Synthesis, antimicrobial, and anti-inflammatory activities of novel 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles

Article abstract of DOI:10.1016/j.ejmech.2006.10.003

Reaction of 1-adamantanecarbonyl chloride with certain carboxylic acid hydrazides in pyridine yielded the corresponding N-acyl adamantane-1-carbohydrazide derivatives 3a-j, which were cyclized to the corresponding 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles 4a-j via heating with phosphorus oxychloride. Treatment of 1-adamantylisothiocyanate with some carboxylic acid hydrazides in ethanol yielded the corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides 7a-g, which were cyclized to the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazole derivatives 8a-g. Compounds 4a-j, 7a-g, and 8a-g were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or moderate activities particularly against the tested Gram-positive bacteria Bacillus subtilis. Meanwhile, compounds 4i and 8g displayed marked antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenin-induced paw oedema method in rats. The oxadiazole derivatives 4c, 4g, 4i and 4j produced good dose-dependent anti-inflammatory activity.

Full text of DOI:10.1016/j.ejmech.2006.10.003

European Journal of Medicinal Chemistry 42 (2007) 235e242
http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antimicrobial, and anti-inflammatory activities of novel
2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and
2-(1-adamantylamino)-5-substituted-1,3,4-thiadiazoles
Adnan A. Kadi a, Nasser R. El-Brollosy a, Omar A. Al-Deeb a, Elsayed E. Habib b,
Tarek M. Ibrahim c, Ali A. El-Emam a,
*
a Department of Pharmaceutical Chemistry, P. O. Box 2457, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
b Department of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
c Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
Received 21 May 2006; received in revised form 2 October 2006; accepted 5 October 2006
Available online 28 November 2006
Abstract
Reaction of 1-adamantanecarbonyl chloride with certain carboxylic acid hydrazides in pyridine yielded the corresponding N-acyl adaman-
tane-1-carbohydrazide derivatives 3aej, which were cyclized to the corresponding 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles 4aej via
heating with phosphorus oxychloride. Treatment of 1-adamantylisothiocyanate with some carboxylic acid hydrazides in ethanol yielded the
corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarbazides 7aeg, which were cyclized to the corresponding 2-(1-adamantylamino)-5-
substituted-1,3,4-thiadiazole derivatives 8aeg. Compounds 4aej, 7aeg, and 8aeg were tested for in vitro activities against a panel of
Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Several derivatives produced good or mod-
erate activities particularly against the tested Gram-positive bacteria Bacillus subtilis. Meanwhile, compounds 4i and 8g displayed marked
antifungal activity against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using
the carrageenin-induced paw oedema method in rats. The oxadiazole derivatives 4c, 4g, 4i and 4j produced good dose-dependent anti-inflam-
matory activity.
Ó 2006 Elsevier Masson SAS. All rights reserved.
Keywords: 1-Adamantyl derivatives; 1,3,4-Oxadiazoles; 1,3,4-Thiadiazoles; Anti-inflammatory activity; Antimicrobial activity
1. Introduction
[25e27]. Moreover, 1,3,4-thiadiazole nucleus constitutes the
active part of several biologically active compounds, including
antibacterial [28e30], antimycotic [31,32] and anti-inflamma-
tory agents [33e35]. In an earlier work [16], we reported the
synthesis and potent anti-inflammatory and analgesic activities
of series of 3-(1-adamantyl)-4-substituted-1,2,4-triazoline-5-
thiols and their related derivatives. Recently, we reported the
anti-inflammatory and antimicrobial activities of novel series
of 3-(1-adamantyl)-substituted-1,2,4-triazoline-5-thiones and
2-(1-adamantyl)-1,3,4-oxadiazolin-5-thiones, carrying an
acetic or propionic acid moiety [8,17]. In continuation to our
interest in the chemical and pharmacological properties
of adamantane derivatives, we report herein the synthesis,
Derivatives of adamantane have long been known for their
antiviral activity against Influenza A [1e5] and HIV viruses
[6e8]. Several adamantane derivatives were also associated
with central nervous [9e12], antimicrobial [13e16], and
anti-inflammatory activities [15e19]. In addition, several
1,3,4-oxadiazole derivatives were reported to possess signifi-
cant antibacterial [20e24] and anti-inflammatory activities
* Corresponding author. Tel.: þ966 1 4677350; fax: þ966 1 4676220.
E-mail address: elemam5@hotmail.com (A.A. El-Emam).
0223-5234/$ - see front matter Ó 2006 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.10.003

236
A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
antimicrobial, and anti-inflammatory activities of a new series
of 2-(1-adamantyl)-5-substituted-1,3,4-oxadiazoles and 2-(1-
adamantylamino)-5-substituted-1,3,4-thiadiazoles.
