 [(CH3)2C ¼
7.66, 7.39 (2m, 4H, Ar), 6.20 (m, 1H, NH), 5.25 [t, 1H, J ¼ 7.1 Hz,
CHCH2CH2C(CH3) CHCH2N], 118.9 [(CH3)2C CHCH2CH2
¼
¼
(CH3)2C
(CH3)2C
(CH3)2C
¼
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
CHCH2N], 5.03 [m, 1H,
CHCH2N], 4.21 [m, 2H,
CHCH2N], 2.12e1.98 [m, 4H,
C(CH3) ¼ CHCH2N], 55.6 (OCH3), 43.7 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 39.4, 26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 25.6, 17.7, 16.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N];
HRMS (EI): calcd. for C18H26N2OS 318.1766; found, 318.1767
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.69, 1.65, 1.58 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
[M]þ$
.

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
603
4.1.2.31. N-geranyl-N0-(3-pyridyl) thiourea (34). The solid was
purified by column chromatography, using hexaneeethyl acetate
(1:1) as eluent (260 mg, 90% yield). M.p. 110e111 ꢂC; MS (CI): m/z
ethyl acetate (1:5) as eluent (325 mg, 96% yield). MS (EI): m/z 339
(25%) [M]þ$; 1H NMR (500 MHz, CDCl3,
ppm): 7.05 (m, 2H, 2NH),
5.25 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.05 [m, 1H,
(CH3)2C CHCH2CH2C(CH3) CHCH2N], 4.02 [m, 2H,
d
290 (80%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.50, 7.70,
¼
¼
7.30 (3m, 4H, Py), 8.04 (s, 1H, NHPy), 5.92 (m, 1H, NH), 5.22 [t, 1H,
J ¼ 6.6 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.03 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.69 (t, 4H, J ¼ 4.6 Hz,
CH2OCH2), 3.48 (m, 2H, NCH2CH2CH2N), 2.45 [m, 6H, CH2N(CH2)2],
2.11e1.99 [m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.74 (m,
2H, NCH2CH2CH2N), 1.67, 1.59 [2s, 9H, (CH3)2C ¼ CHCH2CH2
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 4.21 [m, 2H,
CHCH2N], 2.10e1.97 [m, 4H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.65, 1.57 [3s, 9H,
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 181.8 (C]S),
CHCH2N], 123.6
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
141.0, 131.9 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
d
ppm): 180.7 (C]S), 147.8, 146.3, 135.2, 124.3 (Py), 141.8, 131.9
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.5 [(CH3)2C ¼ CHCH2
CH2C(CH3) CHCH2N], 66.7 (CH2OCH2), 57.0, 53.5, 24.6
[NCH2CH2CH2N(CH2)2], 42.8 [(CH3)2C CHCH2CH2C(CH3)
[(CH3)2C
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 123.5 [(CH3)2C
¼
¼
¼
CHCH2N], 118.0 [(CH3)2C
¼
CHCH2CH2
¼
¼
C(CH3) ¼ CHCH2N], 43.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.4, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.7, 16.5
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for
CHCH2N], 39.4, 26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.7, 16.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI):
calcd. for C18H33N3OS 339.234435; found, 339.234560 [M]þ$
.
C
C
16H24N3S 290.169095; found, 290.168810 [M þ H]þ. Anal. calcd for
16H23N3S: C, 66.39; H, 8.01; N, 14.52; S, 11.08. Found: C, 66.54; H,
4.1.2.35. N-geranyl-N0-(4-piperidyl) thiourea (38). The solid was
purified by column chromatography, using methanol-ethyl acetate
(1:2) as eluent (240 mg, 80% yield). M.p. 94e95 ꢂC; MS (EI): m/z 295
8.23; N, 14.31; S, 11.08.
4.1.2.32. N-geranyl-N0-[1-(2-piperidino)ethyl]
thiourea
(35).
(15%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 5.35 (m, 1H, NH),
The solid was purified by column chromatography, using ethyl
acetate-methanol (1:1) as eluent (þ2$71 mg, 84% yield). M.p. 94e
5.27 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.05 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.45, 311, 2.95, 1.86, 1.35
95 ꢂC; MS (EI): m/z 323 (10%) [M]
;
1H NMR (500 MHz, CDCl3,
(5m, 9H, piperidine), 4.20 [m, 2H, (CH3)2C
¼
CHCH2CH2
d
ppm): 6.62 (m, 2H, 2NH), 5.25 [t, 1H,
J
¼
6.2 Hz,
C(CH3) ¼ CHCH2N], 2.10e1.98 [m, 4H, (CH3)2C ¼ CHCH2CH2
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 5.04 [m, 1H,
CHCH2N], 4.08 [m, 2H,
C(CH3) ¼ CHCH2N], 1.67, 1.65, 1.58 [3s, 9H, (CH3)2C ¼ CHCH2CH2
¼
¼
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 181.3 (C]S),
CHCH2N], 123.7
CHCH2N], 119.6 [(CH3)2C
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.32 (m, 2H, NCH2CH2N),
140.7, 131.7 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
2.40 [m, 6H, CH2N(CH2)2], 2.10e1.92 [m, 4H, (CH3)2C
CHCH2CH2C(CH3) CHCH2N], 1.67, 1.64, 1.57 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.52 (m, 4H, 2CH2), 1.41
(m, 2H, CH2); 13C NMR (125 MHz, CDCl3,
ppm): 182.4 (C]S),139.5,
131.7 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.7 [(CH3)2C ¼
CHCH2CH2C(CH3) CHCH2N], 119.8 [(CH3)2C CHCH2CH2
¼
[(CH3)2C
¼
CHCH2CH2C(CH3)
¼
¼
¼
CHCH2CH2C(CH3) ¼ CHCH2N], 48.2, 46.3, 34.9 (piperidine), 44.5
[(CH3)2C
[(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 39.4, 26.3
CHCH2N], 25.6, 17.6, 16.4
d
¼
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
¼
¼
C
16H29N3S 295.2082; found, 295.2080 [M]þ$
.
C(CH3) ¼ CHCH2N], 59.4, 54.5 (NCH2CH2N), 43.3 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 42.2, 25.6, 25.5 (piperidine), 39.4,
26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 23.9, 17.6, 16.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
4.1.2.36. N-ethoxycarbonylmethyl-N0-geranyl
thiourea
(39).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (286 mg, 96% yield). MS (EI): m/z 298
C
C
18H33N3S 323.239520; found, 323.239517 [M]þ$. Anal. calcd for
18H33N3S: C, 66.82; H, 10.28; N, 12.99; S, 9.91. Found: C, 66.62; H,
(15%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 6.44 (m, 2H, 2NH),
1.4 Hz, (CH3)2C
5.22 [m, 1H,
J
¼
6.9 Hz, 4J
¼
¼
10.42; N, 12.97; S, 9.72.
CHCH2CH2C(CH3) ¼ CHCH2N], 5.04 [m, 1H, J ¼ 6.9 Hz, 4J ¼ 1.4 Hz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.37 (d, 2H, J ¼ 4.8 Hz,
(NCH2CO2CH2CH3), 4.21 (q, 2H, J ¼ 7.2 Hz, NCH2CO2CH2CH3), 3.95
[m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.10e1.98 [m, 4H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.69, 1.66, 1.58 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.27 (t, 3H, J ¼ 7.2 Hz,
4.1.2.33. N-geranyl-N0-[2-(4-morpholino)ethyl]
thiourea
(36).
The solid was purified by column chromatography, using hexanee
ethyl acetate (1:4) as eluent (300 mg, 92% yield). M.p. 77e78 ꢂC; MS
(EI): m/z 325 (5%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 6.38 (m,
2H, 2NH), 5.26 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
5.06 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.02 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.68 (t, 4H, J ¼ 4.5 Hz,
CH2OCH2), 3.47 (m, 2H, NCH2CH2N), 2.58e2.45 [m, 6H,
CH2N(CH2)2], 2.11e1.99 [m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 1.70, 1.67, 1.59 [2s, 9H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
NCH2CO2CH2CH3); 13C NMR (125 MHz, CDCl3):
d 182.0 (C]S), 170.3
(C]O), 141.3, 131.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.5 [(CH3)2C ¼ CHCH2
CH2C(CH3)
¼
CHCH2N], 61.6 (NCH2CO2CH2CH3), 46.6 (NCH2
CO2CH2CH3), 42.1 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.4,
26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 14.0 (NCH2CO2CH2CH3);
HRMS (EI): calcd. for C15H26N2O2S 298.171500; found, 298.171739
CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm): 182.2 (C]S), 140.7,
131.9 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6 [(CH3)2C ¼ CH
CH2CH2C(CH3) ¼ CHCH2N], 119.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 66.7 (CH2OCH2), 57.7, 53.4, 32.4 [NCH2CH2N(CH2)2], 41.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.5, 26.3 [(CH3)2C ¼
[M]þ$
.
4.1.2.37. N-ethoxycarbonyl-N0-geranyl thiourea (40). The syrup was
purified by column chromatography, using hexaneeethyl acetate
CHCH2CH2C(CH3)
¼
CHCH2N], 25.7, 17.7, 16.5 [(CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C17H31N3OS
325.218785; found, 325.219632 [M]þ$. Anal. Calcd for C17H31N3OS:
C, 62.73; H, 9.60; N,12.91; S, 9.85. Found: C, 62.63; H, 9.84; N,12.66;
S, 9.64.
(10:1) as eluent (235 mg, 83% yield). MS (EI): m/z 284 (20%) [M]þ$
;
1H NMR (500 MHz, CDCl3,
d ppm): 9.51 (m, 1H NH), 8.16 (s, 1H,
NHCO), 5.29 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
[m, 1H, J ¼ 6.8 Hz, 4J ¼ 1.4 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 4.25e4.17 [m, 4H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
4.1.2.34. N-geranyl-N0-[3-(4-morpholino)propyl]
The syrup was purified by column chromatography, using hexanee
thiourea
(37).
CHCH2N, NCO2CH2CH3], 2.13e2.00 [m, 4H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 1.69, 1.67, 1.59 [3s, 9H, (CH3)2C ¼ CHCH2

604
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
CH2C(CH3) ¼ CHCH2N], 1.29 (t, 3H, J ¼ 7.1 Hz, NCO2CH2CH3); 13C
(NCH2CH ¼ CH2), 124.2, 123.4, 118.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2CH2C(CH3) CHCH2N], 117.4 (NCH2CH CH2), 47.0
NMR (125 MHz, CDCl3,
d
ppm): 178.6 (C]S), 152.7 (C]O), 141.6,
¼
¼
131.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6 [(CH3)2C ¼
(NCH2CH ¼ CH2), 42.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 39.6, 39.4, 26.7, 26.2 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.5, 16.0
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N];
HRMS (CI): calcd. for C19H33N2S 321.236446; found, 321.235194
[M þ H]þ.
