Synthesis and antimicrobial activity of novel 5-(1-adamantyl)-2- aminomethyl-4-substituted-1,2,4-triazoline-3-thiones

Article abstract of DOI:10.1016/j.ejmech.2013.07.024

The reaction of 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thione 5a,b and 10a,b with formaldehyde solution and various primary aromatic amines or 1-substituted piperazines yielded the corresponding N-Mannich bases 6a-o, 7a-g and 11a-i. The newly synthesized N-Mannich bases 6a-o, 7a-g and 11a-i were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. The compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f, 11h and 11i displayed moderate to good activity against the tested Gram-positive bacteria, while compounds 7c, 11c, 11d, 11f and 11h showed potent broad spectrum antibacterial activity. None of the newly synthesized compounds were proved to possess marked activity against C. albicans.

Full text of DOI:10.1016/j.ejmech.2013.07.024

European Journal of Medicinal Chemistry 68 (2013) 96e102
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and antimicrobial activity of novel 5-(1-adamantyl)-
2-aminomethyl-4-substituted-1,2,4-triazoline-3-thiones
,
b
a
Ali A. El-Emam a , Abdul-Malek S. Al-Tamimi , Mohamed A. Al-Omar ,
*
Khalid A. Alrashood a, Elsayed E. Habib c
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia
b Department of Pharmaceutical Chemistry, College of Pharmacy, Salman bin Abdulaziz University, Alkharj 11942, Saudi Arabia
c Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Medinah, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 5-(1-adamantyl)-4-substituted-1,2,4-triazoline-3-thione 5a,b and 10a,b with formalde-
hyde solution and various primary aromatic amines or 1-substituted piperazines yielded the corre-
sponding N-Mannich bases 6aeo, 7aeg and 11aei. The newly synthesized N-Mannich bases 6aeo, 7aeg
and 11aei were tested for in vitro inhibitory activities against a panel of Gram-positive and Gram-
negative bacteria and the yeast-like pathogenic fungus Candida albicans. The compounds 6j, 6l, 6m,
7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f, 11h and 11i displayed moderate to good activity against the
tested Gram-positive bacteria, while compounds 7c, 11c, 11d, 11f and 11h showed potent broad spectrum
antibacterial activity. None of the newly synthesized compounds were proved to possess marked activity
against C. albicans.
Received 21 December 2012
Received in revised form
30 April 2013
Accepted 15 July 2013
Available online 8 August 2013
Keywords:
Adamantane derivatives
1,2,4-triazoles
N-Mannich bases
Antimicrobial activity
Ó 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
2. Results and discussion
The incorporation of an adamantyl moiety into several mole-
cules results in compounds with relatively high lipophilicity, which
in turn can modify the biological availability of these molecules. In
almost all cases, an adamantyl-bearing compound will be more
lipophilic than the des-adamantyl analogue. Beyond increasing
partition coefficient, the adamantyl group positively modulates the
therapeutic index of many experimental compounds through a
variety of mechanisms [1,2]. Derivatives of adamantane have long
been known for their antiviral activity against Influenza A [3e6]
and HIV viruses [7e9]. Several adamantane derivatives were also
associated with central nervous [10e12], hypoglycemic [13,14],
antimicrobial [15e20] and anti-inflammatory activities [17e23]. In
addition, several 1,2,4-triazoles and their N-Mannich bases were
identified as potent antimicrobial agents [24e29]. In continuation
to our interest in the chemical and pharmacological properties of
adamantane derivatives [7,17e21,30], we report herein the syn-
thesis and antimicrobial activity of new series of 5-(1-adamantyl)-
4-substituted-1,2,4-triazole N-Mannich bases.
2.1. Chemistry
The starting material adamantane-1-carbohydrazide 3 was pre-
pared starting with adamantane-1-carboxylic acid 1 via esterification
with methanol to yield the corresponding methyl ester 2, which was
reacted with hydrazine to yield 3 [21]. The reaction of 3 with
methyl or 4-chlorophenylisothiocyanate yielded the intermediate
1-(1-adamantylcarbonyl)-4-substituted thiosemicarbazides 4a,b,
which were cyclized to the corresponding 5-(1-adamantyl)-4-
substituted-1,2,4-triazoline-3-thiones 5a,b via heating in 10%
aqueous sodium hydroxide for 2 h [19,21]. Compounds 5a,b were
reacted with primary aromatic amines and formaldehyde solution in
ethanol to yield the corresponding N-Mannich bases 6aeo in good
yields. The reaction was carried out by heating the reactants in
ethanol for 15 min to enhance the solubility of compounds 5a,b. On
monitoring the reaction with thin layer chromatography (TLC), the
starting compounds 5a,b disappeared completely after 15 min
and the products were precipitated after addition of water to the
reaction mixture. The N-Mannich bases 5-(1-adamantyl)-4-(methyl
or 4-chlorophenyl)-2-(4-substituted-1-piperazinylmethyl)-1,2,4-tria
zoline-3-thiones 7aeg were similarly prepared via the reaction of
compounds 5a,b with the corresponding 1-substituted piperazine
* Corresponding author. Tel.: þ966 1 4677350; fax: þ966 1 4676220.
E-mail addresses: elemam5@hotmail.com, a_elemam2002@yahoo.com (A.A. El-
Emam).
0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.07.024

A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
97
and formaldehyde solution in 48e85% yields (Scheme 1, Table 1). The
structures of compounds 6aeo and 7aeg were confirmed by
elemental analyses in addition to the 1H NMR, 13C NMR, and ESI-MS
mass spectral data which were in full agreement with their struc-
tures, in addition to the X-ray spectra of compounds 7a [31] and
7b [32].
The results of the preliminary antimicrobial testing of com-
pounds 6aeo, 7aeg and 11aei (200 g/disc), the antibacterial an-
tibiotics Ampicillin trihydrate, Gentamicin (100 g/disc) and the
antifungal drug Clotrimazole (100 g/disc) and the calculated log P
m
m
m
values (Clog P) of the tested compounds (calculated using the CS
ChemOffice Ultra version 8.0, CambridgeSoft, Cambridge, MA, USA)
are shown in Table 2. The results revealed that the tested com-
pounds showed varying degrees of inhibition against the tested
microorganisms. In general, strong activity was displayed by the
compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f,
11h and 11i, which produced growth inhibition zones ꢀ18 mm
against one or more of the tested microorganisms. Meanwhile, the
compounds 6g, 6h, 6k, 7e and 11g showed moderate activity
(growth inhibition zones 14e17 mm), the compounds 6a, 6b, 6f, 6n
and 7g (growth inhibition zones 10e13 mm) and compounds 6c,
6d, 6e, 6i and 6o were practically inactive (growth inhibition zones
ꢁ10 mm) against the tested microorganisms. The Gram-positive
bacteria B. subtilis and to a lesser extent S. aureus and M. luteus
are considered the most sensitive among the tested microorgan-
isms. The activity against the tested Gram-negative bacteria was
generally lower than that against the Gram-positive bacteria,
compound 7c was strongly active against E. coli, while only
compound 7c was strongly active against P. aeuroginosa. The
inhibitory activity of the compounds against C. albicans was rather
lower than their antibacterial activity, only compound 6m exhibi-
ted marginal activity. The minimal inhibitory concentrations (MIC)
[37] for the most active compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a,
11b, 11c, 11d, 11e, 11f, 11h and 11i, which are shown in Table 2, were
in accordance with the results obtained in the primary.
