Synthesis, antimicrobial and anti-inflammatory activities of novel 5-(1-adamantyl)-1,3,4-thiadiazole derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.08.007

New 1-adamanyl-1,3,4-thiadiazole derivatives namely, 5-(1-adamantyl)-1,3,4- thiadiazoline-2-thione 3, 5-(1-adamantyl)-3-(benzyl- or 4-substituted benzyl)-1,3,4-thiadiazoline-2-thione 4a-d, 5-(1-adamantyl)-3-(4-substituted-1- piperazinylmethyl)-1,3,4-thiadiazoline-2-thiones 5a-c, 2-[5-(1-adamantyl)-2- thioxo-1,3,4-thiadiazolin-3-yl]acetic acid 7, (±)-2-[5-(1-adamantyl)-2- thioxo-1,3,4-thiadiazolin-3-yl]propionic acid 9, 3-[5-(1-adamantyl)-2-thioxo-1, 3,4-thiadiazolin-3-yl]propionic acid 11, N-[5-(1-adamantyl)-1,3,4-thiadiazol-2- yl]-N′-arylthioureas 15a-c and 5-(1-adamantyl)-1,3,4-thiadiazoline-2-one 16, were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7, 9, 15b and 15c displayed marked activity against the tested Gram-positive bacteria, while compound 3 was highly active against the tested Gram-negative bacteria. Compounds 4b, 7 and 15c were weakly or moderately active against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was determined using the carrageenan-induced paw oedema method in rats. The propionic acid derivative 9 produced good dose-dependent anti-inflammatory activity.

Full text of DOI:10.1016/j.ejmech.2010.08.007

European Journal of Medicinal Chemistry 45 (2010) 5006e5011
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, antimicrobial and anti-inflammatory activities
of novel 5-(1-adamantyl)-1,3,4-thiadiazole derivatives
Adnan A. Kadi a, Ebtehal S. Al-Abdullah a, Ihsan A. Shehata a, Elsayed E. Habib b,
,
Tarek M. Ibrahim c, Ali A. El-Emam a
*
a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia
b Department of Microbiology, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
c Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Mansoura, Mansoura, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
New 1-adamanyl-1,3,4-thiadiazole derivatives namely, 5-(1-adamantyl)-1,3,4-thiadiazoline-2-thione 3,
5-(1-adamantyl)-3-(benzyl- or 4-substituted benzyl)-1,3,4-thiadiazoline-2-thione 4aed, 5-(1-ada-
mantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-thiadiazoline-2-thiones 5aec, 2-[5-(1-adamantyl)-
2-thioxo-1,3,4-thiadiazolin-3-yl]acetic acid 7, (ꢀ)-2-[5-(1-adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]
propionic acid 9, 3-[5-(1-adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]propionic acid 11, N-[5-(1-ada-
mantyl)-1,3,4-thiadiazol-2-yl]-N0-arylthioureas 15aec and 5-(1-adamantyl)-1,3,4-thiadiazoline-2-one
16, were synthesized and tested for in vitro activities against a panel of Gram-positive and Gram-
negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compounds 7, 9, 15b and 15c
displayed marked activity against the tested Gram-positive bacteria, while compound 3 was highly active
against the tested Gram-negative bacteria. Compounds 4b, 7 and 15c were weakly or moderately active
against C. albicans. In addition, the in vivo anti-inflammatory activity of the synthesized compounds was
determined using the carrageenan-induced paw oedema method in rats. The propionic acid derivative 9
produced good dose-dependent anti-inflammatory activity.
Received 19 June 2010
Received in revised form
4 August 2010
Accepted 6 August 2010
Available online 12 August 2010
Keywords:
1-Adamantyl derivatives
1,3,4-Thiadiazoles
Antimicrobial activity
Anti-inflammatory activity
Ó 2010 Elsevier Masson SAS. All rights reserved.
1. Introduction
to our interest in the chemical and pharmacological properties of
adamantane derivatives, we report herein the synthesis, antimicro-
Covalent conjugation of biologically active compounds acting by
different mechanisms could, in a favorable case, lead to synergism to
obtain compounds with improved activity and reduced toxicity.
Adamantane derivatives has long been known for their antiviral
activity against Influenza A [1e4] and HIV viruses [5e8]. Several
adamantane derivatives were also associated with central nervous
[9e11], antimicrobial [6,12e15], and anti-inflammatory activities
[12,13,15e18]. In addition, 1,3,4-thiadiazole nucleus constitutes the
active part of several biologically active compounds, including
antibacterial [19e21], antimycotic [22,23], and anti-inflammatory
agents [24e26]. Acetic acid and propionic acid derivatives consti-
tute the most important class of nonsteroidal anti-inflammatory
agents [27].
bial, and anti-inflammatory activities of new series of 5-(1-ada-
mantyl)-1,3,4-thiadiazoles and related derivatives.