CHCH2CH2C(CH3) CHCH2N], 117.9 [(CH3)2C CHCH2CH2
¼
¼
C(CH3) ¼ CHCH2N], 62.6 (NCO2CH2CH3), 43.7 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 39.4, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 25.6, 17.6, 16.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
14.1 (NCO2CH2CH3); HRMS (EI): calcd. for C14H24N2O2S 284.155850;
found, 284.155992 [M]þ$
.
4.1.2.41. N-farnesyl-N0-phenyl thiourea (44). The solid was purified
by column chromatography, using hexaneeethyl acetate (7:1) as
eluent (341 mg, 96% yield). M.p. 54e55 ꢂC; MS (CI): m/z 357 (40%)
4.1.2.38. N-farnesyl-N0-methyl thiourea (41). The syrup was puri-
fied by column chromatography, using hexaneeethyl acetate
(35:10) as eluent (276 mg, 94% yield). MS (CI): m/z 295 (100%)
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.89 (s, 1H, NHPh),
7.45e7.17 (m, 5H, Ph), 5.90 (m, 1H, NH), 5.20 [t, 1H, J ¼ 7.0 Hz,
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 6.05, 5.84 (2m, 2H,
2NH), 5.24 [t, 1H, J ¼ 6.7 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 5.06 [m, 2H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.99 [m, 2H, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.99 (d, 3H,
J ¼ 3.1 Hz, NCH3), 2.12e1.93 [m, 8H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2CH2C(CH3) ¼ CHCH2N], 1.68, 1.65, 1.58 [3s, 12H, (CH3)2C ¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.05
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.22 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.10e1.90 [m, 8H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],1.67,1.66,1.59,1.56 [4s,12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
CHCH2CH2C(CH3)
(125 MHz, CDCl3,
¼
CHCH2CH2C(CH3)
ppm): 182.3 (C]S), 141.3, 135.5, 131.3
¼
CHCH2N]; 13C NMR
NMR (125 MHz, CDCl3, d ppm): 180.3 (C]S), 141.1, 135.4, 131.3
d
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
124.2, 123.4, 118.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 42.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2
136.2, 130.2, 127.1, 125.0 (Ph), 124.2, 123.5, 118.8
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.7
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.6,
39.4, 26.7, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 25.6, 17.6, 16.5, 16.0 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C22H33N2S
CH2C(CH3)
¼
CHCH2N], 39.6, 39.4, 26.7, 26.2 [(CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 30.9 (NCH3),
25.6, 17.6, 16.4, 16.0 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C17H31N2S 295.220796;
found, 295.220282 [M þ H]þ.
357.236446; found, 357.236188 [M
þ
H]þ. Anal. calcd for
C22H32N2S: C, 74.11; H, 9.05; N, 7.86; S, 8.99. Found: C, 74.27; H,
9.18; N, 7.72; S, 8.74.
4.1.2.39. N-tert-butyl-N0-farnesyl thiourea (42). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(6:1) as eluent (265 mg, 79% yield). MS (EI): m/z 336 (10%) [M]þ$; 1H
4.1.2.42. N-farnesyl-N0-(4-nitrophenyl) thiourea (45). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (5:1) as eluent (390 mg, 97% yield). MS (CI): m/z 402 (5%)
NMR (500 MHz, CDCl3,
d ppm): 5.89, 5.49 (2s, 2H, 2NH), 5.29 [m,
1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
5.08 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3)
¼ CHCH2N], 4.09 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.14e1.93 [m, 8H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.71, 1.67, 1.59 [3s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.42
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.34 (s, 1H, NHAr),
8.24, 7.43 (2m, 4H, Ar), 6.25 (m, 1H, NH), 5.28 [t, 1H, J ¼ 7.0 Hz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.23 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.15e1.90 [m, 8H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.72, 1.67, 1.58 [3s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
[NC(CH3)3]; 13C NMR (125 MHz, CDCl3,
d
ppm): 180.9 (C]S), 141.5,
135.6, 131.4 [(CH3)2C
¼
CHCH2CH2C(CH3) CHCH2CH2
¼
C(CH3) ¼ CHCH2N], 124.2, 123.5, 119.1 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 52.8 [NC(CH3)3], 43.5
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7,
NMR (125 MHz, CDCl3, d ppm): 179.9 (C]S), 144.4, 135.7, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],143.1,
142.4, 125.6, 122.3 (Ar), 124.2, 123.3, 117.9 [(CH3)2C
39.4, 26.7, 26.3 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C
¼
CHCH2CH2C(CH3)
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7,
39.4, 26.7, 26.2 [(CH3)2C CHCH2CH2C(CH3) CHCH2CH2
C(CH3) CHCH2N], 25.7, 17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 43.7
(CH3) ¼ CHCH2N], 29.5 [NC(CH3)3], 25.7, 17.7, 16.5, 16.0 [(CH3)2C
¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI):
¼
¼
calcd. for C20H36N2S 336.259921; found, 336.259808 [M]þ$
.
¼
¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI):
4.1.2.40. N-allyl-N0-farnesyl thiourea (43). The syrup was purified
by column chromatography, using hexaneeethyl acetate (6:1) as
eluent (272 mg, 85% yield). MS (CI): m/z 321 (100%) [M þ H]þ; 1H
calcd. for C22H32N3O2S 402.221524; found, 402.219803 [M þ H]þ.
4.1.2.43. N-farnesyl-N0-(3-nitrophenyl) thiourea (46). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (365 mg, 91% yield). MS (CI): m/z 402 (5%)
NMR (500 MHz, CDCl3,
d ppm): 6.00e5.80 (m, 3H, 2NH,
NCH2CH ¼ CH2), 5.24 [t, 1H, J ¼ 6.7 Hz, (CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N, NCH2CH ¼ CH2], 5.07
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.14 (s, 1H, NHAr),
8.08, 7.65, 7.57 (3m, 4H, Ar), 6.05 (m, 1H, NH), 5.27 [m, 1H,
[m, 2H, (CH3)2C
CHCH2N], 4.08 (m, 2H, NCH2CH
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
CH2), 3.98 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.12e
1.93 [m, 8H, (CH3)2C CHCH2CH2C(CH3) CHCH2CH2
1.68, 1.66, 1.59 [3s, 12H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
¼
¼
CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.15e1.85 [m, 8H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.71, 1.67, 1.59, 1.57 [4s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
C(CH3)
¼
CHCH2N],
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
NMR (125 MHz, CDCl3,
d ppm): 181.9 (C]S), 141.5, 135.6, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 133.3
NMR (125 MHz, CDCl3, d ppm): 180.3 (C]S), 148.9, 130.0, 120.9,

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
605
118.8 (Ar), 142.3, 135.6, 131.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CH
CH2CH2C(CH3) CHCH2N], 124.2, 123.4, 118.0 [(CH3)2C
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.8
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7,
¼
¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.6 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.6, 39.4, 26.7,
26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.4,
26.7,
26.2
[(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N],
25.7, 17.7, 16.6,
16.0
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N];
25.7, 17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH
HRMS (EI): calcd. for C22H31ClN2S 390.189649; found, 390.189853
2CH2C(CH3)
¼
CHCH2N]; HRMS (CI): calcd. for C22H32N3O2S
[M]þ$
.
402.2215; found, 402.2205 [M þ H]þ.
4.1.2.47. N-(4-Cyanophenyl)-N0-farnesyl thiourea (50). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (323 mg, 85% yield). MS (EI): m/z 381 (5%)
4.1.2.44. N-farnesyl-N0-(4-trifluoromethyl)phenyl thiourea (47).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (6:1) as eluent (360 mg, 85% yield). MS (EI): m/z 424
[M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 8.16 (s, 1H, NHAr), 7.66,
(10%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.19 (s, 1H, NHAr),
7.39 (2m, 4H, Ar), 6.15 (m, 1H, NH), 5.27 [m, 1H,
7.66, 7.34 (2m, 4H, Ar), 6.03 (m, 1H, NH), 5.25 [t, 1H, J ¼ 6.8 Hz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.07
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CH
¼
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.22 [m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.23 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 2.13e1.88 [m, 8H, (CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],1.69,1.67, 1.59,1.57 [4s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
CH2CH2C(CH3) CHCH2N], 2.13e1.93 [m, 8H, (CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.71, 1.67, 1.59,
1.58 [4s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
ppm): 179.9
CHCH2CH2C(CH3)
CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
NMR (125 MHz, CDCl3,
d
ppm): 180.1 (C]S), 141.8, 135.6, 131.4
(C]S), 141.3, 135.7, 131.4 [(CH3)2C
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
139.9, 127.3, 124.8, 122.6 (Ar), 124.2, 123.4, 118.3 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.8 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.4, 26.7,
26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 142.2, 133.9, 123.4, 122.4 (Ar),
124.2, 123.7, 118.1 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CH
¼
CH2CH2C(CH3) CHCH2N], 108.9 (ArCN), 43.7 [(CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.4, 26.7,
26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
25.7, 17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
25.7, 17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C23H31F3N2S
CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C23H31N3S
424.216006; found, 424.215286 [M]þ$
.
381.223870; found, 381.225555 [M]þ$
.
4.1.2.45. N-farnesyl-N0-(4-fluorophenyl) thiourea (48). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (5:1) as eluent (362 mg, 97% yield). MS (CI): m/z 375
4.1.2.48. N-farnesyl-N0-(4-methoxyphenyl) thiourea (51). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (3:1) as eluent (350 mg, 91% yield). MS (CI): m/z 387
d ppm): 7.61 (s, 1H,
NHAr), 7.16e6.90 (m, 4H, Ar), 5.66 (m, 1H, NH), 5.17 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.05
(100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 7.66 (s, 1H,
(30%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
NHAr), 7.24e7.08 (m, 4H, Ar), 5.69 (m, 1H, NH), 5.19 [t, 1H, J ¼ 6.7 Hz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.05
[m,
CH2C(CH3)
C(CH3)
2H,
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
CHCH2CH2
[m, 2H, (CH3)2C
CHCH2N], 4.21 [m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
¼
CHCH2N], 4.21 [m, 2H, (CH3)2C
CHCH2CH2C(CH3)
¼
¼
¼
¼
CHCH2N], 2.10e1.87 [m, 8H,
CHCH2CH2C(CH3) ¼ CHCH2N], 3.81 (OCH3), 2.10e1.85 [m, 8H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.66,
1.66, 1.59, 1.57 [4s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
1.64, 1.59, 1.56 [4s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3 d ppm):
180.8 (C]S), 158.9, 128.4, 127.7, 115.3 (Ar), 140.9, 135.4, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
180.8 (C]S), 162.4, 160.5, 127.8, 117.1 (Ar), 141.3, 135.5, 131.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 124.2,
123.5, 118.6 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2
124.2,
123.5,
118.9
[(CH3)2C
¼
CHCH2CH2C(CH3)
C(CH3) ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 39.7, 39.4, 26.7, 26.2 [(CH3)2C ¼ CH
CH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.7, 17.7, 16.5, 16.0
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS
(CI): calcd. for C22H32FN2S 375.227024; found, 375.229071 [M þ H]þ.