5-(1-Adamantyl)-4-amino-1,2,4-triazoline-3-thione 9 was pre-
pared according to the previously reported method of El-Emam
et al. [33] via the condensation of adamantane-1-carbohydrazide
3 with carbon disulphide in ethanolic potassium hydroxide to
yield the corresponding potassium N0-(1-adamantylcarbonyl)
dithiocarbazate 8, which was subsequently heated with hydrazine
to yield the target compound 9 in good overall yield. Compound
9 was condensed with 2-hydroxybenzaldehyde or 4-hydroxy
benzaldehyde in ethanol by heating under reflux for 5 h to yield
the target arylideneamino derivatives 10a,b in 79% and 82% yields,
respectively [18]. The piperazinomethyl N-Mannich bases 11aei
were similarly prepared via the reaction of compounds 10a,b with
the corresponding 1-substituted piperazine and formaldehyde so-
lution in 38e85% yields (Scheme 2, Table 1). The structures of
compounds 11aei were confirmed by elemental analyses in addi-
tion to the 1H NMR, 13C NMR, and ESI-MS mass spectral data which
were in full agreement with their structures, in addition to the X-
ray spectra of compounds 11e [34] and 11f [35] which showed the
existence of the imine bond of these derivatives in the E (trans)
stereoisomers.
2.2. In vitro antimicrobial activity
In general, the antibacterial activity seemed to be dependent on
the nature of substituents rather than basic skeleton of the mole-
cules. Within the 5-(1-adamantyl)-4-(methyl or 4-chlorophenyl)-
2-arylaminomethyl-1,2,4-triazoline-3-thiones 6aeo (Table 2), it
was observed that the antibacterial activity is not dependent on the
lipophilicity, and the 4-methyl derivatives 6aed were generally
inactive as well as their corresponding 4-(4-chlorophenyl)
analogues 6e, 6g, 6i, and 6o. The substituents on the 2-
arylaminomethyl moiety greatly influenced the antimicrobial
The newly synthesized compounds 6aeo, 7aeg and 11aei were
tested for their in vitro growth inhibitory activity against the
standard strains of the Institute of fermentation of Osaka (IFO)
namely; Staphylococcus aureus IFO 3060, Bacillus subtilis IFO 3007,
Micrococcus luteus IFO 3232 (Gram-positive bacteria), Escherichia
coli IFO 3301, Pseudomonas aeuroginosa IFO 3448 (Gram-negative
bacteria), and the yeast-like pathogenic fungus Candida albicans IFO
0583. The primary screening was carried out using the agar disc-
diffusion method using MüllereHinton agar medium [36].
H
NH2NH2
CH3OH
COOH
N
O
NH2
CH3
H2SO4
O
O
3
1
2
RNCS/EtOH
N
NH
S
H
N
1. NaOH/H2O
2. HCl
R
N
N
R
S
N
H
H
4a,b
O
5a.b
A
r
N
H
HN N R'
/
C
2
H
E
2 O
t
O
CH2O/EtOH
H
R'
N
N
N R'
N
N
N
N
H
N
N
R
S
S
R
7a-g
6a-o
R = Me, 4-ClC6H4
Scheme 1. Synthesis of compounds 6aeo and 7aeg.

98
A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
Table 1
Recrystallization solvents, melting points, yield percentages, molecular formulae, molecular weights and microanalytical data of compounds 6aeo, 7aeg and 11aei.
Comp. no.
R
R0
Cryst. solvent
M.p. (ꢂC)
Yield (%)
Mol. formula (mol. wt.)
Analysis: % calcd. (found)
C
H
N
S
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
7a
7b
7c
7d
7e
7f
CH3
CH3
CH3
CH3
H
4-F
4-Br
4-OEt
H
2-F
4-F
2-Cl
4-Br
2-CF3
3-CF3
4-CF3
2,6-F2
3,5-Cl2
4-OEt
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
166e8
142e4
199e201
127e9
133e5
121e3
169e71
184e6
193e5
112e4
128e30
127e9
172e4
200e2
183e5
150e2
150e2
186e8
113e5
206e8
201e3
123e5
165e7
124e6
192e4
188e90
164e6
163e5
139e41
200e2
192e4
71
64
92
77
76
68
83
88
90
55
52
60
63
92
80
75
81
56
48
85
80
62
38
48
78
82
38
44
51
85
80
C20H26N4S (354.51)
C20H25FN4S (372.5)
67.76 (67.51)
64.49 (64.26)
55.42 (55.40)
66.30 (66.31)
66.57 (66.58)
64.02 (63.92)
64.02 (63.91)
61.85 (61.82)
56.66 (56.66)
60.17 (60.01)
60.17 (59.82)
60.17 (59.89)
61.66 (61.67)
57.75 (57.38)
65.50 (65.33)
68.05 (67.75)
66.19 (65.98)
61.08 (61.20)
63.60 (63.44)
66.97 (66.68)
65.49 (65.33)
67.46 (67.25)
64.97 (65.01)
61.81 (61.65)
68.15 (67.94)
66.64 (66.55)
68.60 (68.24)
64.97 (64.66)
61.81 (61.43)
68.15 (68.0)
7.39 (7.44)
6.76 (6.81)
5.81 (5.81)
7.59 (7.64)
6.03 (6.21)
5.59 (5.62)
5.59 (5.63)
5.40 (5.44)
4.95 (5.06)
5.05 (5.09)
5.05 (5.24)
5.05 (5.22)
5.17 (5.18)
4.85 (4.98)
6.31 (6.46)
7.85 (8.02)
7.78 (7.90)
6.56 (6.55)
7.26 (7.48)
6.59 (6.71)
6.60 (6.80)
6.79 (6.90)
7.55 (7.70)
6.92 (7.01)
6.86 (7.10)
6.86 (6.90)
7.06 (7.22)
7.55 (7.63)
6.92 (7.05)
6.86 (6.99)
6.86 (7.02)
15.80 (15.69)
15.04 (15.12)
12.93 (12.90)
14.06 (13.90)
12.42 (12.34)
11.95 (11.93)
11.95 (11.88)
11.54 (11.30)
10.57 (10.38)
10.79 (10.75)
10.79 (10.65)
10.79 (10.50)
11.50 (11.23)
10.78 (10.50)
11.32 (11.12)
16.53 (16.50)
15.44 (15.42)
14.25 (14.10)
14.83 (14.65)
13.46 (13.32)
12.73 (12.65)
13.11 (13.0)
17.48 (17.30)
16.02 (15.85)
15.90 (15.78)
15.04 (14.92)
15.48 (15.50)
17.48 (17.22)
16.02 (15.89)
15.90 (15.76)
15.04 (14.87)
9.04 (9.02)
8.61 (8.52)
7.40 (7.33)
8.05 (7.98)
7.11 (7.10)
6.84 (6.82)
6.84 (6.84)
6.60 (6.56)
6.05 (5.98)
6.18 (6.14)
6.18 (6.01)
6.18 (6.08)
6.58 (6.52)
6.17 (6.17)
6.48 (6.45)
7.57 (7.56)