the agar disc-diffusion method [38] using MullereHinton
¨
agar medium. The results of the preliminary antimicrobial
testing of compounds 4aej, 7aeg and 8aeg (200 mg/disc),
the broad spectrum antibacterial antibiotic Ampicillin trihy-
drate (100 mg/disc) and the antifungal drug Clotrimazole
(100 mg/disc) are shown in Table 2. The results revealed that
they showed varying degrees of inhibition against the tested
microorganisms. In general, the best antibacterial activity
was displayed by compounds 4g, 4i, 7a, 7e, 7f, 8c and 8e,
and the Gram-positive bacteria B. subtilis is considered the
most sensitive among the tested microorganisms. Compounds
4g, 7e, 8c and 8c showed good activity against Gram-positive
bacteria S. aureus (inhibition zone > 15 mm), while com-
pounds 4i and 8b were moderately active (inhibition zone
11e16 mm). Compounds 4g, 4i, 7a, 7e, 7f, 8c and 8e showed
strong activity against B. subtilis, while compounds 4b, 4c, 4d,
4h, 7b and 7c were moderately active. Compounds 7a, 7e and
8e produced good activity against the Gram-negative bacteria
E. coli, while compounds 4g, 4i, 8a and 8c were moderately
active. The inhibitory activity against the tested Gram-nega-
tive bacteria P. aeuroginosa was significantly lower than the
other tested microorganisms, only compounds 4i, 7e and 8e
were moderately active, while the other compounds were ei-
ther weakly active or completely inactive (inhibition zo-
ne ꢀ 10 mm). None of the tested compounds were found to
be superior to the Clotrimazole against C. albicans, only com-
pounds 4i, 7g and 8g produced marked activity. The minimal
inhibitory concentration (MIC) for the most active compounds
4g, 4i, 7a, 7e, 7f, 7g, 8c, 8e and 8g against the same microor-
ganism used in the primary screening was calculated using the
2. Chemistry
The starting material 1-adamantanecarbonyl chloride 1 was
obtained via the reaction of 1-adamantane carboxylic acid
with thionyl chloride [36]. The reaction of 1 with various car-
boxylic acid hydrazides 2aej in pyridine yielded the corre-
sponding N-acyl derivatives 3aej in high yields. Compounds
3aej were cyclized by heating with phosphorus oxychloride
for 1 h to yield the corresponding 2-(1-adamantyl)-5-
substituted-1,3,4-oxadiazoles 4aej. Compounds 4aej were
also independently prepared in 85e95% yields by the reaction
of the carboxylic acid hydrazides 2aej with 1-adamantane
carboxylic acid in the presence of phosphorus oxychloride
(Scheme 1, Table 1).
1-Adamantylisothiocyanate 6 was obtained from the com-
mercially available 1-adamantylamine 5 via treatment with
carbon disulphide and potassium hydroxide [37]. The reaction
of 6 with various carboxylic acid hydrazides in ethanol yielded
the corresponding 1-acyl-4-(1-adamantyl)-3-thiosemicarba-
zides 7aeg. Cyclization of compounds 7aeg was achieved
by the action of sulphuric acid at room temperature to yield
the corresponding 2-(1-adamantylamino)-5-substituted-1,3,4-
thiadiazole derivatives 8aeg (Scheme 2, Table 1). The struc-
tures of all the newly synthesized compounds were confirmed
1
by elemental analyses in addition to the IR, H NMR, 13C
NMR, and mass spectral data which were in full agreement
with their structures.
microdilution susceptibility method in MullereHinton Broth
¨
and Sabouraud Liquid Medium [39]. The MIC of the most ac-
tive compounds, the antibacterial antibiotic Ampicillin trihy-
drate and the antifungal drug Clotrimazole which are shown
in Table 3, were in accordance with the results obtained in
the primary screening.
3. Biological testing
3.1. In vitro antimicrobial activity
The synthesized compounds were tested for their in vitro
antimicrobial activity against a panel of standard strains of
the Gram-positive bacteria (Staphylococcus aureus IFO 3060
and Bacillus subtilis IFO 3007), the Gram-negative bacteria
(Escherichia coli IFO 3301 and Pseudomonas aeuroginosa
IFO 3448), and the yeast-like pathogenic fungus Candida albi-
cans IFO 0583. The primary screening was carried out using
In general, the antibacterial activity seemed to be depen-
dent on the nature of substituents rather the basic skeleton
of the molecules. Within the oxadiazole series 4aej, it was no-
ticed that the substituents at position 5 has great influence on
the antibacterial activity, the highest activity was observed
with the 3,4-dimethoxyphenyl (4g) and the 2-thienyl (4i) de-
rivatives. Meanwhile, the 4-halophenyl derivatives (4b, 4c
O
H
H
R
N
Cl
Pyridine
N
NH2
2a-j
+
N
H
R
O
O
O
1
3a-j
POCl3
COOH
O
N
R
N
4a-j
Scheme 1.

A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
237
Table 1
Crystallization solvents, melting points, yield percentages, molecular formulae, and molecular weights of compounds 4aej, 7aeg and 8aeg
Compound
R
Crystallization solvent
M.p. (ꢁC)
Yielda (%)
Mol. formula (Mol. wt.)
4a
4b
4c
4d
4e
4f
C6H5
4-FC6H4
EtOH/H2O
EtOH
EtOH
108e110
149e151
178e180
188e190
238e240
200e202
145e147
153e155
110e112
318e320
189e191
162e164
190e192
195e197
190e192
188e190
210e212
169e171
227e229
262e264
280e282
263e265
223e225
238e240
82 (88)
85 (91)
85 (90)
83 (88)
85 (91)
88 (93)
82 (89)
86 (88)
80 (85)
88 (95)
77
C18H20N2O (280.36)
C18H19FN2O (298.35)
C18H19ClN2O (314.81)
C18H19BrN2O (359.26)
C18H19N3O3 (325.36)
C18H18N4O5 (370.36)
C20H24N2O3 (340.42)
C18H18ClN3O3 (359.81)
C16H18N2OS (286.39)
C22H30N2O (338.49)
C18H23N3OS (329.46)
C18H22FN3OS (347.45)
C18H22ClN3OS (363.90)
C18H22BrN3OS (408.36)
C18H22N4O3S (374.46)
C16H21N3OS2 (335.49)
4-ClC6H4
4-BrC6H4
4-NO2C6H4
3,5-(NO2)2C6H3
3,4-(OCH3)2C6H3
2-Cl,4-NO2C6H3
2-Thienyl
1-Adamantyl
C6H5
EtOH/CHCl3
EtOH/CHCl3
EtOH
4g
4h
4i
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH
4j
7a
7b
7c
7d
7e
7f
4-FC6H4
81
83
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Thienyl
1-Adamantyl
C6H5
EtOH
EtOH
85
85
EtOH/H2O
EtOH
EtOH
75
85
7g
8a
8b
8c
8d
8e
8f
C22H33N3OS (387.58)
EtOH/H2O
EtOH/H2O
EtOH/H2O
EtOH/CHCl3
EtOH/CHCl3
EtOH/H2O
EtOH/H2O
69
72
C18H21N3S (311.44)
C18H20FN3S (329.43)
C18H20ClN3S (345.89)
C18H20BrN3S (390.34)
C18H20N4O2S (356.44)
C16H19N3S2 (317.47)
C22H31N3S (369.57)
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Thienyl
1-Adamantyl
72
74
79
66
8g
a
82
The figures shown in parentheses represent the yields obtained by method B.