¼
CHCH2CH2C(CH3)
¼
CHCH2N],
55.5 (OCH3), 43.7
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.6,
39.4, 26.7, 26.2 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3) CHCH2N], 25.7, 17.7, 16.5, 16.0 [(CH3)2
¼
¼
¼
C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI):
calcd. for C23H35N2OS 387.2470; found, 387.2478 [M þ H]þ.
4.1.2.46. N-(4-Chlorophenyl)-N0-farnesyl thiourea (49). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (6:1) as eluent (300 mg, 78% yield). MS (EI): m/z 390 (5%)
4.1.2.49. N-farnesyl-N0-(3-methoxyphenyl) thiourea (52). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (350 mg, 91% yield). MS (CI): m/z 387
[M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 7.62 (s, 1H, NHAr), 7.39,
7.16 (2m, 4H, Ar), 5.79 (m, 1H, NH), 5.21 [t, 1H, J ¼ 6.8 Hz,
(80%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 7.62 (s, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
NHAr), 7.31, 6.82, 6.77, 6.72 (4m, 4H, Ar), 5.99 (m, 1H, NH), 5.22 [m,
1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
5.06 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
CHCH2N], 2.11e1.92 [m, 8H, (CH3)2C
¼
CH
¼
CHCH2N], 4.22 [m, 2H, (CH3)2C
CH2CH2C(CH3)
¼
¼
¼
CHCH2N], 4.24 [m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CH
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.60, 1.57
CH2CH2C(CH3)
¼
CHCH2N], 3.80 (OCH3), 2.10e1.91 [m, 8H,
[3s, 12H, (CH3)2C
CHCH2N]; 13C NMR (125 MHz, CDCl3,
135.6, 131.4 [(CH3)2C CHCH2CH2C(CH3)
C(CH3) CHCH2N], 134.7e126.3 (Ar), 124.2, 123.4, 118.3
¼
CHCH2CH2C(CH3)
ppm): 180.1 (C]S), 141.8,
CHCH2CH2
¼
CHCH2CH2C(CH3)
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67,
d
1.59,
1.57
[3s,
12H,
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
¼
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d ppm):
¼
180.3 (C]S), 161.0, 137.3, 130.9, 116.8, 112.8, 110.6 (Ar), 141.2, 135.5,

606
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
131.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
124.3, 123.6, 118.8 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3) CHCH2N], 55.4 (OCH3), 43.8 [(CH3)2C CH
[m,
6H,
CH2N(CH2)2],
2.10e1.90
[m,
8H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.68,
¼
¼
1.64,
1.56
[3s,
12H,
(CH3)2C
¼
CHCH2CH2C(CH3)
CH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.5, 26.7,
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
CHCH2
26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
181.7 (C]S), 140.4, 135.4, 131.2 [(CH3)2C
¼
25.7, 17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 124.1, 123.4, 119.2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 66.6
(CH2OCH2), 57.8, 53.3, 41.3 [NCH2CH2N(CH2)2], 42.7 [(CH3)2
C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.6, 39.5,
26.6, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼
CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C23H35N2OS
387.2470; found, 387.2481 [M þ H]þ.
4.1.2.50. N-farnesyl-N0-(2-methoxyphenyl) thiourea (53). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (4:1) as eluent (355 mg, 92% yield). MS (EI): m/z 386 (5%)
CHCH2N], 25.7, 17.6, 16.5, 15.9 [(CH3)2C
¼
CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
[M]þ$
;
1H NMR (500 MHz, CDCl,
d
ppm): 7.51 (s, 1H, NHAr), 7.21,
C
22H39N3OS 393.281385; found, 393.281302 [M]þ$
.
6.97 (2m, 4H, Ar), 6.00 (m, 1H, NH), 5.24 [m, 1H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.07
4.1.2.53. N-farnesyl-N0-[3-(4-morpholino)propyl] thiourea (56).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (1:5) as eluent (365 mg, 90% yield). MS (EI): m/z 407
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 4.23 [m, 2H, (CH3)2C
CH2CH2C(CH3)
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.68,
¼
CHCH2CH2C(CH3)
¼
CH
¼
CHCH2N], 3.85 (OCH3), 2.11e1.89 [m, 8H,
(10%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 7.20 (m, 2H, 2NH),
5.26 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3)
1.60, 1.57 [3s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
ppm): 180.3
¼ CHCH2N], 5.08 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2
CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
CH2C(CH3)
¼
CHCH2N], 4.03 [m, 2H, (CH3)2C
¼
CHCH2CH2
(C]S), 161.2, 124.4, 121.0, 112.0 (Ar), 141.1, 135.5, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.70 (t, 4H, J ¼ 4.6 Hz,
CH2OCH2), 3.50 (m, 2H, NCH2CH2CH2N), 2.13e1.93 [m, 8H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.75
124.3, 123.6, 118.9 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
CH
CH2C(CH3)
¼
CHCH2N], 55.7 (OCH3), 43.7 [(CH3)2C
¼
[m,
6H,
CH2N(CH2)2],
1.68,
1.67,
1.60
[3s,
12H,
CH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.5, 26.7,
26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
NMR (125 MHz, CDCl3,
d ppm): 181.8 (C]S), 142.0, 135.6, 131.4
25.7, 17.7, 16.5, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
124.2, 123.6, 119.5 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3) ¼ CHCH2N], 66.7 (CH2OCH2), 55.6, 53.6, 53.5, 24.8
[NCH2CH2CH2N(CH2)2], 43.0 [(CH3)2C CHCH2CH2C(CH3)
CHCH2CH2C(CH3) CHCH2N], 39.7, 39.5, 26.7, 26.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.7,
17.7, 16.6, 16.0 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3) CHCH2N]; HRMS (EI): calcd for C23H41N3OS
407.297035; found, 407.297296 [M]þ$
CH2C(CH3)
¼
CHCH2N]; HRMS (EI): calcd. for C23H34N2OS
¼
¼
386.2392; found, 386.2366 [M]þ$
.
¼
4.1.2.51. N-farnesyl-N0-[2-(1-piperidino)ethyl]
thiourea
(54).
¼
¼
The solid was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (332 mg, 85% yield). M.p. 67e69 ꢂC; MS
¼
¼
(EI): m/z 391 (5%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 6.58 (m,
CHCH2CH2C(CH3)
CHCH2N], 5.07 [m, 2H, (CH3)2
¼
2H, 2NH), 5.27 [m, 1H, (CH3)2C
CHCH2CH2C(CH3)
¼
.
¼
¼
C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.09 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.35
(m, 2H, NCH2CH2N), 2.44 [m, 6H, CH2N(CH2)2], 2.12e1.92 [m, 8H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.68,
1.66, 1.58 [3s, 12H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 1.53 (m, 4H, 2CH2), 1.42 (m, 2H, CH2); 13C NMR
4.1.2.54. N-Ethoxycarbonylmethyl-N0-farnesyl
thiourea
(57).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (5:1) as eluent (351 mg, 96% yield). MS (CI): m/z 366
(25%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 6.39 (m, 2H,
2NH), 5.23 [m, 1H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
CHCH2
CH2C(CH3)
¼
CHCH2N], 5.07 [m, 2H, (CH3)2C
¼
(125 MHz, CDCl3,
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
124.2, 123.6, 119.8 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3) CHCH2N], 59.8, 54.5 (NCH2CH2N), 42.2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 42.0,
25.6 (piperidine), 39.6, 39.5, 26.6, 26.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 23.9,
17.7, 16.4, 15.9 [(CH3)2C CHCH2CH2C(CH3) CHCH2
CH2C(CH3)
d
ppm): 182.8 (C]S), 141.5, 135.4, 131.3
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.37 (d, 2H, J ¼ 4.7 Hz,
(NCH2CO2CH2CH3), 4.21 (q, 2H, J ¼ 7.1 Hz, NCH2CO2CH2CH3), 3.95
¼
¼
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
[m, 8H,
¼
CHCH2CH2C(CH3)
¼
¼
CHCH2N], 2.12e1.93
(CH3)2C
¼
CHCH2
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.70, 1.66, 1.58 [3s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.28
(t, 3H, J ¼ 7.1 Hz, NCH2CO2CH2CH3); 13C NMR (125 MHz, CDCl3,
¼
¼
d
ppm): 182.0 (C]S), 170.3 (C]O), 141.5, 135.5, 131.3
¼
CHCH2N]; HRMS (EI): calcd. for C23H41N3S
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
391.302120; found, 391.303697 [M]þ$. Anal. calcd for C23H41N3S: C,
70.53; H, 10.55; N, 10.73; S, 8.19. Found: C, 70.56; H, 10.72; N, 10.59;
S, 8.11.
124.2, 123.6, 118.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3)
¼
CHCH2N], 61.6 (NCH2CO2CH2CH3), 46.7 (NCH2CO2
CH2CH3), 42.1 [(CH3)2C
CH2C(CH3) CHCH2N], 39.6, 39.4, 26.7, 26.3 [(CH3)2C
¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,17.6,16.4,
15.9 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
14.1 (NCH2CO2CH2CH3); HRMS (CI): calcd. for C20H35N2O2S
367.241925; found, 367.239998 [M þ H]þ.