7.07 (6.99)
6.52 (6.45)
6.79 (6.70)
6.16 (6.11)
5.83 (5.67)
6.00 (5.87)
6.67 (6.50)
6.11 (6.10)
6.06 (5.98)
5.74 (5.74)
5.91 (5.82)
6.67 (6.65)
6.11 (6.10)
6.06 (6.04)
5.74 (5.68)
C20H25BrN4S (433.41)
C22H30N4OS (398.56)
C25H27ClN4S (451.03)
C25H26ClFN4S (469.02)
C25H26ClFN4S (469.02)
C25H26Cl2N4S (485.47)
C25H26BrClN4S (529.92)
C26H26ClF3N4S (519.02)
C26H26ClF3N4S (519.02)
C26H26ClF3N4S (519.02)
C25H25ClF2N4S (487.01)
C25H25Cl3N4S (519.92)
C27H31ClN4OS (495.08)
C24H33N5S (423.62)
C25H35N5OS (453.64)
C25H32F3N5S (491.62)
C25H34ClN5S (472.09)
C29H34ClN5S (520.13)
C30H36ClN5OS (550.16)
C30H36ClN5S (534.16)
C26H36N6OS (480.67)
C27H36N6O3S (524.68)
C30H36N6OS (528.71)
C31H38N6O2S (558.74)
C31H38N6OS (542.74)
C26H36N6OS (480.67)
C27H36N6O3S (524.68)
C30H36N6OS (528.71)
C31H38N6O2S (558.74)
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
CH3
C6H5
CH3
CH3
2-CH3OC6H4
3-CF3C6H4
C2H5
EtOH
EtOH/H2O
EtOH/H2O
EtOH
EtOH
EtOH/H2O
EtOH
EtOH/H2O
EtOH
EtOH
EtOH/H2O
EtOH
EtOH/H2O
EtOH/CHCl3
EtOH/CHCl3
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-OH
2-OH
2-OH
2-OH
2-OH
4-OH
4-OH
4-OH
4-OH
C6H5
2-CH3OC6H4
CH2C6H5
C2H5
COOC2H5
C6H5
2-CH3OC6H4
CH2C6H5
C2H5
COOC2H5
C6H5
7g
11a
11b
11c
11d
11e
11f
11g
11h
11i
2-OCH3C6H4
66.64 (66.32)
activity, the trifluoromethylphenyl and the 2,6-difluorophenyl
substituents were optimistic within their 4-(4-chlorophenyl) de-
rivatives. Meanwhile, the 4-bromophenyl, 4-ethoxyphenyl and to a
lesser extent the 3,5-dichlorophenyl substituents were not favor-
able for antimicrobial activity.
known antibacterial drugs. Though, the active compounds are
considered as good candidates for newer antibacterial agents. The
mechanism of the biological activity needs further investigations,
which are in progress.
The replacement of the 2-arylaminomethyl moiety with a
4-substituted-1-piperazinylmethyl (compounds 7aeg) greatly
enhanced the antibacterial activity and in contrary to the arylami-
nomethyl derivatives 6aeo, the 4-methyl derivatives 7aec displayed
higher antibacterial activity than their 4-(4-chlorophenyl) analogues
despite their lower lipophilicity. In addition, the antibacterial activity
of the 4-phenylpiperazin-1-yl, 4-(2-methoxyphenyl)piperazin-1-yl
and 4-(3-trifluormethylphenyl)piperazin-1-yl derivatives were su-
perior to their 4-ethylpiperazin-1-yl and 4-benzylpiperazin-1-yl
analogues. In addition, the 3-trifluormethylphenyl analogue 7c dis-
played broad spectrum antibacterial activity against the tested
Gram-positive and Gram-negative bacteria.
The replacement of the methyl or 4-chlorophenyl substituents in
compounds 7aeg with 2- or 4-hydroxybenzylideneamino sub-
stituents (compounds 11aei) greatly enhanced the antibacterial ac-
tivity. It was observed that neither the position of the phenolic OH
group nor the lipophilicity of the compounds has influence on the
antibacterial activity. Although derivatives 11aei showed moderate
to good level of activity, a 4-ethoxycarbonylpiperazin-1-yl substitu-
ent is detrimental for antibacterial activityof this class of compounds.
4. Experimental protocols
Melting points (ꢂC) were measured in open glass capillaries
using a Branstead 9001 Electrothermal melting point apparatus
and are uncorrected. NMR spectra were obtained on a Bruker AC
500 Ultra Shield NMR spectrometer (Fällanden, Switzerland)
operating at 500.13 MHz for 1H and 125.76 MHz for 13C, the
chemical shifts are expressed in
d (ppm) downfield from tetrame-
thylsilane (TMS) as internal standard; coupling constants (J) are
expressed in Hertz. Electrospray ionization mass spectra (ESI-MS)
were recorded on an Agilent 6410 Triple Quad tandem mass
spectrometer at 4.0 and 3.5 kV for positive and negative ions,
respectively. Monitoring the reactions and checking the purity of
the final products were carried out by thin layer chromatography
(TLC) using silica gel precoated aluminium sheets (60 F254, Merck)
and visualization with ultraviolet light (UV) at 365 and 254 nm. The
bacterial strains and C. albicans fungus were obtained from the
Institute of Fermentation of Osaka (IFO), Osaka, Japan. The refer-
ence drugs Ampicillin trihydrate (CAS 7177-48-2) and Clotrimazole
(CAS 23593-75-1) were obtained from SigmaeAldrich Chemie
GmbH, Taufkirchen, Germany.
3. Conclusion
4.1. 5-(1-Adamantyl)-2-arylaminomethyl-4-(methyl or 4-
In this study, new N-Mannich bases of 5-(1-adamantyl)-4-
substituted-1,2,4-triazoline-3-thiones were synthesized and their
antimicrobial activity was determined. The newly synthesized
compounds 6j, 6l, 6m, 7a, 7b, 7c, 7d, 7f, 11a, 11b, 11c, 11d, 11e, 11f,
11h and 11i displayed promising antibacterial activity compared to
chlorophenyl)-1,2,4-triazoline-3-thiones (6aeo)
A mixture of 5a or 5b (1.0 mmol), the appropriate primary ar-
omatic amine (1.0 mmol) and 37% formaldehyde solution (1 mL), in
ethanol (8 mL), was heated under reflux for 15 min when a clear

A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
99
S
H
N
CS2 / KOH
EtOH, r.t.