and 4d) were more active than their phenyl analog (4a). The
nitrophenyl derivatives 4e and 4f were completely inactive.
In the acyclic thiosemicarbazide derivatives 7aeg, the highest
activity was observed with the phenyl, 4-nitrophenyl and 2-
thienyl derivatives, whereas, the halophenyl and 1-adamantyl
derivatives were almost inactive. In the adamantylaminothia-
diazole series, it seems that the presence of 4-fluoro, chloro
or nitrophenyl moieties enhance the activity particularly
against S. aureus. In addition, marked antifungal activity
was only observed in the diadamantyl derivatives 4j, 7g and
8g and the 2-thienyl derivative 4i, which may be attributed
to their high lipophilicity.
3.2. Acute anti-inflammatory activity
The acute anti-inflammatory activity of the synthesized
compounds was determined following the carrageenin-in-
duced paw oedema method in rats [40]. Each compound was
tested in three dose levels: 20, 40 and 60 mg/kg. The results
of the anti-inflammatory activity of the synthesized com-
pounds and the well-known anti-inflammatory drug Indometh-
acin (10 mg/kg) are shown in Table 4. The majority of the
oxadiazole derivatives 4aej, and to a less extent the thiadia-
zole derivatives 8aeg showed significant dose-dependent
anti-inflammatory activity. The best activity was observed
with the oxadiazole derivatives 4c, 4g, 4i and 4j which dis-
played strong dose-dependent inhibition of carrageenin-in-
duced oedema producing >50% inhibition at 60 mg/kg dose.
Meanwhile, the oxadiazole derivatives 4a, 4b and the thiadia-
zole derivatives 8a, 8b, 8c, 8f and 8g were found moderately
active producing <50% inhibition of carrageenin-induced oe-
dema. The oxadiazole derivatives 4d, 4e, 4f, and 4h, the thia-
diazole derivatives 8d and 8e and all the thiosemicarbazide
derivatives 7aeg were practically inactive.
CS2
KOH
NH2
NCS
6
5
Ar-CONHNH2
EtOH
S
H
N
R
N
N
H
H
O
7a-g
H2SO4
r.t., 24h
The structureeanti-inflammatory activity relationship of the
synthesized compounds revealed that the activity is dependent
on the basic molecular skeleton; most of the cyclic oxadiazoles
and to a lesser extent the thiadiazoles are activewhereas the acy-
clic thiosemicarbazides are generally inactive. In the oxadiazole
series, it seemed that 4-chlorphenyl, 3,4-dimethoxyphenyl,
N
N
N
R
S
H
8a-g
Scheme 2.

238
A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
Table 2
Table 4
Antimicrobial activity of compounds 4aej, 7aeg and 8aeg (200 mg/8 mm
disc), the broad spectrum antibacterial drug Ampicillin (100 mg/8 mm disc)
and the antifungal drug Clotrimazole (100 mg/8 mm disc) against Staphylococ-
cus aureus IFO 3060 (SA), Bacillus subtilis IFO 3007 (BS), Escherichia coli
IFO 3301 (EC), Pseudomonas aeuroginosa IFO 3448 (PA), and Candida albi-
cans IFO 0583 (CA)
Anti-inflammatory effect of intraperitoneal injection of various doses of com-
pounds 4aej, 7aeg, 8aeg and Indomethacin (10 mg/kg) against carrageenin-
induced paw oedema in rats
Compound
% Reduction of paw oedema from controla
20 mg/kg
40 mg/kg
60 mg/kg
Controlb
4a
e
e
e
Compound
Diameter of growth inhibition zone (mm)
23.16* ꢂ 4.03 31.28* ꢂ 6.12 34.50* ꢂ 4.80
11.72* ꢂ 5.81 29.15* ꢂ 5.16 38.62 ꢂ 4.80
SA
BS
EC
PA
CA
4b
4c
4a
4b
e
e
e
e
e
e
e
e
e
e
10
12
e
e
e
e
e
15
e
e
e
e
e
e
12
e
e
15
NT
e
e
e
e
e
e
e
e
16
10
e
e
e
e
e
e
16
e
e
e
e
e
e
18
NT
21
34.50* ꢂ 6.31 44.66* ꢂ 4.18 50.71* ꢂ 4.12
e
e
12
13
14
e
e
10
e
4d
4e
11.60* ꢂ 5.63 13.15* ꢂ 7.23
9.92* ꢂ 7.01 13.56* ꢂ 5.16
13.01 ꢂ 8.29