2. Results and discussion
2.1. Chemistry
5-(1-Adamantyl)-1,3,4-thiadiazoline-2-thione 3 was prepared
starting from adamantane-1-carboxylic acid hydrazide 1 via treat-
ment with potassium hydroxide and carbon disulphide to afford
potassium N0-(1-adamantylcarbonyl) dithiocarbazate 2 in almost
quantitative yield [28]. Dehydrative cyclization of compound 2
using sulphuric acid at room temperature yielded the target
compound 3, which was reacted with benzyl- or 4-substituted
benzyl chlorides to yield the corresponding 5-(1-adamantyl)-3-
(benzyl- or 4-substituted benzyl)-1,3,4-thiadiazoline-2-thiones
4aed. On the other hand, the reaction of compound 3 with
1-methyl-, ethyl- or phenylpiperazine and formaldehyde
solution in ethanol at room temperature yielded the corresponding
Recently, we reported the anti-inflammatory and antimicrobial
activities of novel series of 3-(1-adamantyl)-substituted-1,2,4-tri-
azolin-5-thiones and 2-(1-adamantyl)-1,3,4-oxadiazolin-5-thiones,
carrying an acetic or propionic acid moiety [12,13,15]. In continuation
* Corresponding author. Tel.: þ966 1 4677350; fax: þ966 1 4676220.
E-mail address: elemam5@hotmail.com (A.A. El-Emam).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.007

A.A. Kadi et al. / European Journal of Medicinal Chemistry 45 (2010) 5006e5011
5007
for 10 min (Scheme 3, Table 1). The structures of all the newly
synthesized compounds were confirmed by elemental analyses in
addition to the IR, 1H NMR, 13C NMR, and mass spectral data which
were in full agreement with their structures.
S
H
N
H
N
CS2 / KOH
EtOH, r.t.
N
H
S- K+
NH2
O
O
2
1
H2SO4
r.t., 24 h
2.2. In vitro antimicrobial activity
The newly synthesized compounds 3, 4aed, 5aec, 7, 9, 11, 15aec
and 16 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), Escher-
ichia coli IFO 3301, Pseudomonas aeruginosa IFO 3448 (Gram-nega-
tive 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 [30].
HN
N
R
N
N
N
NH
N
N
R
CH2O
S
S
5a-c
S
S
3
ArCH2Cl
K2CO3
N
N
S
S
The results of the preliminary antimicrobial testing of compound
3, 5, 4aed, 5aec, 7, 9,11,15aec and 16 (200
antibiotics Ampicillin trihydrate, Gentamicin (100
antifungal drug Clotrimazole (100 g/disc) are shown in Table 2. The
m
g/disc), the antibacterial
4a-d
X
mg/disc) and the
Scheme 1. Synthesis of compounds 4aed and 5aec.
m
results revealed that the compounds showed varying degrees of
inhibition against the tested microorganisms. In general, strong
activity was displayed by the compounds 3, 7, 9, 15b and 15c, which
produced growth inhibition zones ꢁ19 mm against one or more of
the tested microorganisms. Meanwhile, compounds 5a, 5c and 15a
showed moderate activity (growth inhibition zones 14e18 mm),
compounds 4b, 5b and 11 exhibited weak activity (growth inhibition
zones 10e13 mm) and compounds 4a, 4c, 4d and 16 were practically
inactive 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 microorganisms. The
tested compoundswere generally inactive against the Gram-negative
bacteria, onlycompound 3 showed strong activityagainst E. coli and P.
aeruginosa. The inhibitory activity of the compounds against C. albi-
cans was rather lower than their antibacterial activity, only
compounds 4b, 7 and 11 displayed moderate or weak activity. The
minimal inhibitory concentrations (MIC) [31] for the most active
compounds 3, 7, 9, 15b, 15c which are shown in Table 3, were in
accordance with the results obtained in the primary screening.
According to the results of the antimicrobial activity, it seems
difficult to abstract definite structureeactivity relationship.
However, we can conclude that the antibacterial activity greatly
diminished on introduction of the benzyl- or 4-substituted benzyl
moieties (compounds 4aed). Meanwhile, the introduction of the 4-
substituted-1-piperazinylmethyl moieties (compounds 5aec) led
5-(1-adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-
thiadiazoline-2-thiones 5aec (Scheme 1, Table 1).
The reaction of compound 3 with ethyl bromoacetate, ꢀ-ethyl
2-bromopropionate or ethyl 3-bromopropionate, in ethanol, in the
presence of anhydrous potassium carbonate yielded the corre-
sponding ethyl esters 6, 8 and 10, which were consequently
hydrolyzed by heating in 10% aqueous sodium hydroxide solution
to afford the corresponding carboxylic acids 7, 9 and 11 (Scheme 2,
Table 1).