H
N
S- K+
NH2
N
H
O
O
8
3
NH2NH2
N
NH
N
N
S
NH
ArCHO/EtOH
N
10a,b
N
S
H2N
9
R
N
R'
N
N
H
N
N R'
N
N
S
N
11a-i
R = 2-OH, 4-OH
R
Scheme 2. Synthesis of compounds 11aei.
solution was obtained. Stirring was continued for 12 h at room
temperature and the mixture was allowed to stand overnight. Cold
water (5 mL) was added and the reaction mixture was stirred for
20 min. The precipitated crude products were filtered, washed with
water, dried, and recrystallized from ethanol. 6a: 1H NMR (CDCl3):
(s, 1H, NH), 6.11 (s, 2H, CH2), 6.78 (d, 2H, AreH, J ¼ 7.0 Hz), 6.89 (d,
2H, AreH, J ¼ 7.0 Hz). 13C NMR:
d 15.17 (CH2CH3), 27.83, 33.70,
35.20, 38.94 (AdamantaneeC), 33.60 (CH3), 63.80 (CH2CH3), 64.49
(CH2), 115.37, 116.71, 139.15, 141.06 (AreC), 156.63 (Triazole C-5),
167.88 (C]S). ESI-MS, m/z (Rel. Int.): 399.1 (M þ H, 100)þ. 6e: 1H
d
1.67e1.78 (m, 6H, AdamantaneeH), 2.04e2.25 (m, 9H, Ada-
NMR (CDCl3): d 1.68e1.70 (m, 6H, AdamantaneeH), 1.86 (s, 6H,
mantaneeH), 3.79 (s, 3H, CH3), 5.89 (s, 1H, NH), 6.18 (s, 2H, CH2),
AdamantaneeH),1.97 (s, 3H, AdamantaneeH), 5.83 (s,1H, NH), 6.27
(s, 2H, CH2), 6.75e6.86 (m, 2H, AreH), 7.19e7.41 (m, 5H, AreH),
6.78e6.96 (m, 3H, AreH), 7.20 (t, 2H, AreH, J ¼ 7.0 Hz). 13C NMR:
d
27.82, 33.62, 35.16, 38.93 (AdamantaneeC), 33.50 (CH3), 65.0
7.54e7.64 (m, 2H, AreH). 13C NMR:
d 27.72, 33.62, 36.06, 39.88
(CH2), 114.25, 119.11, 129.21, 145.04 (AreC), 156.71 (Triazole C-5),
167.95 (C]S). ESI-MS, m/z (Rel. Int.): 355.2 (M þ H, 100)þ. 6b: 1H
(AdamantaneeC), 65.14 (CH2), 114.41, 114.93, 129.19, 129.93, 131.13,
134.80, 136.30, 146.51 (AreC), 156.89 (Triazole C-5), 169.62 (C]S).
ESI-MS, m/z (Rel. Int.): 453.1 (M þ H þ 2, 29)þ, 451.1 (M þ H, 100)þ.
NMR (CDCl3):
d 1.75e1.83 (m, 6H, AdamantaneeH), 2.05 (s, 6H,
AdamantaneeH), 2.18 (s, 3H, AdamantaneeH), 3.79 (s, 3H, CH3),
6f: 1H NMR (CDCl3):
d 1.74e1.86 (m, 9H, AdamantaneeH), 1.96 (s,
5.74 (s, 1H, NH), 6.12 (s, 2H, CH2), 6.96e7.09 (m, 4H, AreH). 13C
6H, AdamantaneeH), 6.02 (s, 1H, NH), 6.24 (s, 2H, CH2), 6.94e7.24
NMR:
d
27.80, 33.65, 36.28, 38.93 (AdamantaneeC), 33.50 (CH3),
(m, 5H, AreH), 7.36e7.56 (m, 3H, AreH). 13C NMR:
d
27.76, 36.46,
65.37 (CH2), 115.52, 115.71, 140.0, 156.50 (AreC), 156.79 (Triazole C-
39.22, 39.82 (AdamantaneeC), 68.42 (CH2), 115.28, 115.90, 117.28,
125.30, 128.24, 129.95, 131.0, 132.22, 134.20, 155.82 (AreH), 157.22
(Triazole C-5), 170.10 (C]S). ESI-MS, m/z (Rel. Int.): 471.2
5), 168.0 (C]S). ESI-MS, m/z (Rel. Int.): 373.2 (M þ H, 100)þ. 6c: 1H
NMR (CDCl3):
d 1.75e1.83 (m, 6H, AdamantaneeH), 2.04 (s, 6H,
AdamantaneeH), 2.12 (s, 3H, AdamantaneeH), 3.77 (s, 3H, CH3),
5.76 (s, 1H, NH), 6.12 (s, 2H, CH2), 7.26 (d, 2H, AreH, J ¼ 7.5 Hz), 7.40
(M þ H þ 2, 29)þ, 469.2 (M þ H, 100)þ. 6g: 1H NMR (CDCl3):
d 1.82e
1.85 (m, 9H, AdamantaneeH), 1.97 (s, 6H, AdamantaneeH), 5.82 (s,
1H, NH), 6.21 (s, 2H, CH2), 6.94e7.05 (m, 3H, AreH), 7.21e7.25 (m,
(d, 2H, AreH, J ¼ 7.5 Hz). 13C NMR:
d 27.80, 33.69, 35.78, 38.91
(AdamantaneeC), 33.69 (CH3), 64.98 (CH2), 112.24, 116.74, 131.79,
145.62 (AreC),156.82 (Triazole C-5),168.14 (C]S). ESI-MS, m/z (Rel.
Int.): 434.1 (M þ H þ 2, 98)þ, 432.1 (M þ H, 100)þ. 6d: 1H NMR
2H, AreH), 7.54e7.56 (m, 3H, AreH). 13C NMR:
d 27.70, 36.04, 39.84,
39.88 (AdamantaneeC), 65.47 (CH2), 115.79, 116.53, 129.95, 131.09,
134.75, 136.34, 143.0, 156.84 (AreH), 157.0 (Triazole C-5), 169.69
(C]S). ESI-MS, m/z (Rel. Int.): 471.2 (M þ H þ 2, 34)þ, 469.2 (M þ H,
(CDCl3):
d
1.54 (t, 3H, CH2CH3, J ¼ 7.5 Hz), 1.75e1.84 (m, 6H, Ada-
mantaneeH), 2.05 (s, 6H, AdamantaneeH), 2.17 (s, 3H, Ada-
mantaneeH), 3.81 (s, 3H, CH3), 4.07 (q, 2H, CH2CH3, J ¼ 7.5 Hz), 5.73
100)þ. 6h: 1H NMR (CDCl3):
d 1.83e1.87 (m, 9H, AdamantaneeH),
1.97 (s, 6H, AdamantaneeH), 5.64e5.67 (m, 3H, CH2 & NH), 6.76 (t,

100
A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
Table 2
131.01, 133.55, 134.70, 136.14, 150.87, 152.78 (AreC & CF3), 156.66
(Triazole C-5), 169.61 (C]S). ESI-MS, m/z (Rel. Int.): 521.2
Antimicrobial activity of compounds 6aeo, 7aeg and 11aei (200
broad spectrum antibacterial drugs Gentamicin (100 g/8 mm disc), Ampicillin
(100 g/8 mm disc) and the antifungal drug Clotrimazole (100 g/8 mm disc) against
mg/8 mm disc), the
m
(M þ H þ 2, 30)þ, 519.2 (M þ H, 100)þ. 6l: 1H NMR (CDCl3):
d 1.77e
m
m
1.86 (m, 9H, AdamantaneeH), 1.97 (s, 6H, AdamantaneeH), 5.84 (s,
2H, CH2), 6.24 (s, 1H, NH), 7.21e7.25 (m, 4H, AreH), 7.55e7.65 (m,
Staphylococcus aureus IFO 3060 (SA), Bacillus subtilis IFO 3007 (BS), Micrococcus
luteus IFO 3232 (ML), Escherichia coli IFO 3301 (EC), Pseudomonas aeuroginosa IFO
3448 (PA), and Candida albicans IFO 0583 (CA).