¼
CHCH2CH2C(CH3)
¼
CHCH2
¼
4.1.2.52. N-farnesyl-N0-[2-(4-morpholino)ethyl]
thiourea
(55).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (1:3) as eluent (300 mg, 76% yield). MS (EI): m/z 393
(5%) [M]þ$
5.24 [t, 1H,
CHCH2CH2C(CH3)
¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.01 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.65
(t, 4H, J ¼ 4.4 Hz, CH2OCH2), 3.44 (m, 2H, NCH2CH2N), 2.55e2.43
;
1H NMR (500 MHz, CDCl3,
d
ppm): 5.59 (m, 2H, 2NH),
6.6 Hz, (CH3)2C CHCH2CH2C(CH3)
CHCH2N], 5.05 [m, 2H, (CH3)2C
J
¼
¼
¼
¼
4.1.2.55. N-ethoxycarbonyl-N0-farnesyl thiourea (58). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(20:1) as eluent (338 mg, 96% yield). MS (CI): m/z 353 (100%)
[M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 9.51 (m, 1H NH), 8.06

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
607
(s, 1H, NHCO), 5.30 [m, 1H, (CH3)2C
¼
CHCH2CH2C(CH3)
4.1.2.61. N-(1-dodecyl)-N0-(3-nitrophenyl) thiourea (64). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (3:1) as eluent (300 mg, 82% yield). MS (EI): m/z 365
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.09 [m, 2H, (CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.25e4.17 [m, 4H,
(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N,
CHCH2CH2
(15%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 8.13 (s, 1H), 8.10,
NCO2CH2CH3], 2.14e1.94 [m, 8H, (CH3)2C
¼
7.60 (2m, 4H, NHAr), 6.15 (m, 1H, NH), 3.62 (m, 2H, CH2N), 1.7e1.2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.70, 1.67, 1.59 [3s, 12H,
[m, 20H, (CH2)10], 0.88 (t, 3H, J ¼ 7.0 Hz, CH3); 13C NMR (125 MHz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.30
CDCl3,
d ppm): 180.6 (C]S), 149.0, 138.2, 130.7, 130.2, 121.1, 119.0
(t, 3H, J ¼ 7.1 Hz, NCO2CH2CH3); 13C NMR (125 MHz, CDCl3,
d
ppm):
(Ar), 45.7 (CH2N), 31.9e22.7 [(CH2)10], 14.1 (CH3); HRMS (EI): cald.
178.6 (C]S), 152.6 (C]O), 141.7, 135.5, 131.2 [(CH3)2C
¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 124.3, 123.5,
117.9 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
for C19H31N3O2S 365.2137; found, 365.2121 [M]þ$
.
4.1.2.62. N-(1-dodecyl)-N0-(4-methoxyphenyl)
thiourea
(65).
62.6 (NCO2CH2CH3), 43.8 [(CH3)2C
¼
CHCH2CH2C(CH3)
The syrup was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (335 mg, 96% yield). MS (EI): m/z 350
¼
CHCH2CH2C(CH3)
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.6, 16.5, 16.0 [(CH3)2C CHCH2CH2C(CH3) CHCH2
¼
CHCH2N], 39.6, 39.4, 26.7, 26.2
(30%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 7.96 (s, 1H), 7.12,
¼
¼
6.91 (2m, 4H, NHAr), 5.79 (m, 1H, NH), 3.79 (s, 3H, OCH3), 3.55 (m,
CH2C(CH3) ¼ CHCH2N], 14.1 (NCO2CH2CH3); HRMS (CI): calcd. for
2H, CH2N), 1.6e1.2 [m, 20H, (CH2)10], 0.85 (t, 3H, J ¼ 6.9 Hz, CH3);
C
19H33N2O2S 353.226275; found, 353.225595 [M þ H]þ.
13C NMR (125 MHz, CDCl3):
d 180.9 (C]S), 158.8, 128.5, 127.6, 115.2
(Ar), 55.4 (OCH3), 45.4 (CH2N), 31.8e22.6 [(CH2)10], 14.0 (CH3);
4.1.2.56. N-isobutyl-N0-(4-nitrophenyl) thiourea (59). The solid was
purified by column chromatography, using hexaneeethyl acetate
(25:10) as eluent (225 mg, 89% yield). M.p. 97e98 ꢂC; MS (CI): m/z
HRMS (EI): calcd. for C20H34N2OS 350.2392; found, 350.2406
[M]þ$
.
254 (100%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.41 (s,
4.1.2.63. N-(1-Dodecyl)-N0-(3-methoxyphenyl)
thiourea
(66).
1H, NHAr), 8.27, 7.42 (2m, 4H, Ar), 6.40 (m, 1H, NH), 3.49 [m, 2H,
(CH3)2CHCH2N], 1.98 [m, 1H, (CH3)2CHCH2N], 0.98 [d, 6H,
The syrup was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (325 mg, 93% yield). MS (EI): m/z 350
J ¼ 6.8 Hz, (CH3)2CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
(60%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 7.64 (s, 1H), 7.33,
180.2 (C]S), 137.5 [(CH3)2C ¼ CHCH2N], 144.5, 142.9, 125.7, 122.4
(Ar), 53.1 [(CH3)2CHCH2N], 27.9 [(CH3)2CHCH2N], 20.3
[(CH3)2CHCH2N]; HRMS (CI): calcd. for C11H16N3O2S 254.096324;
found, 254.097405 [M þ H]þ; Anal. Calcd for C11H15N3O2S: C,
52.15; H, 5.97; N, 16.59; S, 12.66. Found: C, 52.34; H, 5.66; N, 16.32;
S, 12.41.
6.83, 6.77, 6.72 (4m, 4H, NHAr), 6.10 (m, 1H, NH), 3.80 (s, 3H, OCH3),
3.62 (m, 2H, CH2N), 1.6e1.2 [m, 20H, (CH2)10], 0.87 (t, 3H, J ¼ 7.0 Hz,
CH3); 13C NMR (125 MHz, CDCl3,
d ppm): 180.4 (C]S), 161.0, 137.1,
131.0, 117.0, 112.9, 110.7 (Ar), 55.4 (OCH3), 45.7 (CH2N), 31.9e22.7
[(CH2)10], 14.1 (CH3); HRMS (EI): calcd. for C20H34N2OS 350.2392,
found 350.2390 [M]þ$
.
4.1.2.57. N-isopentyl-N0-(4-nitrophenyl) thiourea (60). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (2:1) as eluent (245 mg, 92% yield). MS (EI): m/z 267
4.1.2.64. N-(1-dodecyl)-N0-(2-methoxyphenyl)
thiourea
(67).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (3:1) as eluent (300 mg, 86% yield). MS (EI): m/z 350
(70%) [M]þ$
;
1H NMR (500 MHz, CDCl3,
d
ppm): 8.41 (s, 1H), 8.26,
(25%) [M]þ$ 1H NMR (500 MHz, CDCl3,
; d ppm): 7.54 (s, 1H), 7.21,
7.40 (2m, 5H, NHAr), 6.28 (m, 1H, NH), 3.67 [m, 2H,
6.96 (2m, 4H, NHAr), 6.14 (m, 1H, NH), 3.82 (s, 3H, OCH3), 3.59 (m,
(CH3)2CHCH2CH2N], 1.64 [m, 1H, (CH3)2CHCH2CH2N], 1.53 [m, 2H,
2H, CH2N), 1.6e1.2 [m, 20H, (CH2)10], 0.86 (t, 3H, J ¼ 6.9 Hz, CH3);
(CH3)2CHCH2CH2N], 0.95 [d, 6H, J ¼ 6.8 Hz, (CH3)2CHCH2CH2N]; 13
C
13C NMR (125 MHz, CDCl3,
d ppm): 180.4 (C]S), 152.4, 127.4, 125.3,
NMR (125 MHz, CDCl3,
d
ppm): 180.0 (C]S), 144.5, 125.7, 122.5 (Ar),
124.7, 120.9, 112.0 (Ar), 55.6 (OCH3), 45.5 (CH2N), 31.8e22.6
44.2 [(CH3)2CHCH2CH2N], 37.5 [(CH3)2CHCH2CH2N], 20.0
[(CH3)2CHCH2CH2N], 22.4 [(CH3)2CHCH2CH2N]; HRMS (EI): calcd.
[(CH2)10], 14.0 (CH3); HRMS (EI): calcd. for C20H34N2OS 350.2392;
found, 350.2393 [M]þ$
.
for C12H17N3O2S 267.104149; found, 267.104037[M]þ$
.
4.1.2.65. N-(4-Morpholino)-N0-(4-nitrophenyl)
thiourea
(68).
4.1.2.58. N-benzyl-N0-(4-nitrophenyl) thiourea (61). The syrup [40]
was purified by column chromatography, using hexaneeethyl
acetate (3:1) as eluent (275 mg, 96% yield). MS (EI): m/z 287
The syrup was purified by column chromatography, using hexanee
ethyl acetate (1:1) as eluent (255 mg, 90% yield). MS (EI): m/z 282
(20%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d ppm): 9.46 (s, 1H, NHAr),
(30%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.24, 7.37 (2m, 9H,
8.24, 7.98 (2m, 4H, Ar), 7.12 (m, 1H, NH), 3.98, 3.92 (2m, 4H,
Ar), 7.89 (s, 1H, NHAr), 6.49 (m, 1H, NH), 4.87 [m, 2H, PhCH2N].
CH2OCH2), 3.07, 2.80 (m, 4H, CH2NCH2); 13C NMR (125 MHz, CDCl3,
d
ppm): 177.8 (C]S), 144.3, 143.6, 125.0, 124.5 (Ar), 66.4 (CH2OCH2),
55.8 (CH2NCH2); HRMS (EI): calcd. for C11H14N4O3S 282.078662;
found, 282.078770 [M]þ$
4.1.2.59. N-cyclohexyl-N0-(4-nitrophenyl) thiourea (62). The syrup
was purified by column chromatography [41], using hexaneeethyl
acetate (2.5:1) as eluent (250 mg, 90% yield). MS (CI): m/z 280
(100%) [M þ H]þ.
.
4.1.2.66. N-(4-Ethyl)-N0-(3-methyl-2-butenyl) urea (69). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (5:1) as eluent (136 mg, 87% yield). MS (EI): m/z 156
4.1.2.60. N-(1-dodecyl)-N0-(4-nitrophenyl) thiourea (63). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (2:1) as eluent (360 mg, 99% yield). MS (EI): m/z 365
(45%) [M]þ$
(CH3)2C
;
1H NMR (500 MHz, CDCl3,
CHCH2N, NHCH2CH3], 3.70 [t, 2H,
d
ppm): 5.27e5.17 [m, 2H,
6.7 Hz,
¼
J
¼
(5%) [M]þ$
;
1H NMR (500 MHz, CDCl3,
d
ppm): 8.40 (s, 1H),
(CH3)2C ¼ CHCH2N], 3.17 (q, 2H, J ¼ 5.4 Hz, NHCH2CH3), 1.72, 1.67
8.25, 7.41 (2m, 4H, NHAr), 6.35 (m, 1H, NH), 3.64 (m, 2H,
(2s, 6H, (CH3)2C ¼ CHCH2N], 0.97 (t, 3H, J ¼ 5.4 Hz, NHCH2CH3); 13
C
CH2N), 1.7e1.2 [m, 20H, (CH2)10], 0.87 (t, 3H, J ¼ 7.0 Hz, CH3);
NMR (125 MHz, CDCl3,
d
ppm): 158.8 (C]O), 134.9
13C NMR (125 MHz, CDCl3,
d
ppm): 180.0 (C]S), 144.5, 143.0,
[(CH3)2C
[(CH3)2C
¼
CHCH2N], 121.5 [(CH3)2C
CHCH2N], 35.0 (NHCH2CH3),
¼
CHCH2N], 38.2
25.5, 17.6
125.7, 122.4 (Ar), 45.7 (CH2N), 31.9e22.7 [(CH2)10], 14.1 (CH3);
HRMS (EI): calcd. for 19H31N3O2S 365.213699; found
365.215957 [M]þ$
¼
C
[(CH3)2C ¼ CHCH2N], 15.4 (NHCH2CH3); HRMS (EI): calcd. for
.
