Synthesis and evaluation of new furanyl and thiophenyl azoles as antileishmanial agents

Article abstract of DOI:10.1016/j.ejmech.2011.02.021

A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more than 90% inhibition against promastigotes at 20 μM

Full text of DOI:10.1016/j.ejmech.2011.02.021

European Journal of Medicinal Chemistry 46 (2011) 1694e1700
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and evaluation of new furanyl and thiophenyl azoles
as antileishmanial agents
,
Vijay K. Marrapu a, Monika Mittal b, Rahul Shivahare b, Suman Gupta b, Kalpana Bhandari a
*
a Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226 001, India
b Division of Parasitology, Central Drug Research Institute, CSIR, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of benzyloxy furanyl and benzyloxy thiophenyl azoles were synthesized and screened for their in
vitro antileishmanial activity against Leishmania donovani. Among all, 16 compounds have shown more
Received 24 September 2010
Received in revised form
10 February 2011
Accepted 12 February 2011
Available online 22 February 2011
than 90% inhibition against promastigotes at 20
3.04e9.39 M against amastigotes. Compound 4, a 3-chlorobenzyloxy furanyl imidazole emerged as the
most active compound in the series with IC50 value of 3.04 M and SI value of 19.80, and was several
folds more potent than the reference drugs miltefosine and miconazole.
Ó 2011 Elsevier Masson SAS. All rights reserved.
mM while 11 compounds exhibited IC50 in the range of
m
m
Keywords:
Antileishmanial
Miconazole
Azoles
Sterol biosynthesis inhibitors (SBIs)
1. Introduction
miltefosine is an effective drug, but there are side effects and
drawbacks related to treatment. These facts [9] call for safer,
cheaper, and more effective new antileishmanial drugs.
The discovery and development of essential drugs for neglected
diseases such as leishmaniasis is a major concern in the pharma-
ceutical world. Leishmaniasis [1,2] are a group of tropical diseases
caused by parasites of about 20 species of the genus Leishmania,
and are transmitted by a group of 50 species and subspecies of
phlebotomine insects [3,4]. Official data show that there are 20
million infected people around the world, 400 million at risk of
acquiring the disease, and 1.5 to 2 million that will be infected
annually [5,6]. The protozoa of the genus Leishmania, which are
distributed throughout the world, are the cause of various clinical
syndromes. Visceral leishmaniasis (VL), commonly known as kala
azar is caused by Leishmania donovani and is most lethal, if left
untreated [7]. Cutaneous leishmaniasis (CL) can be associated with
significant morbidity and occasional deforming scars. Leishmani-
asis showed a complex and diverse clinical manifestation and
epidemiology [8]. The conventional chemotherapy relies on
multiple parenteral injections with pentavalent antimonials that
are significantly toxic and prone to induce resistance. Second-line
drugs, such as Amphotericin B and its lipid formulations, are either
too toxic or expensive for routine use. The oral anticancer drug
The search for safe and efficacious oral therapy has been
ongoing for more than 2 decades. The azole antifungals ketocona-
zole, miconazole and itraconazole have been used to treat cuta-
neous leishmaniasis with variable success rates [9,10]. There have
been conflicting reports of the success and failure of azoles in the
treatment of VL. Azoles are essentially sterol biosynthesis inhibitors
(SBIs), offer an attractive possibility for the treatment of leish-
maniasis [11]. Leishmania resemble fungi in synthesizing 24-
substituted sterols such as ergosterol, whereas mammals have just
cholesterol. Imidazole and triazole antifungals inhibit C-14 deme-
thylation of lanosterol, which interferes with the production of
leishmanial ergosterol, an essential component of their membrane
structure [12]. This results in impaired membrane stability and in
growth inhibition of fungi and possibly in Leishmania as well.
In continuation of our efforts to develop azole-based anti-
leishmanial compounds coupled with encouraging results [13,14],
we have designed and synthesized a series of furanyl and thio-
phenyl azoles by applying rational drug design approach (Fig. 1), as
modified analogues of the antifungal drug miconazole. The prin-
cipal structural modifications introduced in the miconazole mole-
cule to give the new derivatives 4e23 are summarized in Fig. 1. The
present paper describes the syntheses, in vitro antileishmanial
activity and the structure-activity relationship (SAR) studies for
* Corresponding author. Tel.: þ91 522 2262411x4379; fax: þ91 522 2623405.
E-mail address: bhandarikalpana@rediffmail.com (K. Bhandari).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.02.021

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
1695
Cl
Cl
O
Aliphatic chain
modification
N
N
X
N
Azole ring modifications
imidazole (X=CH),
N
Y
1,2.4-triazole (X=N)
R
Phenyl ring
O
replacement
with furan (Y=O),
thiophene (Y=S)
Substitutions on benzyl ring
R1
Cl
R=Cl, Miconazole
R=H, Econazole
R2
4-23
X=N or CH
Y= S or O
Fig. 1. Strucuture of drugs Miconazole, Econazole and general structure of new benzyloxy furanyl, benzyloxy thiophenyl azoles 4e23 for SAR study.
a designed series of substituted benzyloxy furanyl and thiophenyl
azoles (4e23).
Parasitology, C.D.R.I., Lucknow) since 2005 as detailed by Sunduru
et al. [15]. The in vitro effect of the compounds on the growth of
promastigotes was assessed by monitoring the luciferase activity of
viable cells after treatment. The transgenic promastigotes of late log
ml medium 199 well in 96-well
flat bottomed microtitre (MT) plates (CELLSTAR) and incubated for
2. Chemistry
phase were seeded at 5 ꢀ105/100
Synthesis of benzyloxy thiophenyl azoles and benzyloxy furanyl
azoles has been carried out as outlined in Scheme 1. Ketones (2-
acetyl thiophene or 2-acetyl furan) 1ae1b were reacted with pyr-
rolidine and paraformaldehyde under Mannich conditions [14] to
give the corresponding Mannich products. Subsequent replace-
ment of the pyrrolidine with imidazole/1H-1,2,4-triazole (amine
exchange reaction) to give the respective azolyl ketones 2ae2d,
followed by sodium borohydride reduction gave the hydroxyl
intermediates 3ae3d. Condensation of the hydroxyl intermediates
3ae3d with substituted benzyl halides furnished the required
benzyl ethers 4e23. All the above synthesized compounds were
well characterized by spectroscopic methods such as IR, mass, NMR
and elemental analyses.
72 h in medium alone or in the presence of compounds (20
Conc.) in DMSO [16]. Parallel dilutions of DMSO were used as
controls. After incubation, an aliquot (50 L) of promastigote
mM
m
suspension was aspirated from each well of a 96-well plate and
mixed with an equal volume of Steady GloÒ reagent (Promega) and
luminescence was measured by a luminometer. The values were
expressed as relative luminescence unit (RLU).