4H, AreH), 13C NMR:
d 27.68, 36.02, 36.09, 39.86 (AdamantaneeC),
Comp. Clog P Diameter of growth inhibition zone (mm)a
no.
64.94 (CH2), 114.14, 114.42, 126.44, 129.98, 131.06, 134.67, 136.42,
147.91,149.06 (AreC & CF3),157.16 (Triazole C-5),169.92 (C]S). ESI-
MS, m/z (Rel. Int.): 521.2 (M þ H þ 2, 38)þ, 519.2 (M þ H, 100)þ. 6m:
SA
BS
ML
EC
PA
CA
1H NMR (CDCl3):
d 1.66e1.82 (m, 9H, AdamantaneeH), 1.87e2.04
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
7a
7b
7c
7d
7e
7f
4.88
5.33
6.05
5.51
7.65
8.09
8.09
8.66
8.81
9.06
9.06
9.06
8.34
9.48
8.28
5.14
5.05
6.32
6.20
7.91
7.82
8.83
4.97
6.51
6.67
6.58
7.59
4.97
6.51
6.67
6.58
e
12
12
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
13
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
12
e
e
e
(m, 6H, AdamantaneeH), 5.72 (s, 2H, CH2), 5.80 (s, 1H, NH), 6.71e
6.91 (m, 2H, AreH), 7.17e7.35 (m, 3H, AreH), 7.49e7.68 (m, 2H, Are
e
e
e
e
e
e
H). 13C NMR:
d 27.73, 35.81, 36.02, 39.81 (AdamantaneeC), 66.38
e
e
e
e
11
14
16
e
12
16
11
e
12
12
e
e
(CH2), 111.91, 121.0, 129.90, 130.95, 131.14, 135.16, 136.12, 156.65
(AreC), 156.11 (Triazole C-5), 169.65 (C]S). ESI-MS, m/z (Rel. Int.):
489.2 (M þ H þ 2, 37)þ, 487.2 (M þ H, 100)þ. 6n: 1H NMR (CDCl3):
e
e
e
e
17
16
16
18
12
e
19 (16)b 14
11
e
d
1.68e1.87 (m, 9H, AdamantaneeH), 1.98e2.04 (m, 6H, Ada-
16
17
mantaneeH), 5.75 (s, 2H, CH2), 6.21 (s, 1H, NH), 6.87e6.99 (m, 1H,
22 (8)b
20 (8)b
13
18 (16)b 14
11
11
AreH), 7.20e7.29 (m, 4H, AreH), 7.54e7.56 (m, 2H, AreH). 13C
17
11
e
14
e
NMR:
d 27.71, 36.04, 39.84, 39.89 (AdamantaneeC), 65.51 (CH2),
e
113.73, 119.75, 129.98, 131.03, 135.25, 136.38, 147.17, 148.63 (AreC),
156.89 (Triazole C-5), 170.20 (C]S). ESI-MS, m/z (Rel. Int.): 523.1
(M þ H þ 4, 34)þ, 521.1 (M þ H þ 2, 89)þ, 519.1 (M þ H, 100)þ. 6o:
e
e
e
19 (8)b
18 (16)b 14
e
e
e
22 (4)b
20 (4)b
19 (16)b 11
30 (0.5)b 33 (0.5)b 28 (4)b
19 (16)b 21 (8)b
1H NMR (CDCl3):
d
1.42 (t, 3H, CH2CH3, J ¼ 7.5 Hz), 1.80e1.84 (m, 9H,
14
16
18 (8)b
17
15
14
e
e
e
e
16
e
e
AdamantaneeH), 1.95 (s, 6H, AdamantaneeH), 4.0 (q, 2H, CH2CH3,
J ¼ 7.5 Hz), 5.77 (s, 1H, NH), 6.19 (s, 2H, CH2), 6.81e7.05 (m, 2H, Are
H), 7.20e7.32 (m, 3H, AreH), 7.52e7.55 (m, 3H, AreH). 13C NMR:
e
18 (16)b 18 (16)b 16
e
7g
11
12
11
e
11a
11b
11c
11d
11e
11f
11g
11h
11i
26 (1)b
18 (4)b
22 (8)b
30 (0.5)b 24 (2)b
11
e
d
14.99 (CH2CH3), 27.71, 35.92, 36.02, 39.84 (AdamantaneeC), 63.87
19 (4)b
25 (4)b
16
(CH2CH3), 65.80 (CH2), 115.39, 115.88, 116.71, 129.90, 131.14, 134.38,
134.88, 152.86 (AreC), 157.05 (Triazole C-5), 169.52 (C]S). ESI-MS,
m/z (Rel. Int.): 497.2 (M þ H þ 2, 30)þ, 495.2 (M þ H, 100)þ.
18 (16)b 14
12
12
11
13
e
28 (0.5)b 33 (0.5)b 25 (2)b
18 (8)b
11
19 (2)b
30 (1)b
17
21 (2)b
29 (1)b
16
17
25 (2)b
14
17
e
4.2. 5-(1-Adamantyl)-4-(methyl or 4-chlorophenyl)-2-(4-
substituted-1-piperazinylmethyl)-1,2,4-triazoline-3-thiones (7aeg)
22 (4)b
30 (1)b
26 (2)b
23 (2)b
NT
22 (4)b
29 (1)b
25 (2)b
19 (16)b 16
18 (16)b 16
e
14
Gentamicin
Ampicillin
Clotrimazole
18 (2)b
20 (0.5)b 19 (1)b NT
21 (0.5)b 19 (2)b
17 (2)b
NT
16 (2)b NT
NT
21 (2)b
A mixture of 5a or 5b (1.0 mmol), the appropriate N-substituted
piperazine (1.0 mmol) and 37% formaldehyde solution (1.0 mL), in
ethanol (8 mL), was heated under reflux for 15 min when a clear
solution was obtained. Stirring was continued for 12 h at room
temperature and the mixture was allowed to stand overnight. Cold
water (5 mL) was added and the reaction mixture was stirred for
20 min. The precipitated crude products were filtered, washed
with water, dried, and recrystallized from ethanol or aqueous
NT
NT
a
(ꢃ): Inactive (inhibition zone <10 mm). (NT): Not tested.
b
The figures shown in parentheses represent the MIC values (mg/mL).