C8H16N2O 156.126263; found, 156.125861 [M]þ$
.

608
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
4.1.2.67. N-allyl-N0-(3-methyl-2-butenyl) urea (70). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(5:1) as eluent (146 mg, 87% yield). MS (EI): m/z 168 (45%) [M]þ$; 1H
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.6 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 119.1 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
52.8 [NC(CH3)3], 43.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
NMR (500 MHz, CDCl3,
[m, 2H, (CH3)2C ¼ CHCH2N, NCH2CH ¼ CHAHB], 5.06 [m, 2H,
NHCH2CH CHAHB, NCH2CH CHAHB], 4.92 [bs, 1H,
(CH3)2C ¼ CHCH2NH], 3.76 [m, 2H, NCH2CH ¼ CH2], 3.72 [m, 2H,
d
ppm): 5.84 (m, 1H, NCH2CH ¼ CH2), 5.17
39.4, 26.3 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 29.5
[NC(CH3)3], 25.7, 17.7, 16.4 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
¼
¼ CHCH2N]; HRMS (EI): calcd. for C15H28N2O 252.220164; found,
252.220115 [M]þ$
.
(CH3)2C
¼
CHCH2N], 1.68, 1.64 [dd, 6H, 4J
0
1.0 Hz,
(CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 158.5 (C]
4.1.2.72. N-allyl-N0-geranyl urea (75). The syrup was purified by
column chromatography, using hexaneeethyl acetate (5:1) as
eluent (245 mg, 98% yield). MS (EI): m/z 236 (25%) [M]þ$; 1H NMR
O), 137.8 [(CH3)2C ¼ CHCH2N], 133.3 (NCH2CH ¼ CH2), 119.0
[(CH3)2C ¼ CHCH2N], 117.3 (NCH2CH ¼ CH2), 46.9 (NCH2CH ¼ CH2),
42.5 [(CH3)2C ¼ CHCH2N], 25.6, 18.0 [(CH3)2C ¼ CHCH2N]; HRMS
(500 MHz, CDCl3,
5.28e5.18 [m, 3H, (CH3)2C
NCH2CH ¼ CH2], 5.04 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 4.09 (m, 2H, NCH2CH CH2), 3.98 [m, 2H,
d
ppm): 6.10e5.80 (m, 3H, 2NH, NCH2CH ¼ CH2),
(EI): calcd. for C9H16N2O 168.126263; found, 168.125700 [M]þ$
.
¼
CHCH2CH2C(CH3) CHCH2N,
¼
4.1.2.68. N-phenyl-N0-(3-methyl-2-butenyl) urea (71). The syrup
was purified by column chromatography, using hexaneeethyl
acetate (6:1) as eluent (140 mg, 63% yield). MS (EI): m/z 204
¼
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 2.11e1.98 [m, 4H,
¼
¼
CHCH2N], 1.67, 1.57 [2s, 9H,
(20%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.01 (s, 1H, NHPh),
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
7.46e7.16 (m, 5H, Ph), 5.91 (m, 1H, NH), 5.19 [m, 1H,
(CH3)2C ¼ CHCH2N], 4.20 [m, 2H, (CH3)2C ¼ CHCH2N], 1.69, 1.65 [2s,
d
ppm): 182.0 (C]O), 158.2, 131.9 [(CH3)2C
¼
CHCH2CH2
CH2), 123.5 [(CH3)2C
C(CH3)
¼
CHCH2N], 133.3 (NCH2CH
¼
6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 155.0
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.7 [(CH3)2C ¼ CHCH2CH2
(C]O), 137.5 [(CH3)2C ¼ CHCH2N], 136.2, 130.1, 127.1, 125.0 (Ph),
119.0 [(CH3)2C ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2N], 25.6, 18.0
[(CH3)2C ¼ CHCH2N]; HRMS (EI): calcd. for C12H16N2O 204.126199;
C(CH3) ¼ CHCH2N], 117.4 (NCH2CH ¼ CH2), 47.0 (NCH2CH ¼ CH2),
42.4 [(CH3)2C
[(CH3)2C
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for
14H24N2O 236.188864; found, 236.187843 [M]þ.
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 39.4, 26.3
¼
CHCH2CH2C(CH3) CHCH2N], 25.6, 17.6, 16.4
¼
found, 204.126263 [M]þ$
.
C
.
4.1.2.69. N-(3-methyl-2-butenyl)-N0-(4-nitrophenyl)
urea
(72).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (25:10) as eluent (206 mg, 83% yield). MS (EI): m/z 249
4.1.2.73. N-geranyl-N0-phenyl urea (76). The syrup was purified by
column chromatography, using hexaneeethyl acetate (6:1) as
(30%) [M]þ$; 1H NMR (500 MHz, CDCl3,
d
ppm): 8.39 (s, 1H, NHAr),
eluent (270 mg, 98% yield). MS (EI): m/z 272 (25%) [M]þ$ 1H NMR
;
8.24, 7.43 (2m, 4H, Ar), 6.26 (m, 1H, NH), 5.27 [m, 1H,
(500 MHz, CDCl3,
5.91 (m, 1H, NH), 5.20 [m, 1H, (CH3)2C
CH2C(CH3) CHCH2N], 5.02 [m, 1H, (CH3)2C
CH2C(CH3) ¼ CHCH2N], 4.22 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3)
d ppm): 7.93 (s, 1H, NHPh), 7.44e7.18 (m, 5H, Ph),
(CH3)2C ¼ CHCH2N], 4.21 [m, 2H, (CH3)2C ¼ CHCH2N], 1.75, 1.71 [2s,
¼
CHCH2
CHCH2
6H, (CH3)2C ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
d
157.6
¼
¼
(C]O), 137.5 [(CH3)2C
¼
CHCH2N], 143.3e122.3 (Ar), 119.0
[(CH3)2C
[(CH3)2C ¼ CHCH2N]; HRMS (EI): calcd. for C12H15N3O3 249.1113;
found, 249.1125 [M]þ$
¼
CHCH2N], 43.7 [(CH3)2C
¼
CHCH2N], 25.6, 18.0
¼
¼
CHCH2N], 2.08e1.96 [m, 4H, (CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2
d ppm): 156.3 (C]
CHCH2N], 1.65, 1.64, 1.56 [3s, 9H, (CH3)2C
¼
.
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
O), 139.1, 138.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 131.8e
125.0 (Ph), 123.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 120.8
4.1.2.70. N-(4-ethyl)-N0-geranyl urea (73). The syrup was purified
by column chromatography, using hexaneeethyl acetate (3:1) as
eluent (223 mg, 98% yield). MS (EI): m/z 224 (20%) [M]þ$; 1H NMR
[(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 43.7 [(CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2N], 39.4, 26.2 [(CH3)2C ¼ CHCH2C
H2C(CH3) ¼ CHCH2N], 25.6, 17.6, 16.5 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C17H24N2O 272.188864;
(500 MHz, CDCl3,
d
ppm): 5.28e5.18 [m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3) ¼ CHCH2N,], 3.78 [m, 2H, (CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 3.2 [q, 2H, J ¼ 7.2 Hz, NCH2CH3], 1.98e2.00
[m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.57 [3s, 9H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.10 [t, 3H, J ¼ 7.2 Hz,
found, 272.187893[M]þ$
.
4.1.2.74. N-geranyl-N0-(4-nitrophenyl) urea (77). The syrup was
purified by column chromatography, using hexaneeethyl acetate
NCH2CH3]; 13C RMN (125 MHz, CDCl3,
d ppm): 158.5 (C]O), 138.8,
131.9 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 123.5 [(CH3)2C ¼
CHCH2CH2C(CH3) CHCH2N], 121.1 [(CH3)2C CHCH2
CHCH2N], 42.4 [(CH3)2C CHCH2CH2
CHCH2N], 35.2 (NCH2CH3) 39.4, 26.3
CHCH2CH2C(CH3) CHCH2N], 25.6, 17.6, 16.4
(35:10) as eluent (317 mg, 94% yield). MS (EI): m/z 317 (35%) [M]þ$
;
¼
¼
1H NMR (500 MHz, CDCl3,
d ppm): 8.46 (s, 1H, NHAr), 8.3e7.4 (m,
CH2C(CH3)
C(CH3)
[(CH3)2C
¼
¼
4H, Ar), 7.90 (m, 1H, NH), 5.28 [m, 1H, (CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 5.04 [m, 1H, (CH3)2C ¼ CHCH2CH2C(CH3)
¼ CHCH2N], 3.82 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
2.12e2.01 [m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.71,
1.65, 1.58 [3s, 9H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR
¼
¼
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 15.4 (NCH2CH3); HRMS
(EI): calcd. for C13H24N2O 224.188864; found, 224.188413 [M]þ.
.
(125 MHz, CDCl3,
d
ppm): 154.8 (C]O), 123.5, 119.8
4.1.2.71. N-tert-butyl-N0-geranyl urea (74). The syrup was purified
by column chromatography, using hexaneeethyl acetate (4:1) as
eluent (244 mg, 97% yield). MS (EI): m/z 252 (20%) [M]þ$; 1H NMR
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 145.7e123.5 (Ar), 123.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.0 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 43.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 39.4, 26.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.7, 16.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (EI):
(500 MHz, CDCl3,
d ppm): 5.91, 5.49 (2s, 2H, 2NH), 5.29 [t, 1H,
J ¼ 7.0 Hz, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06 [m, 1H,
(CH3)2C
(CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
CHCH2N], 4.09 [m, 2H,
CHCH2N], 2.13e2.02 [m, 4H,
calcd. for C17H23N3O3 317.1739; found, 317.1746 [M]þ$
.