12.08 ꢂ 7.92
3.66 ꢂ 6.30
4c
4d
e
4f
4g
4.16 ꢂ 7.20
36.73* ꢂ 2.0
19.69 ꢂ 2.27
5.22 ꢂ 7.07
4e
e
e
53.61* ꢂ 3.16 70.20* ꢂ 1.72
4f
4g
e
18
e
e
e
4h
4i
21.65 ꢂ 3.71
19.34 ꢂ 5.31
24
14
18
e
12
10
11
e
35.95* ꢂ 4.81 49.77* ꢂ 4.13 63.72* ꢂ 2.04
44.27* ꢂ 4.19 68.97* ꢂ 1.63 71.52* ꢂ 3.10
4h
4i
4j
7a
14
e
2.32 ꢂ 6.90
9.11 ꢂ 7.91
1.80 ꢂ 8.34
e
e
e
e
e
4j
7a
7b
7c
e
e
e
e
e
22
13
13
10
24
18
e
16
e
7b
7c
e
7d
7e
2.34 ꢂ 6.82
2.16 ꢂ 8.01
e
e
e
e
0.76 ꢂ 6.88
0.96 ꢂ 7.23
e
7d
7e
7f
7g
20
e
19
10
e
12
10
12
e
11.34* ꢂ 8.62
13.08 ꢂ 7.29
10.12 ꢂ 7.82
33.53 ꢂ 6.21
7f
7g
8a
8b
19.69* ꢂ 5.35 34.05* ꢂ 4.80
e
e
18.02* ꢂ 4.31 35.55* ꢂ 3.02 39.35* ꢂ 6.92
21.63* ꢂ 3.90 37.02* ꢂ 2.08 37.11* ꢂ 4.81
8a
8b
e
8c
8d
14
18
e
10
16
e
12.51* ꢂ 7.90
9.11 ꢂ 7.15
13.38 ꢂ 7.40
10.10 ꢂ 7.70
14.16 ꢂ 7.81
10.74 ꢂ 8.02
8c
8d
8e
8f
8g
15.43* ꢂ 5.90 28.62* ꢂ 4.72 37.52* ꢂ 3.62
31.60* ꢂ 5.12 39.65* ꢂ 2.90 44.14* ꢂ 4.18
8e
16
e
18
10
e
18
NT
17
e
8f
8g
Indomethacin (10 mg/kg)
60.4* ꢂ 2.24
60.4* ꢂ 2.24
60.4* ꢂ 2.24
e
19
NT
e
16
NT
*Significantly different from control at p < 0.05.
Ampicillin
Clotrimazole
a
Results are expressed as mean ꢂ S.E.M. (n ¼ 5) and compared with Stu-
dents ‘‘t’’ test.
b
e: Inactive (inhibition zone < 10 mm). NT: not tested.
The group was injected with 1 ml of 0.5% aqueous carboxymethyl cellu-
lose solution.
2-thienyl and 1-adamantyl moieties enhance the activity, while
the nitrophenyl moieties diminished the activity.
There are in fact a high number of enzyme/receptors in-
volved in the inflammatory process. Without specific tests it
is quite difficult to hypothesize a mechanism of action, they
may exert their action via inhibition of the cyclooxygenase en-
zymes like other nonsteroidal anti-inflammatory agents. In ad-
dition, the recently reported activity of some adamantane
derivatives as selective inhibitors of 11b-hydroxysteroid dehy-
drogenase type 1 (11b-HSD1) [41,42] should be taken in
consideration. The 11b-hydroxysteroid dehydrogenase type 1
converts cortisone to the active glucocorticoid cortisol, which
is responsible for various metabolic disorders including water
retention, thus the inhibition of 11b-HSD1 would result in in-
creasing intracellular cortisone level.
Table 3
The minimal inhibitory concentration (MIC, mg/ml) of compounds 4g, 4i, 7a,
7e, 7f, 7g, 8c, 8e, and 8g, the broad spectrum antibacterial drug Ampicillin and
the antifungal drug Clotrimazole against Staphylococcus aureus IFO 3060
(SA), Bacillus subtilis IFO 3007 (BS), Escherichia coli IFO 3301 (EC), Pseu-
domonas aeuroginosa IFO 3448 (PA), and Candida albicans IFO 0583 (CA)
Compound
Minimal inhibitory concentration (MIC, mg/ml)
4. Experimental protocols
SA
BS
EC
PA
CA
4g
2
0.5
2
ND
ND
4
ND
ND
ND
ND
ND
ND
ND
ND
ND
2
ND
2
All melting points (ꢁC, uncorrected) were determined using
a Gallenkamp melting point apparatus. Infra red spectra were
recorded in KBr discs using Jasco FT/IR 460 Plus spectrome-
ter. NMR spectra were obtained on a Bruker AC 500 Ultra
4i
7a
ND
ND
1
1
ND
ND
ND
4
7e
0.5
4
2
7f
7g
ND
ND
2
ND
ND
ND
1
1
ND
ND
2
Shield NMR spectrometer at 500 MHz for H and 125 MHz
8c
8e
ND
ND
2
for 13C, the chemical shifts are expressed in d (ppm) downfield
from tetramethylsilane (TMS). Electron impact mass spectra
were recorded on a Shimadzu GCeMS-QP 5000 instrument.
Elemental analyses (C, H, N, S) were in full agreement with
the proposed structures within ꢂ0.4% of the theoretical
2
8g
Ampicillin
Clotrimazole
ND
1
ND
0.5
ND
ND
2
ND
2
ND
ND
ND
ND: not determined.