Percentage Inhibition ¼ Nen ꢀ 100/N
Where N is average relative luminescence unit (RLU) of control
wells; n is average RLU of treated wells.
3.1.2. Antiamastigote activity
For assessing the activity of compounds against the amastigote
stage of the parasite, mouse macrophage cell line (J-774A.1) infected
with promastigotes expressing luciferase firefly reporter gene was
3. Biological activities
used. Cells wereseeded in a 96-well plate(4 ꢀ104cell/100
mL/well) in
3.1. Materials and methods
RPMI-1640 containing 10% foetal calf serum and the plates were
incubated at 37 ꢁC in a CO2 incubator. After 24 h, the medium was
replaced with fresh medium containing stationary phase promas-
3.1.1. Antipromastigote activity
The luciferase transfected L. donovani (strain MHOM/IN/80/Dd8)
promastigotes are being maintained in this laboratory (Division of
tigotes (4 ꢀ105/100
m
L/well). Promastigotes invade the macrophage
N
X
N
i, ii
iii
N
Y
N
X
Y
Y
O
2a-d
O
1a-b
OH
3a-d
2a
a,
; b,
; Y=O, X=CH
Y=O
Y=S
2b; Y=O, X=CH
2C
; Y=S, X=N
iv
2d; Y=S, X=N
N
X
4; Y=O, X=CH, R1=3-Cl, R2=H
5; Y=O, X=CH, R1=2-Cl, R2=4-Cl
6; Y=O, X=CH, R1=2-Cl, R2=5-Cl
14
N
1
2
; Y=S, X=CH ,R =3-Cl, R =H
Y
15; Y=S, X=CH, R1=2-Cl, R2=4-Cl
16; Y=S, X=CH, R1=2-Cl, R2=5-Cl
O
1
2
1
2
7
; Y=O, X=CH, R =2-F, R =4-F
17
18
19
; Y=S, X=CH, R =2-F, R =4-F
1
2
1
2
8
; Y=O, X=CH, R =2-F, R =5-F
; Y=S, X=CH, R =2-F.R =5-F
R1
9; Y=O, X=N, R1=3-Cl, R2=H
10; Y=O, X=N, R1=2-Cl, R2=4-Cl
11; Y=O, X=N, R1=2-Cl, R2=5-Cl
1
2
; Y=S, X=N, R =3-Cl, R =H
20; Y=S, X=N, R1=2-Cl, R2=4-Cl
R2
21; Y=S, X=N, R1=2-Cl, R2=5-Cl
4-23
1
2
1
2
12
; Y=O, X=N, R =2-F, R =4-F
22
; Y=S, X=N, R =2-F, R =4-F
23
; Y=S, X=N, R =2-F,R =5-F
1
2
1
2
13
; Y=O, X=N, R =2-F,R =5-F
Scheme 1. Reagents and conditions: (i) pyrrolidine, (HCHO)n, isopropanol, 90e95 ꢁC, 6e8 h; (ii) corresponding Mannich salt, imidazole or 1H-1,2,4-triazole, ethanol:H2O (3:2),
90 ꢁC, 5e9 h; (iii) NaBH4/MeOH, 0 ꢁCert, 2 h; (iv) K(t-OBu), DMSO, substituted benzyl halides, 5 ꢁCert, 2e3 h.

1696
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
and are transformed into amastigotes. The test compounds were
added at two fold dilutions up to 7 points in complete medium
are better inhibitors in comparison to thiophenyl azoles and also
imidazole derivatives are more active compare to triazole derivatives.
All the compounds were evaluated in vitro against extracellular
promastigotes and intracellular amastigotes. Table 1 displays the
percentage inhibition of these compounds against promastigotes.
Interestingly, all the 20 compounds exhibited high inhibition of
starting from 40
the plates were incubated at 37 ꢁC in a CO2 incubator for 72 h. After
incubation, the drug containing medium was decanted and 50
mM conc. after replacing the previous medium and
mL
PBS was added in each well and mixed with an equal volume of
Steady Glo reagent. After gentle shaking for 1e2 min, the reading
was taken in a luminometer [16e18]. The values are expressed as
relative luminescence units (RLU). Data are transformed into
a graphic program (Excel). IC50 of antileishmanial activity was
calculated by nonlinear regression analysis of the concentration e
response curve using the four parameter Hill equations.
80e100% at 20
mM concentration against promastigotes. These
compounds were further screened against amastigote model and
their IC50, CC50 and selectivity index (SI) are given in Table 1. All the
10 compounds in the furanyl series (4e13) exhibited more than 90%
inhibition against promastigote form of parasite, while
6
compounds in the thiophenyl series (14, 17, 20e23) showed the
same percentage of inhibition against promastigotes. However, on
further screening, the triazoles were not selective against amasti-
gote model and most of the triazolyl compounds were found to be
inactive. The IC50 and SI values for amastigotes of the furanyl azoles
(4e13) indicate that these compounds exhibited high activity
3.1.3. Cytotoxicity assay
The cell viability was determined using the MTT assay [18].
Exponentially growing cells (KB Cell line) (1 ꢀ 105cells/100
mL/well)
were incubated with test drug for 72 h. The test compounds are
added at three fold dilutions up to 7 points in complete medium
against L. donavani (IC50 ¼ 3.04e9.39
mM), better than the reference
M) except the triazolyl compounds
starting from 400
m
M concentration, and were incubated at 37 ꢁC in
drug miltefosine (IC50 ¼ 13.40
m
a humidified mixture of CO2 and 95% air in an incubator. Podo-
phyllotoxin was used as reference drug. Stock solutions of
compounds were initially dissolved in DMSO and further diluted
10, 12 & 13 which were found to be inactive. Two compounds 4 and
5 produced an interesting selective amastigote activity (SI > 10).
Further, the compound 4, with a 3-chlorobenzyloxy moiety was
with fresh complete medium. After incubation, 25
m
L of MTT
found to be the most potent among all, with an IC50 of 3.04
an SI of 19.80. It was also found to be the least toxic with a CC50 of
60.21 M and was several folds more selective than the standard
drugs miltefosine (SI ¼ 0.24) and miconazole (SI ¼ 1.66).
Among the thiophenyl azoles (14e23) all the imidazole
analogues appeared active exerting a strong inhibitory effect on the
mM and
reagent (5 mg/mL) in PBS medium, followed by syringe filtration
were added to each well and incubated at 37 ꢁC for 2 h. At the end of
the incubation period, the supernatant were removed by tilting
m
plate completely without disturbing cell layer and 150 mL of pure
DMSO are added to each well. After 15 min of shaking the readings
were recorded as absorbance at 544 nm on a micro plate reader.