5-(1-Adamantyl)-2-amino-1,3,4-thiadiazole 14 was previously
prepared in 48% yield from adamantane-1-carboxylic acid hydrazide
1 via reaction with potassium thiocyanate and hydrochloric acid to
yield 1-(1-adamantylcarbonyl)-3-thiosemicarbazide 12, followed by
dehydrative cyclization with sulphuric acid at room temperature
(Method A) [29]. Compound 14 was also prepared in 59% yield via
one-step three-component reaction of adamantane-1-carboxylic
acid 13, thiosemicarbazide and phosphorus oxychloride (Method B).
Compound 14 was reacted with phenyl-, 4-fluorphenyl- or 4-chlor-
ophenylisothiocyanate to yield the corresponding N-[5-(1-ada-
mantyl)-1,3,4-thiadiazol-2-yl]-N0-arylthioureas 15aec in poor yields.
5-(1-Adamantyl)-1,3,4-thiadiazoline-2-one 16 was prepared
through deamination of compound 14 via treatment with sodium
nitrite in cold aqueous hydrochloric acid solution followed by boiling
Table 1
Melting points, yield percentages, molecular formulae, molecular weights and analytical data of compounds 4aed, 5aec, 7, 9, 11, 15aec and 16.
Comp. No.
R/X
M.p. (ꢂC)
Yield (%)
Mol. Formula (Mol. Wt.)
Analysis: % Calcd. (Found)
C
H
N
S
3
e
155e6
139e41
133e5
148e50
196e8
93e5
112e4
149e51
208e10
150e2
149e51
295e7
>300
62
75
77
86
90
36
45
52
59
62
55
33
27
34
61
C12H16N2S2 (252.4)
57.10 (57.23)
66.62 (66.40)
63.30 (63.20)
60.54 (60.56)
58.89 (58.90)
59.30 (59.25)
60.28 (60.02)
64.75 (64.52)
54.17 (54.15)
55.53 (55.43)
55.53 (55.38)
61.59 (61.60)
58.74 (58.71)
56.35 (56.40)
60.99 (61.03)
6.39 (6.51)
6.47 (6.52)
5.87 (5.90)
5.62 (5.64)
5.46 (5.47)
7.74 (7.81)
7.99 (8.12)
7.09 (7.11)
5.84 (5.85)
6.21 (6.20)
6.21 (6.27)
5.98 (6.11)
5.45 (5.55)
5.23 (5.24)
6.82 (6.84)
11.10 (10.89)
8.18 (8.09)
7.77 (7.68)
25.41 (25.12)
18.72 (18.65)
17.79 (17.58)
17.01 (16.96)
16.55 (16.53)
17.59 (17.55)
16.94 (16.90)
15.03 (15.0)
20.66 (20.51)
19.77 (19.58)
19.77 (19.76)
17.31 (17.28)
16.51 (16.50)
15.84 (15.68)
13.57 (13.48)
4a
4b
4c
4d
5a
5b
5c
7
H
F
Cl
NO2
CH3
C2H5
C6H5
e
C19H22N2S2 (342.52)
C19H21FN2S2 (360.51)
C19H21ClN2S2 (376.97)
C19H21N3O2S2 (387.52)
C18H28N4S2 (364.57)
C19H30N4S2 (378.60)
C23H30N4S2 (426.64)
C14H18N2O2S2 (310.43)
C15H20N2O2S2 (324.46)
C15H20N2O2S2 (324.46)
C19H22N4S2 (370.53)
7.43 (7.42)
10.84 (10.84)
15.37 (15.40)
14.80 (14.68)
13.13 (13.10)
9.02 (9.0)
8.63 (8.61)
8.63 (8.60)
15.12 (15.10)
14.42 (14.39)
13.83 (13.62)
11.85 (12.02)
9
e
11
15a
15b
15c
16
e
H
4-F
4-Cl
e
C19H21FN4S2 (388.53)
C19H21ClN4S2 (404.98)
C12H16N2OS (236.33)
291e3
165e7

5008
A.A. Kadi et al. / European Journal of Medicinal Chemistry 45 (2010) 5006e5011
N
NH
H3C
Br
B
r
C
S
S
3
COOEt
H
2 C
H
2 C
K
O
O
E
O
C
C
O
K
t
BrCH2COOEt
K2CO3
N
N
CH3
N
N
S
8
S
COOEt
COOEt
S
10
S
N
N
S
1. NaOH/H2O
2. HCl
1. NaOH/H2O
2. HCl
S
COOEt
6
1. NaOH/H2O
2. HCl
N
N
N
N
CH3
COOH
S
11
S
9
S
S
COOH
N
N
S
S
7
COOH
Scheme 2. Synthesis of compounds 7, 9 and 11.
to the lack of the Gram-negative activity, while the moderate Gram-
positive activity was retained. The acetic and propionic acid
derivatives 7, 9 and 11 were characterized by marked activity
against the Gram-positive bacteria but totally inactive against the
The compounds were tested at 20 and 40 mg/kg dose levels which
showed no signs of acute toxicity. The results of the anti-inflamma-
tory activity of the tested compounds (20 & 40 mg/kg) and the potent
anti-inflammatory drug Indomethacin (5 mg/kg) are listed in Table 4.