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.70, 1.67, 1.60 [3s, 9H,
4.1.2.75. N-(4-Trifluoromethyl)phenyl-N0-geranyl urea (78). The
syrup was purified by column chromatography, using hexanee
ethyl acetate (4:1) as eluent (345 mg, 97% yield). MS (CI): m/z 341
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.42 [NC(CH3)3]; 13C NMR
(125 MHz, CDCl3,
d ppm): 157.7 (C]O), 138.8, 131.6 [(CH3)2C

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
609
(90%) [M þ H]þ$
;
1H NMR (500 MHz, CDCl3,
d
ppm): 8.47 (s, 1H,
CH2C(CH3) ¼ CHCH2N], 39.6, 39.4, 26.7, 26.2 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 35.3 (NHCH2CH3), 25.6,
NHAr), 7.7e7.3 (m, 4H, Ar), 6.50 (s, 1H, NH), 5.24 [t, 1H, J ¼ 6.8 Hz,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.03 [m, 1H, (CH3)2C ¼
17.6, 16.5, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
CHCH2CH2C(CH3)
¼
CHCH2N], 3.90 [m, 2H, (CH3)2C
CHCH2N], 2.12e1.98 [m, 4H, (CH3)2C
¼
¼
CH2C(CH3) ¼ CHCH2N], 15.5 (NHCH2CH3); HRMS (EI): calcd. for
CHCH2CH2C(CH3)
¼
C
18H32N2O 292.251464; found 292.251676 [M]þ$
.
CHCH2CH2C(CH3) ¼ CHCH2N], 1.68, 1.64, 1.57 [3s, 9H, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
4.1.2.79. N-tert-butyl-N0-farnesyl urea (82). The syrup was purified
by column chromatography, using hexaneeethyl acetate (6:1) as
154.7 (C]O), 147.8, 141.7, 131.9 [(CH3)2C ¼ CHCH2CH2C(CH3)
¼
CHCH2N], 139.9e123.8 (Ar), 123.5 [(CH3)2C
C(CH3) ¼ CHCH2N], 118.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
43.7 [(CH3)2C CHCH2CH2C(CH3) CHCH2N], 39.4, 26.2
[(CH3)2C CHCH2CH2C(CH3) CHCH2N], 25.6, 17.6, 16.5
¼
CHCH2CH2
eluent (224 mg, 70% yield). MS (EI): m/z 320 (25%) [M]þ$ 1H NMR
;
(500 MHz, CDCl3,
d ppm): 5.89, 5.49 (2s, 2H, 2NH), 5.29 [m, 1H,
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.08 [m,
¼
¼
2H, (CH3)2C
CHCH2N], 4.09 [m, 2H, (CH3)2C
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for
C
18H23F3N2O 341.184073; found, 341.183521 [M þ H]þ.
¼
CHCH2N], 2.14e1.93 [m, 8H, (CH3)2C
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.71, 1.67, 1.59 [3s,
4.1.2.76. N-(4-chlorophenyl)-N0-geranyl urea (79). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(4:1) as eluent (306 mg, 95% yield). MS (EI): m/z 306 (25%) [M]þ$; 1H
12H, (CH3)2C
CHCH2N], 1.42 [NC(CH3)3]; 13C NMR (125 MHz, CDCl3,
(C]O), 138,2 135.6, 131.4 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
d
ppm): 157.7
¼
CHCH2CH2C(CH3)
NMR (500 MHz, CDCl3,
d
ppm): 7.75 (s, 1H, NHAr), 7.4e7.1 (m, 4H,
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 124.2, 123.5, 119.1 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 52.8 [NC(CH3)3],
43.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
Ar), 5.30 (m, 1H, NH), 5.19 [t, 1H, J ¼ 7.0 Hz, (CH3)2C ¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
CHCH2N], 5.02 [m, 1H, (CH3)2C
CHCH2N], 3.80 [m, 2H, (CH3)2C
CHCH2N], 2.10e1.97 [m, 4H, (CH3)2C
¼
¼
¼
39.7,
39.4,
26.7,
26.3
[(CH3)2C
¼
CHCH2CH2C(CH3)
¼
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 29.5 [NC(CH3)3], 25.7, 17.7, 16.5, 16.0
CHCH2CH2C(CH3) ¼ CHCH2N], 1.67, 1.65, 1.57 [3s, 9H, (CH3)2C ¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS
CHCH2CH2C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm):
(EI): calcd. for C20H36N2O 320.282764; found, 320.282892 [M]þ$
.
155.9 (C]O), 139.7, 137.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
134.7e126.3 (Ar), 123.6 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
120.4 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.8 [(CH3)2C ¼
4.1.2.80. N-allyl-N0-farnesyl urea (83). The syrup was purified by
column chromatography, using hexaneeethyl acetate (6:1) as
eluent (288 mg, 95% yield). MS (CI): m/z 305 (100%) [M þ H]þ; 1H
CHCH2CH2C(CH3)
¼
CHCH2N], 39.4, 26.2 [(CH3)2C
¼
CHCH2
CH2C(CH3) ¼ CHCH2N], 25.6, 17.7, 16.5 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C17H23ClN2O 306.149891;
NMR (500 MHz, CDCl3, d ppm): 6.00e5.80 (m, 3H, 2NH,
NCH2CH ¼ CH2), 5.24 [t, 1H, J ¼ 6.7 Hz, (CH3)2C ¼ CHCH2
found, 306.150764 [M]þ$
.
CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N, NCH2CH ¼ CH2], 5.07
[m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
CH2), 3.98 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 2.12e
1.93 [m, 8H, (CH3)2C CHCH2CH2C(CH3) CHCH2
[3s, 12H,
4.1.2.77. N-(4-cyanophenyl)-N0-geranyl urea (80). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(5:1) as eluent (282 mg, 95% yield). MS (EI): m/z 297 (25%) [M]þ$; 1H
NMR (500 MHz, CDCl3,
7.00 (m, 1H, NH), 5.25 [t, 1H,
¼
CHCH2N], 4.08 (m, 2H, NCH2CH
¼
¼
¼
d
ppm): 8.58 (s,1H, NHAr), 7.7e7.3 (m, 4H, Ar),
7.1 Hz, (CH3)2C
CH2C(CH3)
¼
CHCH2N], 1.68, 1.66, 1.59
J
¼
¼
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
CHCH2CH2C(CH3) ¼ CHCH2N], 5.03 [m, 1H, (CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 3.82 [m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3)
¼ CHCH2N], 2.12e1.98 [m, 4H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼
CHCH2N], 1.69, 1.65, 1.58 [3s, 9H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CH
NMR (125 MHz, CDCl3, d ppm): 158.1 (C]O), 141.5, 135.6, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 133.3
(NCH2CH CH2), 124.2, 123.4, 118.8 [(CH3)2C CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 117.4 (NCH2CH ¼ CH2), 47.0
(NCH2CH CH2), 42.4 [(CH3)2C CHCH2CH2C(CH3)
CHCH2CH2C(CH3) CHCH2N], 39.6, 39.4, 26.7, 26.2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.6, 16.5, 16.0 [(CH3)2C CHCH2CH2C(CH3) CHCH2
¼
¼
CH2N]; 13C NMR (125 MHz, CDCl3,
d
ppm): 154.5(C]O), 143.5
¼
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 140.3e119.9 (Ar), 123.0
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 118.0 [(CH3)2C ¼ CHCH2
CH2C(CH3) ¼ CHCH2N], 108.7 (ArCN), 43.6 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 39.4, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CH
CH2N], 25.6, 17.7, 16.5 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2N];
¼
¼
¼
¼
CH2C(CH3)
¼
CHCH2N]; HRMS (CI): calcd. for C19H33N2O
305.259289; found, 305.259288 [M þ H]þ.
HRMS(EI): calcd. for C18H23N3O 297.184113; found, 297.184327 [M]þ$
.
4.1.2.81. N-farnesyl-N0-phenyl urea (84). The syrup was purified by
column chromatography, using hexaneeethyl acetate (7:1) as
eluent (326 mg, 96% yield). MS (CI): m/z 341 (100%) [M þ H]þ; 1H
4.1.2.78. N-ethyl-N0-farnesyl urea (81). The syrup was purified by
column chromatography, using hexaneeethyl acetate (3:1) as
eluent (288 mg, 95% yield). MS (EI): m/z 292 (10%) [M]þ$; 1H NMR
NMR (500 MHz, CDCl3,
d ppm): 7.89 (s, 1H, NHPh), 7.5e7.1 (m, 5H,
(500 MHz, CDCl3,
d
ppm): 5.24 [t, 1H,
J
¼
6.7 Hz,
Ph), 5.90 (m, 1H, NH), 5.20 [t, 1H, J ¼ 7.0 Hz, (CH3)2C ¼ CHCH2CH2
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.07
C(CH3) CHCH2CH2C(CH3) CHCH2N], 5.05 [m, 2H,
¼
¼
[m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.22
[m, 2H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2
N], 2.10e1.90 [m, 8H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2
C(CH3) ¼ CHCH2N], 1.67, 1.66, 1.59, 1.56 [4s, 12H, (CH3)2C ¼
3.78 [m, 2H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2
C(CH3) ¼ CHCH2N], 3.20 (q, 2H, J ¼ 5.4 Hz, NHCH2CH3), 2.12e1.93 [m,
8H, (CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
1.68, 1.66, 1.59 [3s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
(125 MHz, CDCl3,
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
136.2e125.0 (Ph), 124.2, 123.5, 118.8 [(CH3)2C CHCH2CH2
¼
CHCH2CH2C(CH3)
d ppm): 155.8 (C]O), 141.1, 135.4, 131.3
¼
CHCH2N]; 13C NMR
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 0.97 (t, 3H, J ¼ 5.4 Hz, NHCH2CH3).
13C NMR (125 MHz, CDCl3,
d
ppm): 158.2 (C]O), 149.2, 135.6, 131.3
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 124.2,
123.4, 118.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼
¼
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2CH2
CHCH2N], 42.4 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.6, 39.4, 26.7, 26.2

610
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.6,
17.6, 16.5, 16.0 [(CH3)2C CHCH2CH2C(CH3) CHCH2CH2
C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C22H31ClN2O 374.212492;
¼
¼
found 374.210336 [M]þ$
C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C22H33N2O 341.259289;
found, 341.2592656 [M þ H]þ.