1H, AreH, J ¼ 7.0 Hz), 7.21e7.24 (m, 3H, AreH), 7.29e7.31 (m, 1H,
AreH), 7.37e7.44 (m,1H, AreH), 7.47e7.54 (m, 2H, AreH). 13C NMR:
d
27.71, 36.04, 39.88, 39.90 (AdamantaneeC), 67.78 (CH2), 113.50,
119.37, 120.17, 127.82, 129.38, 129.92, 131.03, 134.70, 136.32, 141.43
(AreH), 156.680 (Triazole C-5), 169.65 (C]S). ESI-MS, m/z (Rel.
Int.): 487.2 (M þ H þ 2, 71)þ, 485.2 (Mþ, 100). 6i: 1H NMR (CDCl3):
ethanol. 7a [31]: 1H NMR (CDCl3):
d 1.77e1.84 (m, 6H, Ada-
mantaneeH), 2.14 (s, 6H, AdamantaneeH), 2.27 (s, 3H, Ada-
mantaneeH), 3.05 (s, 4H, PiperazineeH), 3.27 (s, 4H, Piperazinee
H), 3.82 (s, 3H, CH3), 5.20 (s, 2H, CH2), 6.85e6.93 (m, 3H, AreH),
d
1.77e1.85 (m, 9H, AdamantaneeH), 1.97 (s, 6H, AdamantaneeH),
5.85 (s, 1H, NH), 6.22 (s, 2H, CH2), 7.21e7.25 (m, 4H, AreH), 7.51e
7.25e7.33 (m, 2H, AreH). 13C NMR:
d 27.84, 33.97, 36.31, 39.02
7.56 (m, 4H, AreH). 13C NMR:
d
27.70, 36.03, 39.83, 39.87 (Ada-
(AdamantaneeC), 31.58 (CH3), 49.34, 50.40 (PiperazineeC), 69.23
(CH2), 116.27, 119.86, 129.10, 151.33 (AreC), 156.31 (Triazole C-5),
169.53 (C]S). ESI-MS, m/z (Rel. Int.): 424.2 (M þ H, 100)þ. 7b [32]:
mantaneeC), 65.15 (CH2), 116.32, 116.77, 129.96, 131.08, 131.89,
134.72, 136.37, 145.58 (AreC), 157.03 (Triazole C-5), 169.79 (C]S).
ESI-MS, m/z (Rel. Int.): 533.1 (M þ H þ 2, 28)þ, 531.1 (M þ H, 100)þ.
1H NMR (CDCl3):
d 1.52e1.71 (m, 6H, AdamantaneeH), 2.0 (s, 6H,
6j: 1H NMR (CDCl3):
d
1.73e1.77 (m, 9H, AdamantaneeH), 1.86e
AdamantaneeH), 2.04 (s, 3H, AdamantaneeH), 3.03e3.07 (m, 8H,
PiperazineeH), 3.71 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 5.27 (s, 2H,
CH2), 6.76e6.77 (m, 1H, AreH), 6.84e6.92 (m, 3H, AreH). 13C NMR:
1.94 (m, 6H, AdamantaneeH), 5.54e5.62 (m, 3H, CH2 & NH), 6.78e
6.81 (m, 1H, AreH), 6.95e7.14 (m, 3H, AreH), 7.32e7.47 (m, 4H, Are
H). 13C NMR:
d
27.69, 29.71, 36.03, 39.88 (AdamantaneeC), 57.71
d 27.85, 35.07, 36.33, 38.96 (AdamantaneeC), 33.95 (CH3), 50.55,
(CH2), 114.28, 115.20, 118.32, 125.88, 126.68, 129.93, 131.0, 133.22,
134.64, 136.34, 143.08 (AreC & CF3), 156.84 (Triazole C-5), 169.77
(C]S). ESI-MS, m/z (Rel. Int.): 521.2 (M þ H þ 2, 33)þ, 519.2 (M þ H,
50.79 (PiperazineeC), 55.23 (OCH3), 69.40 (CH2), 110.90, 118.24,
120.91, 123.03, 141.24, 152.17 (AreC), 156.20 (Triazole C-5), 169.50
(C]S). ESI-MS, m/z (Rel. Int.): 454.2 (M þ H, 100)þ. 7c: 1H NMR
100)þ. 6k: 1H NMR (CDCl3):
d
1.67e1.70 (m, 3H, AdamantaneeH),
(CDCl3): d 1.76e1.84 (m, 6H, AdamantaneeH), 2.07 (s, 6H, Ada-
1.78e1.83 (m, 6H, AdamantaneeH), 1.95e1.97 (m, 6H, Ada-
mantaneeH), 5.64e5.84 (m, 3H, CH2 & NH), 6.77e6.79 (m, 1H, Are
H), 7.01e7.19 (s, 3H, AreH), 7.20 (d, 2H, AreH, J ¼ 8.5 Hz), 7.53 (d,
mantaneeH), 2.13 (s, 3H, AdamantaneeH), 2.98 (s, 4H, Pipera-
zineeH), 3.24 (s, 4H, PiperazineeH), 3.80 (s, 3H, CH3), 5.19 (s, 2H,
CH2), 7.03e7.10 (m, 3H, AreH), 7.32e7.35 (m, 1H, AreH). 13C NMR:
2H, AreH, J ¼ 8.5 Hz). 13C NMR:
d
27.71, 28.98, 36.04, 39.90 (Ada-
d
27.82, 35.10, 36.29, 39.02 (AdamantaneeC), 33.98 (CH3), 48.79,
mantaneeC), 57.86 (CH2), 114.36, 114.75, 114.75, 118.88, 129.71,
50.21 (PiperazineeC), 69.15 (CH2), 112.33, 115.89, 118.83, 123.21,

A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
101
125.38, 129.54, 151.38 (AreC & CF3), 156.38 (Triazole C-5), 169.58
(C]S). ESI-MS, m/z (Rel. Int.): 492.2 (M þ H, 100)þ. 7d: 1H NMR
d 14.48 (CH3), 27.18, 34.71, 35.92, 38.06 (AdamantaneeC), 49.76,
56.0 (PiperazineeC), 60.66 (CH2CH3), 68.63 (CH2), 116.76, 118.27,
119.77, 126.64, 134.43, 158.57 (AreC), 154.50 (Triazole C-5), 154.29
(C]O), 162.05 (C]S), 162.86 (CH]N). ESI-MS, m/z (Rel. Int.): 548.3
(M þ H þ Na, 100), 525.3 (M þ H, 6)þ. 11c: 1H NMR (DMSO-d6):
(CDCl3):
d
1.16 (t, 3H, CH3, J ¼ 7.0 Hz),
d 1.76e1.88 (m, 6H, Ada-
mantaneeH), 2.07 (s, 6H, AdamantaneeH), 2.02 (s, 3H, Ada-
mantaneeH), 2.50 (q, 2H, CH2CH3, J ¼ 7.0 Hz), 2.68e3.02 (m, 8H,
PiperazineeH), 5.10 (s, 2H, CH2), 6.88 (d, 2H, AreH, J ¼ 8.0 Hz), 7.34