The cytotoxic effect were expressed as 50% lethal dose, i.e., as the
concentration of a compound which provoked a 50% reduction in
cell viability compared to cell in culture medium alone. CC50 values
were estimated as previously described [19,20].
amastigote form of parasite with IC50 in the range of 5.14e7.81
while all the triazoles (20e23) except that of 19 were found inactive
against amastigote model (no inhibition at 40 M).
mM,
m
The overall activity profile of the test compounds demonstrated
that the biological activity was highly influenced by the azole
moiety. Compounds (4e8 and 14e18) consisting an imidazole
moiety showed the lowest IC50 (3.04e5.65 and 5.14e7.81 mM) and
4. Results and discussion
the maximum SI values, whereas compounds with a triazolyl
moiety (9e13 and 19e23) showed either low inhibition or were
found inactive. Thus it is apparent from the activity results (Table 1)
that the imidazole ring is crucial for the activity as on replacement
The in vitro biological activity of benzyloxy thiophenyl and ben-
zyloxy furanyl azole derivatives (4e23) has shown encouraging
results against L. donovani and clearly suggests that the furanyl azoles
Table 1
In vitro antileishmanial activity and cytotoxicity of synthesized azoles.
Comp. no.
Antipromastigote activity %
Antiamastigote activity
IC50 M)(against MQ amastigotes)
Cytotoxicity against
J774A.1 cell lines CC50 (mM)
SI (selectivity index)
CC50/IC50
inhibition at 20
m
M
(m
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
100
3.04
5.15
4.03
4.20
5.35
7.36
NI
9.39
NI
NI
5.14
5.26
6.75
7.81
7.35
8.04
NI
60.21
56.16
37.55
28.84
30.91
18.56
ND
28.92
ND
ND
45.95
29.71
18.02
34.41
15.12
15.58
ND
19.80
10.90
7.15
6.86
5.77
3.17
NA
3.08
NA
NA
8.93
5.65
2.66
4.40
2.05
1.93
NA
91.83
95.97
95.47
98.99
97.50
97.79
94.45
90.50
98.50
100
87.83
85.90
90.56
86.83
80.62
97.13
97.29
91.97
94.75
99.90
100
20
21
22
23
NI
NI
NI
13.40
6.00
ND
ND
ND
3.23
9.93
NA
NA
NA
0.24
1.66
Miltefosine
Miconazole
NI: no inhibition at 40
mM; ND: not done; NA; not available.

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
1697
of this with triazoles the antiamastigote activity decreased several
folds leading to inactive compounds.
Further, the antiamastigote activity was also noticeably influ-
enced by the type of substituent attached at the benzyloxy nucleus.
Compounds (4, 9, 14 and 19) consisting a 3-chlorobenzyloxy group
concentrated to give the crude product which was purified by
column chromatography using methanol: chloroform (1: 99) as an
eluant to provide the required compounds (2ae2d).
6.1.1. 1-(Furan-2-yl)-3-(1H-imidazol-1-yl)propan-1-one (2a)
From 1-(furan-2-yl)-3-(pyrrolidin-1-yl)propan-1-one hydro-
chloride and 1H-imidazole; Yield: 78%; oil; MS (ESI) m/z: 191 (100)
showed the lowest IC50 (3.04, 7.36, 5.14 and 8.04
mM) and the
maximum SI values in both the series. It is interesting to note that
while the chloro- group at position-2,5 (6, and 16) renders the
molecule moderately active, the same group at position-2,4
enhances the activity in compounds 5 and 15 and in addition, the
presence of same Cl atom at position-3 further confers maximum
selectivity (4 and 14). Moreover, the replacement of chlorine atom
with fluorine (7, 8, 22 & 23) resulted in decreased selectivity. This
finding indicates that benzyloxy moiety with 3-chloro- substituent
should be investigated for the development of highly selective
antileishmanial compounds.
[M þ 1]þ; 1H NMR (300 MHz, CDCl3):
3.31 (t, 2H, J ¼ 6.4 Hz), 4.39
d
(t, 2H, J ¼ 6.4 Hz), 6.53e6.55 (m, 1H), 6.96 (s, 1H, imidazole H), 7.01
(s, 1H, imidazole H), 7.19e7.21 (m, 1H, ArH), 7.53 (s, 1H, imidazole H),
7.58e7.59 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3): 39.5, 40.9, 112.5,
117.7, 119.1, 129.4, 137.3, 146.9, 152.0, 185.5; IR (Neat cmꢂ1): 3020,
2963, 2364, 1682, 1512, 1217, 1012, 769.
6.1.2. 1-(Furan-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one (2b)
From 1-(furan-2-yl)-3-(pyrrolidin-1-yl)propan-1-one hydro-
chloride and 1H-1,2,4-triazole; Yield: 64%; oil; MS (ESI) m/z: 192
5. Conclusions
(100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
3.45 (t, 2H, J ¼ 6.2 Hz),
d
4.61 (t, 2H, J ¼ 6.2 Hz), 6.53e6.55 (m, 1H), 7.20e7.22 (m, 1H),
7.59e7.60 (m, 1H), 7.90 (s, 1H, triazole H), 8.19 (s, 1H, triazole H); 13C
NMR (75 MHz, CDCl3): 39.9, 41.2, 112.8, 118.1, 119.8, 131.1, 149.1,
154.4, 185.7; IR (Neat cmꢂ1): 3101, 2961, 1685, 1271, 782, 677.
In conclusion, this study has identified benzyloxy furanyl and
benzyloxy thiophenyl imidazoles as a new structural class of azoles
with antileishmanial activity. The tested compounds were found
several folds less toxic (CC50 values 15e60
drug miltefosine (CC50 ¼ 3.23 M) and also with miconazole
(CC50 ¼ 9.93 M). They have also shown better selectivity index in
mM) than the reference
m
6.1.3. 3-(1H-imidazol-1-yl)-1-(thiophen-2-yl)propan-1-one (2c)
From 3-(pyrrolidin-1-yl)-1-(thiophen-2-yl)propan-1-one hydro-
chloride and 1H-imidazole; Yield: 81%; oil; MS (ESI) m/z: 207 (100)
m
comparison to miltefosine (SI ¼ 0.24) and miconazole (SI ¼ 1.66)
indicating the clean potential of these compounds in treating
leishmaniasis. The potent activity and simple synthesis of these
azoles suggest that they are potential candidates for the develop-
ment of more efficacious antileishmanial agents.