4.1.2.85. N-(4-Cyanophenyl)-N0-farnesyl urea (88). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(4:1) as eluent (323 mg, 85% yield). MS (CI): m/z 366 (5%) [M þ H]þ;
4.1.2.82. N-farnesyl-N0-(4-nitrophenyl) urea (85). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(5:1) as eluent (335 mg, 87% yield). MS (EI): m/z 385 (5%) [M]þ$; 1H
1H NMR (500 MHz, CDCl3,
d ppm): 8.16 (s, 1H, NHAr), 7.7e7.3 (m,
4H, Ar), 6.15 (m, 1H, NH), 5.27 [m, 1H, (CH3)2C
¼
NMR (500 MHz, CDCl3,
d
ppm): 7.85 (s, 1H, NHAr), 8.3e7.4 (m, 4H,
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.07 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.82
Ar), 5.55 (m, 1H, NH), 5.28 [t, 1H, J ¼ 7.0 Hz, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 4.83
[m, 2H, (CH3)2C
CHCH2N], 2.13e1.93 [m, 8H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
[m, 2H, (CH3)2C
CHCH2N], 2.15e1.90 [m, 8H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 1.71, 1.67, 1.59, 1.58 [4s, 12H,
¼
CHCH2CH2C(CH3)
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 1.72, 1.67, 1.58 [3s, 12H,
NMR (125 MHz, CDCl3, d ppm): 154.6 (C]O), 143.5, 140.3, 135.5
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
142.2e122.4 (Ar), 124.2, 123.7, 118.1 [(CH3)2C CHCH2CH2
C(CH3) CHCH2CH2C(CH3) CHCH2N], 108.9 (ArCN), 43.7
NMR (125 MHz, CDCl3,
d
ppm): 154.9 (C]O), 125.2, 124.2, 123.4
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
¼
¼
145.8e135.5 (Ar), 124.2, 123.3, 117.9 [(CH3)2C CHCH2CH2
¼
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7,
39.4, 26.7, 26.2 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3)
¼ CHCH2N], 25.7, 17.7, 16.6, 16.0 [(CH3)2C ¼ CHCH2CH2C(CH3)
¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI): calcd. for C23H31N3O
366.254538; found, 366.255104 [M þ H]þ.
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.7 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.4, 26.7, 26.2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.7,
17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2
C(CH3) ¼ CHCH2N]; HRMS (EI): calcd. for C22H32N3O3 385.2365;
found, 385.2352 [M]þ$
.
4.1.2.86. N-(1-dodecyl)-N0-(4-nitrophenyl) urea (89). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(2:1) as eluent (324 mg, 93% yield). MS (EI): m/z 349 (5%) [M]þ$; 1H
4.1.2.83. N-farnesyl-N0-(4-trifluoromethyl)phenyl
urea
(86).
The syrup was purified by column chromatography, using hexanee
ethyl acetate (6:1) as eluent (360 mg, 85% yield). MS (CI): m/z 409
NMR (500 MHz, CDCl3, d ppm): 8.40 (s, 1H, NHAr), 8.3e7.4 (m, 4H,
NHAr), 6.35 (m, 1H, NH), 3.64 (m, 2H, CH2N), 1.7e1.2 [m, 20H,
(95%) [M þ H]þ; 1H NMR (500 MHz, CDCl3,
d ppm): 8.19 (s, 1H,
(CH2)10], 0.87 (t, 3H, J ¼ 7.0 Hz, CH3); 13C NMR (125 MHz, CDCl3,
NHAr), 7.7e7.3 (m, 4H, Ar), 6.50 (m, 1H, NH), 5.25 [t, 1H, J ¼ 6.8 Hz,
d ppm): 155.0 (C]O), 144.5e122.4 (Ar), 45.7 (CH2N), 31.9e22.7
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06
[(CH2)10], 14.1 (CH3); HRMS (EI): calcd. for C19H31N3O3 349.2365;
[m, 2H, (CH3)2C
CHCH2N], 3.82 [m, 2H, (CH3)2C
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
CHCH2CH2C(CH3)
¼
¼
¼
found, 349.2371 [M]þ$
.
¼
¼
CHCH2N], 2.13e1.88 [m, 8H, (CH3)2C
4.2. Biological assays
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 1.69, 1.67, 1.59,
1.57 [4s, 12H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2
ppm): 154.7 (C]
CHCH2CH2C(CH3)
4.2.1. Preliminary antimicrobial activity screening
C(CH3) ¼ CHCH2N]; 13C NMR (125 MHz, CDCl3,
d
An established standard disc-plate method [42] was used to
evaluate the antimicrobial activity of the synthesized compounds
against different types of gram-positive (B. subtilis ATCC6633,
S. aureus ATCC2595), gram-negative bacteria, (K. pneumoniae
ATCC10031, P. aeruginosa CECT110, Escherichia coli ATCC25922,
Salmonella enterica ATCC10708 and Serratia marcescens ATCC
14756) and fungi (Candida albicans ATCC2091).
MüllereHinton solid medium plates were prepared according
to the manufacturer’s instructions (SCHARLAU). Each strain was
inoculated into 5 ml of MüllereHinton broth (SCHARLAU) and
incubated at the appropriate temperatures (28 ꢂC for
S. marcencens, C. albicans and Bacillus subtillis and 37 ꢂC for
S. aureus ATCC2595, K. pneumoniae, P. aeruginosa, E. coli and
S. enterica) during 24e48 h. After incubation, the cultures were
diluted 100 times in sterile saline solution (NaCl 0.9% p/v) and
O), 141.8, 135.6, 131.4
[(CH3)2C
¼
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 139.9e122.6 (Ar), 124.2, 123.4,
118.3 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
43.8 [(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
39.7,
39.4,
26.7,
26.2
[(CH3)2C
¼
CHCH2CH2C(CH3)
¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.7, 17.7, 16.6, 16.0 [(CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; HRMS (CI):
calcd. for C23H31F3N2O 409.246674; found409.25811 [M þ H]þ.
4.1.2.84. N-(4-chlorophenyl)-N0-farnesyl urea (87). The syrup was
purified by column chromatography, using hexaneeethyl acetate
(6:1) as eluent (300 mg, 78% yield). MS (EI): m/z 374 (15%) [M]þ$; 1H
NMR (500 MHz, CDCl3,
d ppm): 7.62 (s, 1H, NHAr), 7.4e7.1 (m, 4H,
Ar), 5.79 (m, 1H, NH), 5.21 [t, 1H, J ¼ 6.8 Hz, (CH3)2C ¼
CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 5.06 [m, 2H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 3.80
100
sterile cotton-tipped applicators. Stock solutions of 10 mg/ml of
each compound were prepared in DMSO and 20 l aliquots were
ml aliquots were carefully spread onto the agar plate using
[m, 2H, (CH3)2C
CHCH2N], 2.11e1.92 [m, 8H, (CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2C(CH3)
¼
m
¼
CHCH2CH2C(CH3)
used to impregnate a sterile 6 mm diameter disc (Whatmann).
The discs were placed on inoculated plates, left at 4 ꢂC for 30 min
to allow diffusion of the compound into the agar medium and
further incubated at appropriate temperatures for 24 h or 48 h in
the case of C. albicans.
Compounds 59e68 were prepared in DMF [43]. To ensure the
validity of the results obtained in DMF, our compounds with higher
inhibition zones in DMSO were also prepared in DMF, with the
same results. Negative control tests were performed using DMSO
and DMF at the same concentrations.
¼
CHCH2CH2C(CH3)
¼
CHCH2N], 1.67, 1.60, 1.57 [3s, 12H,
(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N]; 13C
NMR (125 MHz, CDCl3,
d ppm): 155.9 (C]O), 139.6, 137.4, 135.4
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N],
134.7e126.3 (Ar), 124.2, 123.4, 118.3 [(CH3)2C CHCH2CH2
¼
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 43.8 [(CH3)2C ¼ CHCH2CH2
C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 39.7, 39.4, 26.7, 26.2
[(CH3)2C ¼ CHCH2CH2C(CH3) ¼ CHCH2CH2C(CH3) ¼ CHCH2N], 25.7,
17.7, 16.6, 16.0 [(CH3)2C
¼
CHCH2CH2C(CH3)
¼
CHCH2CH2

J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
611
The zone of growth inhibition was measured in millimeters to
estimate the antimicrobial activity of each compound.
were averaged from at least three independent experiments and
were expressed as mean ꢁ standard error of the means (SEM).
4.2.2. Compared analysis of growth in liquid medium
Acknowledgements
Selected synthesized compounds were used to evaluate their
antimicrobial activity compared with commercial ones. The
commercial control used to test antimicrobial activity against
Pseudomonas aeruginose was Tobramycine (Tbr), for S. aureus and
K. pneumoniae was Tetracycline (Te) and for C. albicans, Ketoco-
nazol (Kt) was selected as antifungal control. For the assays each
strain was inoculated into 5 ml of Müller-Hinton broth (SCHAR-
LAU) and incubated at the appropriate temperatures (see previous
The authors thank the Junta de Andalucía, the Spanish Minis-
terio de Educación y Ciencia (MEC), program (P06-FQM-01885 and
CTQ2007-61185) for financial support. Ignacio Periñán thanks the
Junta de Andalucía for a predoctoral grant. Authors are also grateful
to CITIUS (Centro de Investigación, Tecnología e Innovación de la
Universidad de Sevilla) for recording NMR and Mass spectra. Carlos
Palo-Nieto thanks Junta de Andalucía for financial support (P09-
AGR4597) and Ministerio de Asuntos Exteriores y Cooperación
(AECID A/023577/09).
section) until they reached early stationary phase. 50 ml aliquots
were used to inoculate new 5 ml Müller-Hinton broth tubes with
different concentrations of the selected compounds and
commercial controls (0, 20, 50, 100, 200
mg/ml) and they were
Appendix A. Supplementary data
incubated at appropriate temperatures. O.D. was measured at
600 nm in a Spectronic 20Dþ (Thermospectronic) at different
intervals of time. The minimum concentration of commercial
compounds that produced total inhibition of growth was selected
to compare the growth of strains incubated with similar concen-
tration of synthesized ones.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.10.042.
References
[1] E. Oldfield, Acc.Chem. Res. 43 (2010) 1216e1226.
[2] V.C. Menys, P.N. Durrington, Br. J. Pharm. 139 (2003) 881e882.
[3] I. Gaon, T.C. Turek, V.A. Weller, R.L. Edelstein, M.D. Distefano, J. Org. Chem. 61
(1996) 7738e7745.
[4] (a) J. Goldstein, M.S. Brown, Nature 343 (1990) 425e430;
(b) M. Sinensky, R.K. Lutz, Bioassays 14 (1992) 25e31.
[5] Nadin, K.C. Nicolau, Angew. Chem. Int. Ed. Engl. 35 (1990) 1622e1656.