A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
239
values. The bacterial strains and C. albicans fungus were ob-
tained from the Institute of fermentation of Osaka (IFO),
Osaka, Japan. The reference drugs Ampicillin trihydrate
(CAS 7177-48-2), Clotrimazole (CAS 23593-75-1) and Indo-
methacin (CAS 53-86-1) were obtained from SigmaeAldrich
Chemie GmbH, Taufkirchen, Germany. The SpragueeDawley
rats were purchased from local animal house (Abu-Rawash,
Giza, Egypt). The animal experiments for the determination
of the anti-inflammatory activity were carried out in agree-
ment with the pertinent legal and ethical standards of the inter-
national guidelines.
m/z (Rel. Int.): 316 (Mþ þ 2, 39), 314 (Mþ, 100), 257 (7),
1
pound 4d: H NMR (CDCl3): d 1.81 (s, 6H, Adamantane-H),
223 (8), 139 (48), 135 (81), 111 (25), 91 (30), 41 (54). Com-
2.15 (s, 9H, Adamantane-H), 7.64 (d, 2H, Ar-H, J ¼ 8.1 Hz),
7.92 (d, 2H, Ar-H, J ¼ 8.1 Hz). 13C NMR: d 27.74, 34.45,
36.29, 39.96 (Adamantane-C), 123.26, 125.99, 128.23, 132.28
(Ar-C), 163.56 (Oxadiazole C-5), 172.85 (Oxadiazole C-2).
MS m/z (Rel. Int.): 360 (Mþ þ 2, 44), 358 (46), 303 (3), 301
(4), 223 (6), 185 (19), 183 (22), 157 (11), 155 (12), 135 (100),
1
91 (27), 41 (65). Compound 4e: H NMR (CDCl3): d 1.79 (s,
6H, Adamantane-H), 2.08 (s, 9H, Adamantane-H), 7.61e7.72
(m, 2H, Ar-H), 8.33e8.53 (m, 2H, Ar-H). 13C NMR: d 27.10,
33.15, 36.80, 39.82 (Adamantane-C), 125.15, 128.20, 141.95,
145.10 (Ar-C), 163.25 (Oxadiazole C-5), 173.05 (Oxadiazole
C-2). MS m/z (Rel. Int.): 325 (Mþ, 66), 268 (10), 175 (6), 150
4.1. 2-(1-Adamantyl)-5-substituted-1,3,4-oxadiazoles
(4aej)
1
Method A: A mixture of 1-adamantanecarbonyl chloride 1
(1.99 g, 0.01 mol) and the appropriate carboxylic acid hydra-
zide 2aej (0.01 mol), in dry pyridine (10 ml), was heated under
reflux for 30 min. On cooling, the mixture was poured onto cold
water (50 ml) and stirred for 10 min. The separated solid was
filtered, washed thoroughly with cold water and dried to yield
the N-acyl adamantane-1-carbohydrazide derivatives 3aej in
90e95% yields. The products were pure enough to be used in
the next step without further purification. The appropriate com-
pounds 3aej were added to phosphorus oxychloride (6 ml) and
the mixture was heated under reflux for 1 h. On cooling, crushed
ice (50 g) was added cautiously and the mixture was stirred for
30 min. The separated crude product was filtered, washed with
water then with saturated sodium hydrogen carbonate solution
and finally with water, dried and crystallized from ethanol to
yield compounds 4aej in 80e88% overall yields. Method B:
A mixture of the appropriate carboxylic acid hydrazides 2aej
(0.01 mol), 1-adamantane carboxylic acid (1.8 g, 0.01 mol)
and phosphorus oxychloride (8 ml) was heated under reflux
for 1 h. On cooling, crushed ice (50 g) was added cautiously
and the mixture was stirred for 30 min. The separated crude
product was filtered, washed with water then with saturated so-
dium hydrogen carbonate solution and finally with water, dried
and crystallized from ethanol to yield compounds 4aej in 85e
(13), 135 (100), 91 (48), 41 (92). Compound 4f: H NMR
(CDCl3): d 1.80 (s, 6H, Adamantane-H), 2.12 (s, 9H, Adaman-
tane-H), 8.99 (s, 1H, Ar-H), 9.0 (s, 2H, Ar-H). 13C NMR:
d 27.53, 34.23, 36.71, 39.42 (Adamantane-C), 123.27, 127.11,
128.01, 149.31 (Ar-C), 161.93 (Oxadiazole C-5), 173.63 (Oxa-
diazole C-2). MS m/z (Rel. Int.): 370 (Mþ, 100), 313 (17), 195
(16), 175 (14), 135 (62), 105 (22), 91 (32), 41 (98). Compound
4g: 1H NMR (CDCl3): d 1.77 (s, 6H, Adamantane-H), 2.04 (s,
9H, Adamantane-H), 3.74 (s, 3H, OCH3), 3.77 (s, 3H, OCH3),
6.82e7.03 (m, 3H, Ar-H). 13C NMR: d 27.95, 33.85, 35.91,
39.02 (Adamantane-C), 57.32 (OCH3), 58.90 (OCH3), 114.32,
117.61, 123.73, 131.82, 146.73, 149.20 (Ar-C), 162.91 (Oxa-
diazole C-5), 172.80 (Oxadiazole C-2). MS m/z (Rel. Int.):
340 (Mþ, 62), 283 (11), 135 (100), 91 (72), 41 (79). Compound
1
4h: H NMR (CDCl3): d 1.67e1.87 (m, 6H, Adamantane-H),
1.99e2.08 (m, 9H, Adamantane-H), 8.28e8.50 (m, 3H, Ar-
H). 13C NMR: d 27.57, 34.41, 36.10, 38.95 (Adamantane-C),
123.16, 126.51, 128.66, 130.94, 132.80, 149.66 (Ar-C),
161.10 (Oxadiazole C-5), 173.37 (Oxadiazole C-2). MS m/z
(Rel. Int.): 361 (Mþ þ 2, 16), 359 (Mþ, 44), 304 (15), 302
1
(14), 184 (15), 135 (100), 91 (26), 41 (94). Compound 4i: H
NMR (CDCl3): d 1.76 (s, 6H, Adamantane-H), 2.04 (s, 9H,
Adamantane-H), 7.27e7.29 (m, 1H, Thiophene-H), 7.79e
7.93 (m, 2H, Thiophene-H). 13C NMR: d 27.60, 34.17, 36.13,
38.99 (Adamantane-C), 125.56, 129.33, 130.43, 131.67 (Thio-
phene-C), 160.34 (Oxadiazole C-5), 171.23 (Oxadiazole C-2).