[M þ 1]þ; 1H NMR (300 MHz, CDCl3):
3.37 (t, 2H, J ¼ 6.5 Hz), 4.42 (t,
d
2H, J ¼ 6.4 Hz), 6.95e6.96 (m,1H), 6.97 (s,1H, imidazole H), 7.03 (s,1H,
imidazole H), 7.11e7.14 (m,1H), 7.54 (s,1H, imidazole H), 7.66e7.68 (m,
1H); 13C NMR (75 MHz, CDCl3): 40.4, 41.3, 119.1, 128.3, 129.6, 132.3,
134.5, 137.4, 143.2, 189.3; IR (Neat cmꢂ1): 3019, 2967, 1678, 1259,
763, 689.
6. Experimental
IR spectra were recorded on Perkin Elmer 881 and FTIR 8210 PC,
Schimadzu spectrophotometers either on KBr discs or in neat.
Nuclear magnetic resonance (NMR) spectra were recorded on
Bruker Avance DRX-300 MHz spectrometers using TMS as an
internal reference. All shifts are given in ppm and signals were
abbreviated as s, singlet; d, doublet; dd, double doublet; t, triplet;
m, multiplet. EI mass spectra were recorded on JEOL JMS-D-300
spectrometer with the ionization potential of 70 eV and ES mass
spectra on Quantro-II, micro mass. Purity of all tested compounds
was ascertained on the basis of their elemental analysis and was
carried out on Carlo-Erba-1108 instrument. The melting points
were recorded on an electrically heated melting point apparatus
and are uncorrected.
6.1.4. 1-(Thiophen-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-1-one
(2d)
From 3-(pyrrolidin-1-yl)-1-(thiophen-2-yl)propan-1-one hydro-
chloride and 1H-1,2,4-triazole; Yield: 67%; oil; MS (ESI) m/z: 208
(100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
3.53 (t, 2H, J ¼ 6.2 Hz),
d
4.63 (t, 2H, J ¼ 6.1 Hz), 7.11e7.14 (m, 1H), 7.66e7.68 (m, 2H),
7.70e7.72 (m, IH), 7.90 (s, 1H, triazole H), 8.20 (s, 1H, triazole H); 13C
NMR (75 MHz, CDCl3): 40.6, 41.7, 119.8, 129.1, 129.8, 133.6, 149.6,
154.8, 190.2; IR (Neat cmꢂ1): 3020, 2958, 1679, 1217, 1076, 767, 669.
6.2. General procedure for synthesis of compounds 3ae3d
Sodium borohydride (30 mmol) was added in portions to
a stirred and cooled solution of 2ae2d (10 mmol) in methanol
(10 mL) over a period of 30 min. The reaction mixture was further
stirred at room temperature for 2 h. Methanol was distilled under
reduced pressure. The residue was triturated with water (15 mL)
and extracted with dichloromethane (3 ꢀ 10 mL). The combined
organic layer was dried over sodium sulphate and concentrated to
give the crude product which was purified by column chromatog-
raphy using methanol: chloroform (2:98) as an eluant to provide
the hydroxy compound (3ae3d).
6.1. General procedure for synthesis of compounds 2ae2d
To a stirred mixture of 1-(furan-2-yl)ethanone (1a) or 1-(thio-
phen-2-yl)ethanone (1b) (10 mmol), pyrrolidine hydrochloride
(10 mmol) and 1/5th of paraformaldehyde (10 mmol) in iso-
propanol (10 mL) was added conc. HCl dropwise to adjust the pH of
the solution to 4. The reaction mixture was then heated in an oil
bath at 90e95 ꢁC for 30 min with stirring. Other four portion of the
paraformaldehyde were added at 15 min interval. The reaction
mixture was further refluxed for 6e8 h. The solvent was distilled
off. The residue obtained was washed with hexane (2 ꢀ 5 mL). The
Mannich base of pyrrolidine obtained as a HCl salt were used
further without purification.
6.2.1. 1-(Furan-2-yl)-3-(1H-imidazol-1-yl)propan-1-ol (3a)
From 2a; Yield: 91%; oil; MS (ESI) m/z: 193 (100) [M þ 1]þ; 1H
NMR (300 MHz, CDCl3):
d 2.17e2.26 (m, 2H), 3.98e4.06 (m, 1H),
A mixture of above Mannich salt (10 mmol) and imidazole/1H-
1,2,4-triazole (12 mmol) in 10 mL ethanol : water (3:2) was heated
for 5e9 h at 90 ꢁC. The organic solvent was distilled off and the
compound was extracted with dichloromethane (2 ꢀ 5 mL). The
combined organic layer was dried over sodium sulphate and
4.15e4.25 (m, 1H), 4.48 (dd, 1H, J ¼ 2.4, 5.6 Hz), 6.19 (d, 1H,
J ¼ 3.2 Hz), 6.29e6.30 (m, 1H), 6.90 (s, 1H, imidazole H), 6.93 (s, 1H,
imidazole H), 7.93e7.33 (m, 1H), 7.39 (s, 1H, imidazole H); 13C NMR
(75 MHz, CDCl3): 36.4, 43.3, 63.3, 105.7, 110.1, 118.9, 128.7, 137.2,
141.8, 151.7; IR (Neat cmꢂ1): 3512, 3018, 1512, 1237, 1071, 728.

1698
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
6.2.2. 1-(Furan-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-1-ol (3b)
From 2b; Yield: 94%; oil; MS (ESI) m/z: 194 (100) [M þ 1]þ; 1H
6.3.3. 1-(3-(2,5-Dichlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
imidazole (6)
NMR (300 MHz, CDCl3):
d
2.35e2.42 (m, 2H), 4.26e4.47(m, 2H),
From 3a and 2,5-dichlorobenzylbromide; Yield: 69%; oil; MS
4.60 (dd, 1H, J ¼ 2.3, 5.4 Hz), 6.23 (d, 1H, J ¼ 3.2 Hz), 6.31e6.33 (m,
1H), 7.35e7.36 (m, 1H), 7.91 (s, 1H, triazole H), 8.06 (s, 1H, triazole
H); 13C NMR (75 MHz, CDCl3): 34.9, 45.9, 63.8, 106.1, 110.2, 142.1,
143.3, 151.8, 155.8; IR (Neat cmꢂ1): 3518, 3010, 1518, 1212, 1076,
784.