d
1.69e1.70 (m, 6H, AdamantaneeH), 2.02 (s, 3H, AdamantaneeH),
(d, 2H, AreH, J ¼ 8.0 Hz). 13C NMR:
d
12.10 (CH3), 27.87, 34.69,
2.08 (s, 6H, AdamantaneeH), 2.51 (s, 4H, PiperazineeH), 3.13 (s, 4H,
PiperazineeH), 5.14 (s, 2H, CH2), 6.75e6.78 (m, 1H, AreH), 6.91e
7.03 (m, 5H, AreH & OH), 7.18e7.21 (m, 2H, AreH), 7.44e7.46 (m,
1H, AreH), 7.93e7.95 (m, 1H, AreH), 9.86 (s, 1H, CH]N). 13C NMR:
36.50, 38.09 (AdamantaneeC), 49.44 (CH2CH3), 54.30, 56.36
(PiperazineeC), 68.06 (CH2), 119.52, 128.40, 130.88, 133.0 (AreC),
156.04 (Triazole C-5), 165.66 (C]S). ESI-MS, m/z (Rel. Int.): 474.3
(M þ H þ 2, 38)þ, 472.3 (M þ H, 100)þ. 7e: 1H NMR (CDCl3):
d
1.76e
d 27.10, 34.72, 35.91, 38.08 (AdamantaneeC), 48.24, 49.87 (Pipera-
1.84 (m, 6H, AdamantaneeH), 2.04 (s, 6H, AdamantaneeH), 2.22 (s,
3H, AdamantaneeH), 2.98 (s, 4H, PiperazineeH), 3.02 (s, 4H,
PiperazineeH), 5.22 (s, 3H, CH2), 6.75e6.89 (m, 4H, AreH), 6.90e
zineeC), 68.48 (CH2), 115.53, 116.77, 118.27, 118.90, 119.81, 126.64,
128.84, 134.48, 150.96, 162.04 (AreC), 154.28 (Triazole C-5), 158.58
(C]S), 162.85 (CH]N). ESI-MS, m/z (Rel. Int.): 552.3 (M þ H þ Na,
7.02 (m, 3H, AreH), 7.36 (d, 2H, AreH, J ¼ 7.5 Hz). 13C NMR:
d
27.66,
100)þ, 529.2 (M þ H, 11)þ. 11d: 1H NMR (CDCl3):
d 1.79 (s, 6H,
33.56, 35.32, 38.82 (AdamantaneeC), 50.22, 50.68 (PiperazineeC),
69.80 (CH2), 113.92, 117.80, 127.50, 129.30, 129.92, 131.08, 133.90,
150.20 (AreC), 157.01 (Triazole C-5), 170.25 (C]S). ESI-MS, m/z
(Rel. Int.): 522.3 (M þ H þ 2, 39)þ, 520.3 (M þ H, 100)þ. 7f: 1H NMR
AdamantaneeH), 2.13 (s, 9H, AdamantaneeH), 3.11 (s, 8H, Pipera-
zineeH), 3.88 (s, 3H, OCH3), 5.26 (s, 2H, CH2), 6.87e6.89 (m,1H, Are
H), 6.95e7.11 (m, 5H, AreH), 7.45e7.51 (m, 2H, AreH), 9.64 (s, 1H,
CH]N), 10.48 (s, 1H, OH). 13C NMR:
d 27.79, 35.34, 36.30, 38.87
(CDCl3):
d
1.57e1.70 (m, 6H, AdamantaneeH), 1.87 (s, 6H, Ada-
(AdamantaneeC), 50.66, 50.82 (PiperazineeC), 55.28 (OCH3), 69.76
(CH2), 110.91, 116.09, 117.56, 118.29, 120.12, 120.94, 123.15, 133.65,
134.67, 141.18, 152.19, 160.11 (AreC), 154.29 (Triazole C-5), 164.16
(C]S), 169.37 (CH]N). ESI-MS, m/z (Rel. Int.): 582.5 (M þ H þ Na,
mantaneeH), 1.97 (s, 3H, AdamantaneeH), 3.12 (s, 8H, Piperazinee
H), 3.88 (s, 3H, OCH3), 5.26 (s, 2H, CH2), 6.65e7.03 (m, 4H, AreH),
7.22e7.29 (m, 2H, AreH), 7.54e7.56 (m, 2H, AreH). 13C NMR:
d
27.75, 35.88, 36.09, 38.92 (AdamantaneeC), 50.58, 50.85 (Piper-
100)þ, 559.4 (M þ H, 6)þ. 11e [34]: 1H NMR (DMSO-d6):
d 1.71 (br. s,
azineeC), 55.25 (OCH3), 69.63 (CH2), 110.22, 118.27, 120.94, 123.18,
129.90, 130.88, 131.11, 135.22, 136.20, 141.16 (AreC), 152.14 (Tri-
azole C-5), 171.20 (C]S). ESI-MS, m/z (Rel. Int.): 552.3 (M þ H þ 2,
6H, AdamantaneeH), 2.04 (s, 3H, AdamantaneeH), 2.09 (s, 6H,
AdamantaneeH), 2.37 (br. s, 4H, PiperazineeH), 2.72 (s, 4H, Piper-
azineeH), 3.49 (s, 2H, PhCH2), 5.16 (s, 2H, CH2), 6.98e7.03 (m, 2H,
AreH), 7.23e7.32 (m, 5H, AreH), 7.44e7.47 (m, 2H, AreH), 9.85 (s,
34)þ, 550.3 (M þ H, 100)þ. 7g: 1H NMR (CDCl3):
d 1.70e1.77 (m, 6H,
AdamantaneeH), 1.98 (s, 6H, AdamantaneeH), 2.02 (s, 3H, Ada-
mantaneeH), 2.88 (s, 4H, PiperazineeH), 2.98 (s, 4H, Piperazinee
H), 3.56 (s, 2H, PhCH2), 5.04 (s, 2H, CH2), 6.88e7.42 (m, 5H, AreH),
1H, CH]N), 10.50 (br. s, 1H, OH). 13C NMR:
d 27.18, 34.73, 35.92,
38.10 (AdamantaneeC), 49.93, 52.47 (PiperazineeC), 62.08
(PhCH2), 68.69 (CH2), 116.77, 118.28, 119.80, 126.68, 126.85, 128.09,
128.82, 134.44, 138.01, 158.56 (AreC), 154.20 (Triazole C-5), 162.01
(C]S), 162.85 (CH]N). ESI-MS, m/z (Rel. Int.): 566.5 (M þ H þ Na,
7.56e7.68 (m, 4H, AreH). 13C NMR:
d 27.88, 35.68, 35.02, 38.98
(AdamantaneeC), 48.90, 52.05 (PiperazineeC), 61.98 (PhCH2),
70.88 (CH2), 126.80, 127.32, 127.98, 129.22, 129.89, 130.20, 132.02,
136.02 (AreC), 153.04 (Triazole C-5), 171.28 (C]S). ESI-MS, m/z
(Rel. Int.): 536.2 (M þ H þ 2, 33)þ, 534.2 (M þ H, 100)þ.