MS m/z (Rel. Int.): 286 (Mþ, 67), 229 (14), 151 (13), 135
1
95% yields. Compound 4a: H NMR (CDCl3): d 1.77 (s, 6H,
Adamantane-H), 2.06 (s, 9H, Adamantane-H), 7.58e7.62 (m,
3H, Ar-H), 7.99 (d, 2H, Ar-H, J ¼ 6.7 Hz). 13C NMR:
d 27.76, 34.32, 36.26, 39.41 (Adamantane-C), 125.21, 126.25,
132.29 (Ar-C), 163.24 (Oxadiazole C-5), 172.34 (Oxadiazole
C-2). MS m/z (Rel. Int.): 280 (Mþ, 100), 223 (19), 135 (63),
1
(88), 111 (33), 83 (100), 47 (89), 41 (65). Compound 4j: H
NMR (CDCl3): d 1.79 (s, 12H, Adamantane-H), 2.09 (s, 18H,
Adamantane-H). 13C NMR: d 27.70, 34.20, 36.27, 39.79 (Ada-
mantane-C), 171.99 (Oxadiazole-C). MS m/z (Rel. Int.): 338
(Mþ, 100), 281 (19), 203 (13), 175 (5), 135 (81), 41 (74).
1
105 (58), 91 (29), 77 (74), 41 (82). Compound 4b: H NMR
(CDCl3): d 1.77 (s, 6H, Adamantane-H), 2.06 (s, 9H, Adaman-
tane-H), 7.42e7.46 (m, 2H, Ar-H), 8.06e8.08 (m, 2H, Ar-H).
13C NMR: d 27.61, 34.31, 36.16, 39.47 (Adamantane-C),
117.0, 120.78, 129.57, 129.64 (Ar-C), 163.24 (Oxadiazole C-
5), 172.54 (Oxadiazole C-2). MS m/z (Rel. Int.): 289 (Mþ,
100), 232 (17), 135 (73), 95 (19), 91 (32), 41 (75). Compound
4c: 1H NMR (CDCl3): d 1.77 (s, 6H, Adamantane-H), 2.06 (s,
9H, Adamantane-H), 7.66 (d, 2H, Ar-H, J ¼ 8.0 Hz), 8.0 (d,
2H, Ar-H, J ¼ 8.0 Hz). 13C NMR: d 27.62, 34.31, 36.22,
39.42 (Adamantane-C), 123.31, 126.04, 128.11, 132.63 (Ar-
C), 163.24 (Oxadiazole C-5), 172.41 (Oxadiazole C-2). MS
4.2. 1-Acyl-4-(1-adamantyl)-3-thiosemicarbazides
(7aeg)
A mixture of the carboxylic acid hydrazide (0.01 mol) and
1-adamantylisothiocyanate (1.93 g, 0.01 mol), in ethanol
(10 ml) was heated under reflux for 4 h. On cooling, the
precipitated crystalline solid was filtered, washed with cold
ethanol, dried and crystallized from ethanol to yield com-
1
pounds 7aeg in 75e85% yields. Compound 7a: H NMR

240
A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
(DMSO-d6): d 1.63 (s, 6H, Adamantane-H), 2.04 (s, 3H, Ada-
mantane-H), 2.20 (s, 6H, Adamantane-H), 7.49e7.59 (m, 3H,
Ar-H), 7.89 (d, 2H, Ar-H, J ¼ 8.1 Hz), 9.15 (s, 1H, NH), 10.33
(s, 1H, NH). 13C NMR: 29.45, 36.47, 39.96, 41.36 (Adaman-
tane-C), 128.03, 128.91, 132.38, 132.89 (Ar-C), 161.32
(C]O), 166.21 (C]S). MS m/z (Rel. Int.): 329 (Mþ, 2),
311 (8), 295 (12), 194 (19), 193 (42), 135 (100), 105 (75),
4.3. 2-(1-Adamantylamino)-5-aryl-1,3,4-thiadiazoles
(8aeg)
Sulphuric acid (98%) (6 ml) was added dropwise to the ap-
propriate substituted thiosemicarbazides 7aeg (1.0 g) and the
mixture was stirred at room temperature for 24 h. The resulted
homogenous mixture was poured onto crushed ice (100 g), neu-
tralized with ammonium hydroxide solution. The separated pre-
cipitate was filtered, washed with water, dried and crystallized
to yield compounds 8aeg in 66e82% yields. Compound 8a:
1H NMR (DMSO-d6): d 1.66 (s, 6H, Adamantane-H), 2.0e
2.08 (m, 9H, Adamantane-H), 7.43e7.81 (m, 6H, Ar-H and
NH). 13C NMR: 29.14, 35.22, 36.38, 41.37 (Adamantane-C),
125.52, 126.80, 129.72, 131.38 (Ar-C), 162.26 (Thiadiazole-
C), 166.27 (Thiadiazole-C). MS m/z (Rel. Int.): 311 (Mþ, 13),
295 (13), 208 (20), 161 (11), 149 (15), 135 (85), 121 (22), 105
1
79 (46), 77 (76), 41 (48). Compound 7b: H NMR (DMSO-
d6): d 1.63 (s, 6H, Adamantane-H), 2.06 (s, 3H, Adaman-
tane-H), 2.16 (s, 6H, Adamantane-H), 7.32e7.36 (m, 2H,
Ar-H), 7.55e7.69 (d, 2H, Ar-H), 9.13 (s, 1H, NH), 10.35 (s,
1H, NH). 13C NMR: 29.15, 36.37, 39.69, 41.35 (Adaman-