[6] P.J. Casey, M.C. Seabra, J. Biol. Chem. 271 (1996) 5289e5292.
[7] E.S. Furfine, J.J. Levan, A. Landavazo, J.F. Moomaw, P.J. Casey, Biochemistry 34
(1995) 6857e6862.
[8] (a) P. Dunten, U. Kammolott, R. Crowther, D. Weber, R. Palermo, J. Birktoft,
Biochemistry 37 (1998) 7907e7912;
(b) C.L. Strickland, W.T. Windsor, R. Syto, L. Wang, R. Bond, Z. Wu, J. Schwartz,
H.V. Le, L.S. Beese, P. Weber, Biochemistry 37 (1998) 16.601e16,611.
[9] M. Caraglia, A.M. D’Alessandro, M. Marra, G. Giuberti, G. Vitale, C. Viscomi,
A. Colao, S. Del Petre, P. Tagliaferri, P. Tassone, A. Budillon, S. Venuta,
A. Abbruzzese, Oncogene 23 (2004) 6900e6913.
[10] M.K. Clark, S.A. Scott, J. Wojtkowiak, R. Chirco, P. Mathieu, J.J. Reiners,
R.R. Mattingly, R.F. Borch, R.A. Gibbs, J. Med. Chem. 50 (2007) 3274e3282.
[11] L. Goldberg, R. Haklai, V. Bauer, A. Heiss, Y. Kloog, J. Med. Chem. 52 (2009)
197e205.
4.2.3. Citotoxicity assays
4.2.3.1. Materials and cell culture conditions. The HT-29 human
colon adenocarcinoma cell line was cultured in McCoy’s medium
containing 10% fetal bovine serum, 2 mM
penicillin and 100 g/mL streptomycin. The human A549 lung
cancer cell line was maintained in DMEM supplemented with 2 mm
L-glutamine, 100 U/mL
m
glutamine, 50 mg/mL penicillin, 50 mg/mL streptomycin and 10% fetal
bovine serum. Both cell lines were incubated at 37 ꢂC in a 5% CO2
atmosphere with 95% humidity. Sulforhodamine B sodium salt, MTT
[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide]
salt, tricloroacetic acid, 5-Fluorouracil, cisplatin and N-acetylcys-
teine (NAC) were purchased from Sigma Chemical Co. Mn(III) Tet-
rakis(1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP) and
cell culture reagents were obtained from Biomol International.
[12] R.A. Gibbs, T.J. Zahn, J.S. Scholt-Leopold, Curr. Med. Chem.
8 (2001)
4.2.3.2. Cell proliferation assays. The sulforhodamine B (SRB) assay
is a colorimetric technique that estimates cell number indirectly by
staining total cellular protein with the dye SRB. HT-29 cells were
seeded in 96-well plates (5000 cells/well) and incubated for 24 h.
Cells were then treated for 48 h with the drugs. Cell monolayers
were then fixed for 1 h with 10% (wt/vol) trichloroacetic acid,
washed with H2O and stained for 30 min with 0.4% (wt/vol) SRB.
The excess dye was removed by washing repeatedly with 1% (vol/
vol) acetic acid. The protein-bound dye was dissolved in 10 mM Tris
base solution for optical density determination at 492 nm using
1437e1465.
[13] I. Chopr, J. Hodgson, B. Metcalf, G. Poste, Antimicrob. Agents Chemother. 41
(1997) 497e503.
[14] (a) I.J.S. Fairlamb, J.M. Dickinson, R. O’Connor, L.H. Cohen, C.F. van Thiel, Bio-
org. Chem. 31 (2003) 80e97;
(b) M. Mechelke, D.F. Wiemer, Tetrahedron Lett. 39 (1998) 783e786.
[15] S.B. Long, P.J. Casey, S. Beese, Biochemistry 37 (1998) 9612e9618.
[16] A.A. Aly, E.K. Ahmed, K.M. El-Mokadem, M.F. Hegazy, J. Sulf. Chem. 28 (2007)
73e93.
[17] H.M. Faidallah, M.S. Al-Saadi, S.A.F. Rostom, H.T.Y. Fahmy, Med. Chem. Res. 16
(2007) 300e318.
[18] A. Esteves-Souza, K. Pissinate, M.G. Nascimento, N.F. Grynberga,
A. Echevarriaa, Bioorg. Med. Chem. 14 (2006) 492e499.
[19] M.C. Balotescu, C. Limban, A.V. Missir, I.C. Chirita, G.M. Nitulescu, Rev. Chim.
(Bucuresti) 58 (2007) 1064e1068.
[20] G.M. Nitulescu, C. Draghici, M.C. Chifiriuc, L. Marutescu, C. Bleotu, A.V. Missir,
Med. Chem. Res. 21 (2012) 308e314.
[21] H.M. Faidallah, K.A. Khan, A.M. Asiri, J. Fluorine Chem. 132 (2011) 131e137.
[22] H.M. Abdel-Rahman, M.A. Morsy, J. Enzym. Inhib. Med. Chem. 22 (2007)
57e64.
[23] A. Saeed, U. Shaheen, A. Hameed, S.Z.H. Naqvi, J. Fluorine Chem. 130 (2009)
1028e1034.
[24] D. Sriram, P. Yogeeswari, K. Madhu, Bioorg. Med. Chem. Lett. 16 (2006)
876e878.
[25] T.K. Venkatachalam, S. Qazi, P. Samuel, F.M. Uckund, Bioorg. Med. Chem. 11
(2003) 1095e1105.
[26] (a) C.T. Gnewuch, G. Sosnovsky, Chem. Rev. 97 (1997) 829e1013;
(b) S. Liu, A.M. Crider, C. Tang, B. Ho, M. Ankersen, C.E. Stidsen, J. Med. Chem.
41 (1998) 4693e4705.
[27] S. Wilhelm, C. Carter, M. Lynch, T. Lowinger, J. Dumas, R.A. Smith, B. Schwartz,
R. Simantov, S. Kelley, Nat. Rev. Drug Discov. 5 (2006) 835e844.
[28] R. Suhas, S. Chandrashekar, D. Channe Gowda, Eur. J. Med. Chem. 48 (2012)
179e191.
a
microplate reader [44,45]. Cell viability was expressed as
percentage in relation to controls. Data were averaged from at least
three independent experiments and are expressed as
means ꢁ standard error of the means (SEM).
The MTT assay is a colorimetric technique that allows the
quantitative determination of cell viability. It is based on the
capability of viable cells to transform the MTT salt [3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] into a for-
mazan dye. Exponentially growing cells were seeded into 96-well
plates and drugs were added after 24 h. Following an incubation
period of 48 h, the medium was removed and MTT (125
ml, 1 mg/ml
in medium) was added to each well for 5 h. Then 20% sodium
dodecyl sulfate (80
ml) in 0.02 m HCl was added, plates were
incubated for 10 h at 37 ꢂC and optical densities were measured at
540 nm on a multi-well plate spectrophotometer reader. Cell
viability was expressed as a percentage relative to controls. All data

612
J.M. Vega-Pérez et al. / European Journal of Medicinal Chemistry 58 (2012) 591e612
[29] (a) J.M. Vega-Pérez, C. Palo-Nieto, I. Periñán, M. Vega-Holm, J.M. Calderón-Mon-
taño, M. López-Lázaro, F. Iglesias-Guerra, Eur. J. Org. Chem. (2012) 1237e1252;
(b) J.M. Vega-Pérez, M. Vega, E. Blanco, F. Iglesias-Guerra, Tetrahedron Asymm. 15
(2004) 3617e3633;
(c) F. Iglesias-Guerra, J.I. Candela, E. Blanco, F. Alcudia, J.M. Vega-Pérez, Chirality14
(2002) 199e203.
[30] G.M. Coppola, M. Prashad, Synth. Commun. 23 (4) (1993) 535e541.
[31] M. Romero Gómez, J.D. Bautista Palomas, J.M. Vega Pérez, F. Iglesias Guerra, I.
Periñán Domínguez, M.M. Díaz Herrero, M. Jover Cobos, P.C.T. Int. Appl WO
2011/2011076967 A1 (30 Jun 2011).
[36] D. Trachootham, Y. Zhou, H. Zhang, Y. Demizu, Z. Chen, H. Pelicano,
P.J. Chiao, G. Achanta, R.B. Arlinghaus, J. Liu, P. Huang, Cancer Cell 10 (2006)
241e252.
[37] G.D. Fairn, K. Macdonald, C.R. McMaster, J. Biol. Chem. 282 (2007) 4868e4874.
[38] C.H. Hsu, T. Stedeford, E. Okochi-Takada, T. Ushijima, H. Noguchi, C. Muro-
Cacho, J.W. Holder, M. Banasik, J. Environ. Sci. Health C Environ. Carcinog.
Ecotoxicol. Rev. 25 (2007) 155e184.
[39] G.X. Li, H. Hu, C. Jiang, T. Schuster, J. Lu, Int. J. Cancer 120 (2007) 2034e2043.
[40] L.C. Sequeira Aguiar, G.M. Viana, M.V. Dos Santos Romualdo, M.V. Costa,
B.S. Bonato, Lett. Org. Chem. 8 (2011) 540e544.
[32] P. Sharma, N. Rane, V.K. Gurram, Bioorg. Med. Chem. Lett. 14 (2004)
4185e4190.
[33] M. Lopez-Lazaro, Cancer Lett. 252 (2007) 1e8.
[41] C. Levallet, J. Lerpiniere, S.Y. Ko, Tetrahedron 53 (1997) 5291e5304.
[42] J.G. Capuccino, N. Sherman, Microbiology: A Laboratory Manual, The Benaja-
min/Cummings Publishing Co, California, USA, 1996.
[34] (a) J. Alexandre, F. Batteux, C. Nicco, C. Chereau, A. Laurent, L. Guillevin,
B. Weill, F. Goldwasser, Int. J. Cancer 119 (2006) 41e48;
(b) J. Alexandre, Y. Hu, W. Lu, H. Pelicano, P. Huang, Cancer Res. 67 (2007)
3512e3517.
[43] H. Abuo-Melha, A.A. Fadda, Spectrochim. Acta A 89 (2012) 123e128.
[44] P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMahon, D. Vistica,
J.T. Warren, H. Bokesch, S. Kenney, M.R. Boyd, Cancer Inst. 82 (1990)
1107e1112.
[35] H. Pelicano, D. Carney, P. Huang, Drug Resist. Updat. 7 (2004) 97e110.
[45] V. Vichai, K. Kirtikara, Nat. Protoc. 1 (2006) 1112e1116.