19)þ, 543.5 (M þ H, 100)þ. 11f [35]: 1H NMR (CDCl3):
d 1.18 (t, 3H,
CH3, J ¼ 6.5 Hz), 1.69e1.76 (m, 6H, AdamantaneeH), 1.95 (s, 6H,
AdamantaneeH), 2.03 (s, 3H, AdamantaneeH), 2.56 (q, 2H, CH2CH3,
J ¼ 6.5 Hz), 2.85e3.90 (m, 8H, PiperazineeH), 5.18 (s, 2H, CH2), 6.75
(d, 2H, AreH, J ¼ 8.0 Hz), 7.67 (d, 2H, AreH, J ¼ 8.0 Hz), 9.21 (s, 1H,
4.3. 5-(1-Adamantyl)-4-[E-(2- or 4-hydroxybenzylideneamino)]-2-
(4-substituted-1-piperazinylmethyl)-1,2,4-triazoline-3-thiones
(11aei)
CH]N). 13C NMR:
d 11.11 (CH3), 27.84, 35.09, 36.48, 38.39 (Ada-
mantaneeC), 49.50 (CH2CH3), 52.29, 58.43 (PiperazineeC), 68.56
(CH2), 116.53, 123.49, 130.87, 161.53 (AreC), 154.94 (Triazole C-5),
163.34 (C]S), 164.65 (CH]N). ESI-MS, m/z (Rel. Int.): 504.1
A mixture of 10a or 10b (1.0 mmol), the appropriate N-
substituted piperazine (1.0 mmol) and 37% formaldehyde solution
(1 mL), in ethanol (8 mL), was heated under reflux for 15 min when
a clear solution was obtained. Stirring was continued for 12 h at
room temperature and the mixture was allowed to stand overnight.
Cold water (5 mL) was added and the reaction mixture was stirred
for 20 min. The precipitated crude products were filtered, washed
with water, dried, and recrystallized from ethanol or aqueous
(M þ H þ Na, 100)þ, 481.1 (M þ H, 5)þ. 11g: 1H NMR (CDCl3):
d 1.26
(t, 3H, CH3, J ¼ 7.0 Hz), 1.77 (s, 6H, AdamantaneeH), 2.08 (s, 6H,
AdamantaneeH), 2.14 (s, 3H, AdamantaneeH), 2.84 (s, 4H, Pipera-
zineeH), 3.53 (s, 4H, PiperazineeH), 4.15 (q, 2H, CH2CH3, J ¼ 7.0 Hz),
5.18 (s, 2H, CH2), 6.96 (d, 2H, AreH, J ¼ 8.0 Hz), 7.75 (d, 2H, AreH,
J ¼ 8.0 Hz), 9.58 (s, 1H, CH]N). 13C NMR:
d 14.62 (CH3), 27.85, 35.36,
36.50, 38.60 (AdamantaneeC), 43.67, 50.32 (PiperazineeC), 58.56
(CH2CH3), 69.20 (CH2),116.23,124.48,130.95,160.65 (AreC),155.50,
155.76 (C]O & Triazole C-5), 163.18 (C]S), 164.16 (CH]N). ESI-MS,
m/z (Rel. Int.): 547.3 (M þ H þ Na, 100)þ, 525.3 (M þ H, 2)þ. 11h: 1H
ethanol. 11a: 1H NMR (DMSO-d6):
d
0.95 (t, 3H, CH3, J ¼ 7.0 Hz),
1.70e1.72 (m, 6H, AdamantaneeH), 2.03 (s, 3H, AdamantaneeH),
2.09 (s, 6H, AdamantaneeH), 2.32e2.38 (m, 6H, PiperazineeH &
CH2CH3), 2.72e2.75 (m, 4H, PiperazineeH), 5.05 (s, 2H, CH2), 6.98e
7.03 (m, 2H, AreH), 7.44e7.47 (m, 1H, AreH), 7.92e7.94 (m, 1H, Are
NMR (CDCl3):
d 1.78 (s, 6H, AdamantaneeH), 2.09 (s, 6H, Ada-
mantaneeH), 2.14 (s, 3H, AdamantaneeH), 3.08 (s, 4H, Piperazinee
H), 3.25 (s, 4H, PiperazineeH), 5.25 (s, 2H, CH2), 6.90e6.98 (m, 6H,
AreH & OH), 7.28e7.31 (m, 2H, AreH), 7.72 (d, 2H, AreH,
H), 9.85 (s, 1H, CH]N), 10.50 (br. s, 1H, OH). 13C NMR:
d 11.78 (CH3),
27.19, 34.72, 35.93, 38.11 (AdamantaneeC), 49.77 (CH2CH3), 51.54,
52.15 (PiperazineeC), 68.54 (CH2), 116.77, 118.28, 119.78, 126.64,
134.44, 158.58 (AreC), 154.18 (Triazole C-5), 162.0 (C]S), 162.80
(CH]N). ESI-MS, m/z (Rel. Int.): 504.1 (M þ H þ Na, 100)þ, 481.1
J ¼ 8.0 Hz), 9.52 (s,1H, CH]N). 13C NMR:
d 27.86, 35.38, 36.52, 38.62
(AdamantaneeC), 49.50, 50.53 (PiperazineeC), 69.10 (CH2), 116.28,
116.56, 120.28, 124.70, 129.18, 130.97, 151.22, 160.20 (AreC), 155.47
(Triazole C-5),163.07 (C]S), 164.42 (CH]N). ESI-MS, m/z (Rel. Int.):
552.3 (M þ H þ Na, 100)þ, 529.2 (M þ H, 4)þ. 11i: 1H NMR (CDCl3):
(M þ H, 14)þ. 11b: 1H NMR (DMSO-d6):
1.14 (t, 3H, CH3, J ¼ 7.0 Hz),
d
1.69e1.70 (m, 6H, AdamantaneeH), 2.02 (s, 3H, AdamantaneeH),
2.08 (s, 6H, AdamantaneeH), 2.69 (s, 4H, PiperazineeH), 3.36 (s, 4H,
PiperazineeH), 3.99 (q, 2H, CH2CH3, J ¼ 7.0 Hz), 5.09 (s, 2H, CH2),
6.97e7.03 (m, 2H, AreH), 7.43e7.47 (m, 1H, AreH), 7.92 (d, 1H, Are
H, J ¼ 6.5 Hz), 9.85 (s, 1H, CH]N), 10.50 (br. s, 1H, OH). 13C NMR:
d
1.74 (s, 6H, AdamantaneeH), 1.96 (s, 3H, AdamantaneeH), 2.04 (s,
6H, AdamantaneeH), 2.92 (s, 4H, PiperazineeH), 3.06 (s, 4H,
PiperazineeH), 3.75 (s, 3H, OCH3), 5.02 (s, 2H, CH2), 6.68e7.04 (m,
5H, AreH & OH), 7.22e7.28 (m, 2H, AreH), 7.68 (d, 2H, AreH,

102
A.A. El-Emam et al. / European Journal of Medicinal Chemistry 68 (2013) 96e102
J ¼ 8.0 Hz), 9.56 (s,1H, CH]N). 13C NMR:
d 27.66, 35.38, 36.50, 38.96
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ꢀ
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Acknowledgements
The authors would like to extend their appreciation to the
Deanship of Scientific Research at King Saud University for funding
this research through the research group project No. RGP-VPP-274.
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