tane-C), 128.14, 128.16, 131.36, 136.02 (Ar-C), 163.62
(C]O), 165.65 (C]S). MS m/z (Rel. Int.): 347 (Mþ, 2),
313 (9), 193 (27), 194 (12), 154 (23), 135 (100), 123 (82),
1
95 (62), 79 (42), 41 (43). Compound 7c: H NMR (DMSO-
1
d6): d 1.63 (s, 6H, Adamantane-H), 2.04 (s, 3H, Adaman-
tane-H), 2.19 (s, 6H, Adamantane-H), 7.57 (d, 2H, Ar-H,
J ¼ 8.0 Hz), 7.90 (d, 2H, Ar-H, J ¼ 8.0 Hz), 9.14 (s, 1H,
NH), 10.40 (s, 1H, NH). 13C NMR: 29.31, 36.38, 39.89,
41.32 (Adamantane-C), 129.01, 129.98, 131.74, 137.17 (Ar-
C), 162.03 (C]O), 165.24 (C]S). MS m/z (Rel. Int.): 365
(Mþ þ 2, 1), 363 (Mþ, 3), 345 (4), 329 (6), 212 (19), 193
(44), 141 (54), 139 (93), 135 (100), 113 (29), 111 (71), 93
(31), 91 (29), 77 (100), 41 (96). Compound 8b: H NMR
(DMSO-d6): d 1.67 (s, 6H, Adamantane-H), 1.96e2.16 (m,
9H, Adamantane-H), 7.35e7.95 (m, 5H, Ar-H and NH),
7.55e7.69 (d, 2H, Ar-H), 9.13 (s, 1H, NH), 10.35 (s, 1H,
NH). 13C NMR: 28.07, 35.42, 39.02, 41.06 (Adamantane-C),
118.71, 128.95, 130.02, 131.63 (Ar-C), 162.61 (Thiadiazole-
C), 166.82 (Thiadiazole-C). MS m/z (Rel. Int.): 329 (Mþ, 8),
314 (9), 208 (17), 135 (100), 107 (72), 95 (62), 79 (42), 41
(44). Compound 8c: 1H NMR (DMSO-d6): d 1.62 (s, 6H, Ada-
mantane-H), 1.93e2.04 (s, 9H, Adamantane-H), 7.42 (d, 2H,
Ar-H, J ¼ 8.0 Hz), 7.75 (d, 2H, Ar-H, J ¼ 8.0 Hz). 13C NMR:
28.02, 35.31, 37.90, 41.0 (Adamantane-C), 124.52, 128.91,
129.55, 136.77 (Ar-C), 161.92 (Thiadiazole-C), 166.29 (Thia-
diazole-C). MS m/z (Rel. Int.): 347 (Mþ þ 2, 2), 3645 (Mþ,
7), 330 (21), 208 (21), 135 (100), 124 (13), 111 (28), 79 (63),
1
(51), 79 (63), 41 (59). Compound 7d: H NMR (DMSO-d6):
d 1.63 (s, 6H, Adamantane-H), 2.04 (s, 3H, Adamantane-H),
2.19 (s, 6H, Adamantane-H), 7.72 (d, 2H, Ar-H, J ¼ 8.1 Hz),
7.82 (d, 2H, Ar-H, J ¼ 8.1 Hz), 9.14 (s, 1H, NH), 10.40 (s,
1H, NH). 13C NMR: 29.45, 36.37, 39.84, 41.32 (Adaman-
tane-C), 126.14, 130.15, 131.95, 136.23 (Ar-C), 162.95
(C]O), 165.39 (C]S). MS m/z (Rel. Int.): 409 (Mþ þ 2,
1), 407 (Mþ, 1), 375 (7), 373 (8), 193 (14), 185 (44), 183
(43), 157 (23), 155 (24), 135 (100), 81 (34), 79 (69), 41
(44). Compound 7e: 1H NMR (DMSO-d6): d 1.63 (s, 6H, Ada-
mantane-H), 2.05 (s, 3H, Adamantane-H), 2.21 (s, 6H, Ada-
mantane-H), 8.04 (d, 2H, Ar-H, J ¼ 8.0), 8.30 (d, 2H, Ar-H,
J ¼ 8.0), 9.20 (s, 1H, NH), 10.14 (s, 1H, NH). 13C NMR:
29.23, 36.15, 39.79, 41.53 (Adamantane-C), 125.71, 129.30,
131.63, 138.17 (Ar-C), 163.02 (C]O), 166.19 (C]S). MS
m/z (Rel. Int.): 374 (Mþ, 2), 356 (9), 340 (11), 338 (15),
239 (15), 220 (26), 193 (37), 181 (19), 150 (56), 135 (100),
1
41 (59). Compound 8d: H NMR (DMSO-d6): d 1.65 (s, 6H,
Adamantane-H), 1.99e2.08 (m, 9H, Adamantane-H), 7.67e
7.79 (m, 6H, Ar-H & NH). 13C NMR: 28.21, 34.17, 36.72,
41.63 (Adamantane-C), 124.15, 127.23, 129.91, 133.45 (Ar-
C), 162.36 (Thiadiazole-C), 166.59 (Thiadiazole-C). MS m/z
(Rel. Int.): 391 (Mþ þ 2, 4), 389 (Mþ, 4), 375 (7), 373 (8),
241 (13), 239 (13), 208 (23), 201 (14), 199 (15), 183 (30), 181
(18), 157 (22), 155 (23), 149 (14), 135 (100), 91 (35), 79 (54),
1
41 (73). Compound 8e: H NMR (DMSO-d6): d 1.66 (s, 6H,
Adamantane-H), 1.97e2.07 (s, 3H, Adamantane-H), 7.93e
8.38 (m, 5H, Ar-H and NH). 13C NMR: 29.32, 36.24, 36.32,
41.18 (Adamantane-C), 124.90, 126.50, 127.58, 137.21 (Ar-
C), 162.51 (Thiadiazole-C), 167.03 (Thiadiazole-C). MS m/z
(Rel. Int.): 356 (Mþ, 3), 341 (13), 297 (18), 208 (33), 206
(14), 166 (28), 135 (100), 121 (12), 91 (54), 79 (55), 41 (83).