(ESI) m/z: 351 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.20e2.57 (m, 2H), 4.01e4.20 (m, 2H), 4.25e4.30 (m, 1H),
4.37e4.47 (m, 2H), 6.33e6.37 (m, 2H, ArH), 6.89 (s, 1H, imidazole H),
7.06 (s, 1H, imidazole H), 7.17e7.28 (m, 2H, ArH), 7.40e7.43 (m, 3H,
ArH); 13C NMR (75 MHz, CDCl3):
d 35.5, 43.2, 67.2, 71.4, 109.2, 110.2,
118.8, 128.7, 128.9, 129.6, 130.3, 130.9, 132.7, 137.2, 137.3, 143.0,
152.2; IR (Neat cmꢂ1): 3013, 2957, 1635, 1508, 1231, 1021, 767; Anal.
Calcd. for C17H16Cl2N2O2 : C, 58.13; H, 4.59; N, 7.98; Found C, 58.15;
H, 4.67; N, 8.07.
6.2.3. 3-(1H-imidazol-1-yl)-1-(thiophen-2-yl)propan-1-ol (3c)
From 2c; Yield: 89%; oil; MS (ESI) m/z: 209(100) [M þ 1]þ; 1H
NMR (300 MHz, CDCl3):
d 2.15e2.34 (m, 2H), 4.00e4.09 (m, 1H),
4.20e4.29 (m, 1H), 4.53 (dd, 1H, J ¼ 4.8, 8.7 Hz), 6.92e6.94 (m, 2H),
6.96e6.99 (m, 2H), 7.23e7.26 (m, 1H), 7.43 (s, 1H, imidazole H); 13C
NMR (75 MHz, CDCl3): 36.7, 44.1, 63.8, 105.7, 110.7, 119.2, 129.1,
137.9, 141.1,153.6; IR (Neat cmꢂ1): 3521, 3023,1519,1226, 1078, 798.
6.3.4. 1-(3-(2,4-Difluorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
imidazole (7)
From 3a and 2,4-difluorobenzylbromide; Yield: 58%; oil; MS (ESI)
m/z: 319 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.13e2.49 (m,
6.2.4. 1-(Thiophen-2-yl)-3-(1H-1,2,4-triazol-1-yl)propan-1-ol (3d)
2H), 3.97e4.16 (m, 2H), 4.20e4.25 (m, 1H), 4.33e4.43 (m, 2H),
6.31e6.38 (m, 2H, ArH), 6.77e6.89 (m, 3H, ArH), 7.05 (s,1H, imidazole
H), 7.24e7.32 (m,1H, ArH), 7.41e7.43 (m, 2H, ArH); 13C NMR (75 MHz,
From 2d; Yield: 82%; oil; MS (ESI) m/z: 210(100) [M þ 1]þ; 1H
NMR (300 MHz, CDCl3):
d 2.17e2.33 (m, 2H), 4.03e4.08 (m, 1H),
4.25e4.38 (m, 1H), 4.56 (dd, 1H, J ¼ 4.8, 8.7 Hz), 7.01e7.04 (m, 2H),
7.22e7.28 (m, 1H), 7.91 (s, 1H, triazole H), 8.06 (s, 1H, triazole H); 13C
NMR (75 MHz, CDCl3): 38.4, 47.2, 65.2, 106.1, 110.8, 122.9, 129.7,
151.8, 159.7; IR (Neat cmꢂ1): 3512, 3015, 1521, 1217, 1072, 792.
CDCl3): d 35.5, 43.1, 63.9, 70.8, 103.9, 108.9, 110.2, 111.1, 111.4, 118.8,
120.9, 129.5, 131.3, 131.4, 137.2, 142.9, 152.5; IR (Neat cmꢂ1): 3033,
2923,1619,1507,1220, 763; Anal. Calcd. for C17H16F2N2O2 : C, 64.14; H,
5.07; N, 8.80; Found C, 64.21; H, 5.13; N, 8.86.
6.3.5. 1-(3-(2,5-Difluorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
imidazole (8)
6.3. General procedure for synthesis of compounds 4e23
From 3a and 2,5-difluorobenzylbromide; Yield: 56%; oil; MS (ESI)
To a stirred suspension of 3ae3d (1 mmol) in dimethylsulfoxide
(DMSO) (3 mL) at 5e10 ꢁC was added potassium t-butoxide
(1.2 mmol) in small portions within a period of 10 min. After stir-
ring 30 min appropriate benzyl halide (1 mmol) was added and
then stirring was continued at room temperature for 2e3 h. The
reaction mixture was quenched with ice cold (5 mL) water and
extracted with ethyl acetate (3 ꢀ 5 mL), the combined organic
layers were dried over Na2SO4 and concentrated under reduced
pressure to obtain the crude product which was purified by column
chromatography by using silica gel (60e120 mesh) to give the
desired compounds 4e23.
m/z: 319 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.16e2.53 (m,
2H), 4.00e4.19 (m, 2H), 4.19e4.25 (m, 1H), 4.35e4.44 (m, 2H),
6.32e6.37 (m, 2H, ArH), 6.88 (s, 1H, imidazole H), 6.94e7.01 (m, 2H,
ArH), 7.04e7.09 (m, 2H, ArH), 7.42e7.43 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3):
d 35.7, 43.8, 64.2, 71.7, 102.8, 109.3, 110.8, 111.3,
113.1, 118.7, 123.1, 128.9, 131.6, 132.5, 137.8, 143.7, 153.1; IR (Neat
cmꢂ1): 3116, 2935,1574,1271, 781, 674; Anal. Calcd. for C17H16F2N2O2
: C, 64.14; H, 5.07; N, 8.80; Found C, 64.19; H, 5.11; N, 8.84.
6.3.6. 1-(3-(3-Chlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-1,2,4-
triazole (9)
From 3b and 3-chlorobenzylchloride; Yield: 71%; oil; MS (ESI)
6.3.1. 1-(3-(3-Chlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
imidazole (4)
m/z: 318 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.34e2.59
(m, 2H), 4.21e4.29 (m, 3H), 4.32e4.46 (m, 2H), 6.30e6.37 (m, 2H,
ArH), 7.12e7.16 (m, 1H, ArH), 7.25e7.28 (m, 3H, ArH), 7.43 (s, 1H,
ArH), 7.92 (s, 1H, triazole H), 7.93 (s, 1H, triazole H); 13C NMR
From 3a and 3-chlorobenzylchloride; Yield: 68%; oil; MS (ESI)
m/z: 317 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.17e2.50 (m,
2H), 4.02e4.12 (m, 2H), 4.21e4.32 (m, 2H), 4.41e4.49 (m, 1H),
6.30e6.40 (m, 2H, ArH), 6.86 (s, 1H, imidazole H), 7.06 (s, 1H,
imidazole H), 7.15e7.16 (m, 1H, ArH), 7.28e7.30 (m, 4H, ArH), 7.43 (s,
(75 MHz, CDCl3): d 35.8, 43.4, 64.5, 70.8, 104.7, 108.6, 110.4, 111.5,
112.0, 118.8, 120.7, 130.4, 133.2, 137.2, 143.8, 153.5; IR (Neat cmꢂ1):
3023, 2361, 1638, 1216, 764, 671; Anal. Calcd. for C16H16F2N2O2 : C,
60.47; H, 5.08; N, 13.22; Found C, 60.51; H, 5.13; N, 13.29.
1H, imidazole H); 13C NMR (75 MHz, CDCl3):
d 35.6, 43.2, 69.6, 70.9,
109.0, 110.2, 118.7, 125.7, 127.7, 127.9, 129.6, 129.7, 134.3, 137.1, 139.8,
142.9, 152.6; IR (Neat cmꢂ1): 3020, 2983, 1602, 1509, 1217, 767;
Anal. Calcd. for C17H17ClN2O2 : C, 64.46; H, 5.41; N, 8.84; Found C,
64.43; H, 5.48; N, 8.91.
6.3.7. 1-(3-(2,4-Dichlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
1,2,4-triazole (10)
From 3b and 2,4-dichlorobenzylchloride; Yield: 73%; oil; MS
(ESI) m/z: 352 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
6.3.2. 1-(3-(2,4-Dichlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
imidazole (5)
d 2.43e2.56 (m, 2H), 4.25e4.42 (m, 3H), 4.45e4.49 (m, 2H),
6.34e6.35 (m, 2H, ArH), 7.22e7.26 (m, 1H, ArH), 7.32e7.42 (m, 3H,
From 3a and 2,4-dichlorobenzylchloride; Yield: 71%; oil; MS
ArH), 7.93 (s, 1H, triazole H), 7.97 (s, 1H, triazole H); 13C NMR
(ESI) m/z: 351 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
(75 MHz, CDCl3):
d 34.0, 46.0, 67.2, 71.4, 108.9, 110.2, 127.0, 129.1,
d
2.21e2.52 (m, 2H), 4.03e4.16 (m, 2H), 4.27e4.31 (m, 1H),
130.3, 133.7, 134.0, 134.1, 142.9, 143.1, 151.9, 152.6; IR (Neat cmꢂ1):
3015, 2984, 1612, 1210, 714, 698; Anal. Calcd. for C16H15Cl2N3O2 : C,
54.56; H, 4.29; N, 11.93; Found C, 54.61; H, 4.32; N, 12.02.
4.38e4.49 (m, 2H), 6.33e6.37 (m, 2H, ArH), 6.88 (s,1H, imidazole H),
7.06 (s, 1H, imidazole H), 7.23e7.28 (m, 1H, ArH), 7.33e7.37 (m, 3H,
ArH), 7.43 (s, 1H, imidazole H); 13C NMR (75 MHz, CDCl3):
d 35.5,
43.2, 67.1, 71.3, 109.0, 110.2, 118.7, 127.1, 129.1, 129.6, 130.2, 133.7,
134.0, 134.1, 137.1, 142.9, 152.5; IR (Neat cmꢂ1): 3023, 2962, 1579,
1487, 1231,786; Anal. Calcd. for C17H16Cl2N2O2 : C, 58.13; H, 4.59; N,
7.98; Found C, 58.19; H, 4.62; N, 8.01.
6.3.8. 1-(3-(2,5-Dichlorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
1,2,4-triazole (11)
From 3b and 2,5-dichlorobenzylbromide; Yield: 68%; oil; MS
(ESI) m/z: 352 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):

V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
1699
d
2.38e2.64 (m, 2H), 4.24e4.38 (m, 3H), 4.44e4.48 (m, 2H),
(m, 2H), 4.01e4.18 (m, 2H), 4.35e4.47 (m, 1H), 4.48e4.52 (m, 1H),
6.89 (s, 1H, imidazole H), 6.99e7.02 (m, 2H, ArH), 7.07 (s, 1H, imid-
azole H), 7.19e7.23 (m, 1H, ArH), 7.32e7.34 (m, 2H, ArH), 7.39e7.41
(m,1H), 7.42e7.43 (m, 2H, ArH þ imidazole H); 13C NMR (75 MHz,
6.34e6.37 (m, 2H, ArH), 7.20e7.27 (m, 2H, ArH), 7.41e7.42 (m, 2H,
ArH), 7.95 (s, 1H, triazole H), 7.99 (s, 1H, triazole H); 13C NMR
(75 MHz, CDCl3):
d 34.0, 45.9, 67.2, 71.6, 109.0, 110.2, 128.7, 129.0,
130.3, 130.9, 132.7, 137.3, 142.9, 143.2, 152.1, 152.3; IR (Neat cmꢂ1):
3021, 1615, 1221, 785, 682; Anal. Calcd. for C16H15Cl2N3O2 : C, 54.56;
H, 4.29; N, 11.93; Found C, 54.59; H, 4.37; N, 11.97.
CDCl3): d 39.7, 43.4, 67.1, 74.1, 118.8, 125.9, 126.3, 126.7, 128.8, 129.0,
129.6, 130.4, 131.0, 132.7, 137.2, 137.3, 143.8; IR (Neat cmꢂ1): 3012,
2987, 1615, 1212, 781, 686; Anal. Calcd. for C17H16Cl2N2OS : C, 55.59;
H, 4.39; N, 7.63; Found C, 55.51; H, 4.45; N, 7.69.
6.3.9. 1-(3-(2,4-Difluorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
1,2,4-triazole (12)
6.3.14. 1-(3-(2,4-Difluorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
imidazole (17)
From 3b and 2,4-difluorobenzylbromide; Yield 51%; oil; MS (ESI)
m/z: 320 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.33e2.56 (m,
From 3c and 2,4-difluorobenzylbromide; Yield: 69%; oil; MS
2H), 4.20e4.30 (m, 2H), 4.33e4.35 (m, 1H), 4.37e4.45 (m, 2H),
6.31e6.37 (m, 2H, ArH), 6.77e6.88 (m, 2H, ArH), 7.25e7.32 (m, 1H,
ArH), 7.41e7.42 (m,1H, ArH), 7.93 (s,1H, triazole H), 7.96 (s,1H, triazole
(ESI) m/z: 335 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.12e2.43 (m, 2H), 3.97e4.17 (m, 2H), 4.31e4.48 (m, 3H),
6.78e6.85 (m, 2H, ArH), 6.86 (s, 1H, imidazole H), 6.98e7.01 (m, 2H,
ArH), 7.06 (s, 1H, imidazole H), 7.28e7.33 (m, 2H, ArH), 7.42 (s, 1H,
H); 13C NMR (75 MHz, CDCl3):
d 34.0, 45.8, 63.9, 71.0, 103.5, 104.2,
108.8,110.2,111.1,111.4,120.9,131.2,131.4,142.8,143.2,152.6; IR (Neat
cmꢂ1):3100,3024,1528,1224, 743, 618;Anal. Calcd. forC16H15F2N3O2
: C, 60.18; H, 4.73; N, 13.16; Found C, 60.22; H, 4.79; N, 13.19.