1
93 (36), 79 (37), 41 (76). Compound 7f: H NMR (DMSO-
d6): d 1.63 (s, 6H, Adamantane-H), 2.04 (s, 3H, Adaman-
tane-H), 2.19 (s, 6H, Adamantane-H), 7.18e7.27 (m, 1H,
Thiophene-H), 7.65e7.88 (m, 2H, Thiophene-H), 9.14 (s,
1H, NH), 10.35 (s, 1H, NH). 13C NMR: 29.13, 36.72, 39.89,
41.38 (Adamantane-C), 128.11, 129.81, 132.04, 137.23 (Thio-
phene-C), 161.16 (C]O), 166.37 (C]S). MS m/z (Rel. Int.):
335 (Mþ, 2), 301 (13), 193 (18), 142 (31), 135 (92), 111 (100),
1
Compound 8f: H NMR (DMSO-d6): d 1.65 (s, 6H, Adaman-
tane-H), 1.96e2.08 (m, 9H, Adamantane-H), 7.31e7.78 (m,
4H, Thiophene-H and NH). 13C NMR: 29.31, 35.23, 36.29,
41.24 (Adamantane-C), 125.99, 127.77, 128.64, 129.51
(Thiophene-C), 161.42 (Thiadiazole-C), 165.87 (Thiadiazole-
C). MS m/z (Rel. Int.): 317 (Mþ, 5), 301 (27), 208 (12), 183
(13), 167 (21), 151 (15), 135 (100), 127 (20), 111 (42), 93
1
83 (24), 79 (41), 41 (86). Compound 7g: H NMR (DMSO-
d6): d 1.63e1.68 (m, 12H, Adamantane-H), 1.81 (s, 3H, Ada-
mantane-H), 1.83 (m, 3H, Adamantane-H), 1.97e2.14 (m,
12H, Adamantane-H), 9.15 (s, 1H, NH), 9.73 (s, 1H, NH).
13C NMR: 29.14, 29.41, 36.34, 36.44, 38.78, 39.62, 40.55,
41.41 (Adamantane-C), 162.13 (C]O), 165.98 (C]S). MS
m/z (Rel. Int.): 387 (Mþ, 1), 252 (13), 237 (12), 163 (15),
193 (15), 135 (100), 93 (24), 79 (38), 41 (64).
1
(43), 79 (57), 41 (91). Compound 8g: H NMR (DMSO-d6):
d 1.65e1.72 (m, 12H, Adamantane-H), 1.95e2.14 (m, 18H,
Adamantane-H), 7.95 (s, 1H, NH). 13C NMR: 29.14, 29.41,
36.34, 36.44, 38.78, 39.62, 40.55, 41.41 (Adamantane-C),

A.A. Kadi et al. / European Journal of Medicinal Chemistry 42 (2007) 235e242
241
162.13 (Thiadiazole-C), 165.98 (Thiadiazole-C). MS m/z (Rel.
Int.): 369 (Mþ, 3), 353 (21), 235 (20), 208 (20), 149 (15), 135
(100), 93 (50), 79 (61), 41 (76).
the test compound. The values are expressed as the mean -
ꢂ S.E.M. Statistical significance between the control and
treated groups was performed using the Students ‘‘t’’ test.
4.4. Determination of in vitro antimicrobial activity
Acknowledgement
The primary screening was carried out using the agar disc-
diffusion method using MullereHinton agar medium. Sterile
The financial support of the Research Center of the College
of Pharmacy, King Saud University (Project # C.P.R.C.164), is
greatly appreciated.
¨
filter paper discs (8 mm diameter) were moistened with the
compound solution in dimethylsulphoxide of specific concen-
tration (200 mg/disc), the antibacterial antibiotic Ampicillin tri-
hydrate (100 mg/disc) and the antifungal drug Clotrimazole
(100 mg/disc) were carefully placed on the agar culture plates
that had been previously inoculated separately with the micro-
organisms. The plates were incubated at 37 ꢁC, and the diameter
of the growth inhibition zones was measured after 24 h in case
of bacteria and 48 h in case of C. albicans. The minimal inhib-
itory concentration (MIC) for the compounds 4g, 4i, 7a, 7e, 7f,
7g, 8c, 8e and 8g against the same microorganisms used in the
primary screening was carried out using the microdilution sus-
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ꢄ 100
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_
_
ˇ
_
_
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