imidazole H); 13C NMR (75 MHz, CDCl3):
d 38.3, 45.9, 67.2, 74.4,
125.8, 126.3, 126.8, 127.8, 128.8, 130.6, 131.4, 131.9, 134.3, 134.1,
134.9,142.9,143.8; IR (Neat cmꢂ1): 3025, 2928,1611,1219,1015, 783,
672; Anal. Calcd. for C17H16F2N2OS : C, 61.06; H, 4.82; N, 8.38; Found
C, 61.13; H, 4.73; N, 8.46.
6.3.10. 1-(3-(2,5-Difluorobenzyloxy)-3-(furan-2-yl)propyl)-1H-
1,2,4-triazole (13)
From 3b and 2,5-difluorobenzylbromide; Yield 54%; oil; MS
6.3.15. 1-(3-(2,5-Difluorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
imidazole (18)
(ESI) m/z: 320 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.35e2.59 (m, 2H), 4.22e4.31 (m, 2H), 4.33e4.35 (m, 1H),
From 3c and 2,5-difluorobenzylbromide; Yield : 74%; oil; MS
4.37e4.46 (m, 2H), 6.32e6.37 (m, 2H, ArH), 6.92e7.00 (m, 2H, ArH),
7.03e7.09 (m, 1H, ArH), 7.42e7.43 (m, 1H, ArH), 7.94 (s, 1H, triazole
(ESI) m/z: 335 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.15e2.47 (m, 2H), 3.99e4.19 (m, 2H), 4.34e4.49 (m, 3H), 6.88 (s,
H), 7.97 (s, 1H, triazole H); 13C NMR (75 MHz, CDCl3):
d
34.0, 45.8,
1H, imidazole H), 6.94e7.01 (m, 4H, ArH), 7.06 (s, 1H, imidazole H),
7.07e7.10 (m,1H, ArH), 7.32e7.34 (m,1H, ArH), 7.42 (s,1H, imidazole
63.9, 71.2, 108.9, 110.2, 115.4, 115.7, 116.5, 126.5, 126.8, 132.5, 133.7,
142.9, 143.2, 152.4; IR (Neat cmꢂ1): 3011, 2961, 1631, 1213, 764, 670;
Anal. Calcd. for C16H15F2N3O2 : C, 60.18; H, 4.73; N, 13.16; Found C,
60.25; H, 4.81; N, 13.22.
H); 13C NMR 75 MHz, CDCl3
d 38.3, 46.2, 67.2, 74.3, 125.9, 126.6,
126.9, 127.5, 128.6, 130.7, 131.4, 131.9, 134.7, 134.4, 135.2, 142.7,
143.8; IR (Neat cmꢂ1): 3013, 2922, 1612, 1218, 1012, 789, 698; Anal.
Calcd. for C17H16F2N2OS : C, 61.06; H, 4.82; N, 8.38; Found C, 61.09;
H, 4.83; N, 8.35.
6.3.11. 1-(3-(3-Chlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
imidazole (14)
From 3c and 3-chlorobenzylchloride; Yield 63%; oil; MS (ESI) m/
6.3.16. 1-(3-(3-Chlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
1,2,4-triazole (19)
z: 333 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.16e2.47 (m,
2H), 3.99e4.17 (m, 2H), 4.21 (d, 1H, J ¼ 11.7 Hz), 4.44 (d, 1H,
J ¼ 8.7 Hz), 4.45 (d, 1H, J ¼ 11.7 Hz), 6.86 (s, 1H, imidazole H),
6.96e7.01 (m, 2H, ArH), 7.06 (s, 1H, imidazole H), 7.14e7.16 (m, 1H,
ArH), 7.27e7.30 (m, 3H, ArH), 7.32e7.34 (m, 1H, ArH), 7.40 (s, 1H,
From 3d and 3-chlorobenzylchloride; Yield :66%; oil; MS (ESI)
m/z: 334 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d 2.3e2.47 (m,
2H), 4.21e4.45 (m, 4H), 4.45e4.51 (m, 1H), 6.97e7.01 (m, 2H, ArH),
7.15e7.17 (m, 1H, ArH), 7.27e7.34 (m, 4H, ArH), 7.93 (s, 1H, triazole
imidazole H); 13C NMR (75 MHz, CDCl3):
d
40.1, 43.8, 70.0, 73.9,119.1,
H), 7.95 (s, 1H, triazole H); 13C NMR (75 MHz, CDCl3):
d 38.2, 46.0,
126.2,126.5, 127.1,128.3, 128.4, 130.0, 130.1,133.1,134.8,137.5,140.2,
144.6; IR (Neat cmꢂ1): 3021, 2989, 1611, 1215, 779, 682; Anal. Calcd.
for C17H17ClN2OS : C, 61.34; H, 5.15; N, 8.42; Found C, 61.27; H, 5.04;
N, 8.56.
69.6, 73.6, 125.7, 125.8, 126.0, 126.7, 127.9, 128.0, 129.7, 134.3, 139.8,
143.1, 144.2, 152.1; IR (Neat cmꢂ1): 3083, 2982, 1611, 1510, 1210,
1017, 776; Anal. Calcd. for C16H16ClN3OS : C, 57.56; H, 4.83; N, 12.59;
Found C, 57.62; H, 4.91; N, 12.47.
6.3.12. 1-(3-(2,4-Dichlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
imidazole (15)
6.3.17. 1-(3-(2,4-Dichlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
1,2,4-triazole (20)
From 3c and 2,4-dichlorobenzylchloride; Yield: 59%; oil; MS
From 3d and 2,4-dichlorobenzylchloride; Yield: 53%; oil; MS
(ESI) m/z: 367 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
(ESI) m/z: 368 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.16e2.48 (m, 2H), 4.00e4.19 (m, 2H), 4.35e4.44 (m, 1H),
d 2.36e2.53 (m, 2H), 4.23e4.50 (m, 4H), 4.54e4.59 (m, 1H),
4.48e4.52 (m, 1H), 4.49e4.52 (m, 1H), 6.88 (s, 1H, imidazole H),
6.99e7.01 (m, 2H, ArH), 7.06 (s, 1H, imidazole H), 7.23e7.24 (m, 1H,
ArH), 7.31e7.36 (m, 2H, ArH), 7.37e7.38 (m, 1H, ArH), 7.43 (s, 1H,
6.99e7.00 (m, 2H, ArH), 7.22e7.26 (m, 1H, ArH), 7.31e7.36 (m, 2H,
ArH), 7.38 (d, 1H, J ¼ 2.0 Hz, ArH); 7.94 (s, 1H, triazole H), 7.97 (s, 1H,
triazole H); 13C NMR (75 MHz, CDCl3):
d 38.2, 46.1, 67.2, 74.1, 125.8,
imidazole H); 13C NMR (75 MHz, CDCl3):
d
39.8, 43.4, 67.4, 74.6,
126.1, 126.7, 127.1,,129.2, 130.4, 133.9, 134.0, 134.7, 143.2, 143.9,
152.1; IR (Neat cmꢂ1): 3022, 1626, 1506, 1214, 1082, 761; Anal.
Calcd. for C16H15Cl2N3OS : C, 52.18; H, 4.11; N, 11.41; Found C, 52.26;
H, 4.18; N, 11.46.
118.4, 126.3, 126.1, 126.9, 128.6, 129.3, 129.7, 131.2, 131.9, 133.3, 137.7,
138.1, 144.2; IR (Neat cmꢂ1): 3015, 2972, 1623, 1218, 783, 678; Anal.
Calcd. for C17H16Cl2N2OS : C, 55.59; H, 4.39; N, 7.63; Found C, 55.68;
H, 4.44; N, 7.54.
6.3.18. 1-(3-(2,5-Dichlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
1,2,4-triazole (21)
6.3.13. 1-(3-(2,5-Dichlorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
imidazole (16)
From 3d and 2,5-dichlorobenzylbromide; Yield: 64%; oil; MS
From 3c and 2,5-dichlorobenzylbromide; Yield 61%; oil; MS(ESI)
(ESI) m/z: 368 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
m/z: 367 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.18e2.52
d 2.37e2.58 (m, 2H), 4.25e4.49 (m, 4H), 4.54e4.59 (m, 1H),

1700
V.K. Marrapu et al. / European Journal of Medicinal Chemistry 46 (2011) 1694e1700
6.98e7.01 (m, 2H, ArH), 7.19e7.29 (m, 2H, ArH), 7.32e7.34 (m, 1H,
ArH), 7.43 (d, 1H, J ¼ 2.2 Hz, ArH); 7.96 (s, 1H, triazole H), 7.99 (s, 1H,
thankful to S.A.I.F. Division, CDRI, Lucknow for providing spectro-
scopic data. Thanks are also due to Mr. Anoop Kumar for technical
assistance. CDRI communication No: 8022.
triazole H); 13C NMR (75 MHz, CDCl3):
d 38.2, 46.0, 67.2, 74.2, 125.9,
126.2, 126.7, 128.8, 129.1, 130.4, 131.0, 132.7, 137.7, 143.2, 143.8,
152.2; IR (Neat cmꢂ1): 3018, 1627, 1527, 1209, 1012, 796, 686; Anal.
Calcd. for C16H15Cl2N3OS : C, 52.18; H, 4.11; N, 11.41; Found C, 52.26;
H, 4.18; N, 11.46.
References
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6.3.19. 1-(3-(2,4-Difluorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
1,2,4-triazole (22)
From 3d and 2,4-difluorobenzylbromide; Yield: 57%; oil; MS
(ESI) m/z: 336 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.37e2.45 (m, 2H), 4.22e4.46 (m, 4H), 4.47e4.52 (m, 1H),
[6] http://www.who.int/tdr/dw/leish2004.htm.
6.78e6.89 (m, 2H, ArH), 6.98e7.00 (m, 2H, ArH), 7.28e7.33 (m, 2H,
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784e786;
ArH), 7.94 (s, 1H, triazole H), 7.97 (s, 1H, triazole H); 13C NMR
(75 MHz, CDCl3):
d 38.2, 46.0, 63.9, 73.7, 104.2, 111.4, 120.8, 125.7,
126.0, 126.7, 131.3, 131.5, 143.2, 143.3, 144.1, 152.1; IR (Neat cmꢂ1):
3017, 1624, 1506, 1487,1216, 1082, 782; Anal. Calcd. for
C16H15F2N3OS : C, 57.30; H, 4.51; N, 12.53; Found C, 57.38; H, 4.54;
N, 12.47.
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133e139.
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1388e1395;
(b) A. Foroumadi, S. Emami, S. Pournourmohammadi, A. Kharazmi, A. Shafiee,
Eur. J. Med. Chem. 40 (2005) 1346e1350.
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(2006) 560e567;
6.3.20. 1-(3-(2,5-Difluorobenzyloxy)-3-(thiophen-2-yl)propyl)-1H-
1,2,4-triazole (23)
From 3d and 2,5-difluorobenzylbromide; Yield: 68%; oil; MS
(ESI) m/z: 336 (100) [M þ 1]þ; 1H NMR (300 MHz, CDCl3):
d
2.36e2.51 (m, 2H), 4.24e4.46 (m, 4H), 4.48e4.52 (m, 1H),
6.95e7.0 (m, 4H, ArH), 7.05e7.11 (m, 1H, ArH), 7.32e7.34 (m, 1H,
(b) J.A. Urbina, Parasitology 114 (1997) 91e96.
ArH), 7.96 (s, 1H, triazole H), 7.98 (s, 1H, triazole H); 13C NMR
[13] K. Bhandari, N. Srinivas, S. Palne, Nishi, S. Gupta, Ind. Pat. DEL 610 (2008).
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Med. Chem. Lett. 20 (2010) 291e293.
[15] N. Sunduru, Nishi, S. Palne, P.M.S. Chauhan, S. Gupta, Eur. J. Med. Chem. 44
(2009) 2473e2481.
(75 MHz, CDCl3):
d 38.1, 45.9, 63.8, 73.9, 115.6, 115.7, 116.0, 116.1,
116.2, 116.5, 125.8, 126.1, 126.7, 143.3, 143.9, 152.1; IR (Neat cmꢂ1):
3124, 2927, 1617, 1518, 1227, 768, 660; Anal. Calcd. for C16H15F2N3OS
: C, 57.30; H, 4.51; N, 12.53; Found C, 57.35; H, 4.57; N, 12.49.
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Acknowledgements
V.K.M. thanks the Council of Scientific and Industrial Research
(India) for the award of Senior Research Fellowship. We are also