The tested compounds showed varying degrees of activity. The
highest activity was shown by the propionic acid derivative 9, which
produced strong dose-dependent inhibition of carrageenan-induced
paw oedema (>50%). The activity of the 2-propionic acid derivative 9
was superior to the acetic and 3-propionic acid derivatives 7 and 11
which were weakly or moderately active. The ethylpiperazine
derivative 5b showed weak activity at 20 mg/kg dose level;
increasing the dose to 40 mg/kg did not result in improving the anti-
inflammatory activity. There are in fact a high number of enzyme/
receptors involved in the inflammatory process. Without specific
tests it is quite difficult to hypothesize the mechanism of action of
active compounds, the active compounds may exert their action via
Gram-negative bacteria. In addition, compound
7 showed
moderate activity against C. albicans. The thiourea derivatives
15aec were generally active against the Gram-positive bacteria
and totally inactive against the tested Gram-negative bacteria and
C. albicans. The thiadiazoline-2-one 16 was completely inactive
against the tested microorganisms.
2.3. Acute anti-inflammatory activity
The acute in vivo anti-inflammatory activity of the newly
synthesized compounds 4a, 5b, 7, 9 and 11 was determined following
the carrageenan-induced paw oedema method in rats [32]. The
selection of the representative compounds and dose levels was made
after carrying out pilot experiments which showed the absence of
significant anti-inflammatory activity in compounds 3,15aec and 16.
Table 2
Antimicrobial activity of compounds 3, 4aed, 5aec, 7, 9, 11, 15aec and 16 (200
8 mm disc), the 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
mg/
m
m
m
S
disc) against 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).
H
N
H
N
KNCS / HCl
EtOH
N
H
NH2
NH2
O
O
12
Comp. No.
Diameter of Growth Inhibition Zone (mm)a
1
SA
BS
ML
EC
PA
CA
1. H2SO4, r.t.
2. NH4OH
3
4a
13
e
13
e
e
27
e
20
e
e
e
e
4b
4c
e
e
e
e
e
14
e
e
e
e
e
e
N
N
1. H2NCSNHNH2/POCl3
2. KOH
4d
5a
5b
5c
7
9
11
15a
e
e
e
e
e
e
COOH
13
12
e
14
13
14
22
20
13
14
19
20
e
14
e
e
e
e
S
NH2
e
e
e
14
13
e
e
e
e
18
18
11
13
14
15
e
16
13
e
e
e
17
e
1. NaNO2/HCl
2. H2O, Heat
e
e
e
e
11
e
15
11
12
e
e
e
15b
15c
16
e
e
e
N
N
e
e
e
S
N
NH
e
e
e
S
N
Gentamicin
Ampicillin
Clotrimazole
26
23
NT
25
21
NT
18
19
NT
20
17
NT
19
17
NT
NT
NT
21
N
H
S
O
H
16
X
15a-d
a
Scheme 3. Synthesis of compounds 15aec and 16.
(ꢃ): Inactive (inhibition zone < 10 mm). (NT): Not tested.

A.A. Kadi et al. / European Journal of Medicinal Chemistry 45 (2010) 5006e5011
5009
500.13 MHz for 1H and 125.76 MHz for 13C, the chemical shifts are
expressed in (ppm) downfield from tetramethylsilane (TMS) as
Table 3
The minimal inhibitory concentrations (MIC, mg/ml) of compounds 3, 7, 9, 15b, 15c,
d
the broad spectrum antibacterial drugs Gentamicin, Ampicillin and the antifungal
drug Clotrimazole against Staphylococcus aureus IFO 3060 (SA), Bacillus subtilis IFO
3007 (BS), Micrococcus luteus IFO 3232 (ML), Escherichia coli IFO 3301 (EC), Pseudo-
monas aeruginosa IFO 3448 (PA), and Candida albicans IFO 0583 (CA).
internal standard; coupling constants (J) are expressed in Hz. Elec-
trospray ionization mass spectra (ESI-MS) were recorded on
a Waters QuatroMicro triple quadrupole tandem mass spectrometer
at 4.0 and 3.5 kV for positive and negative ions, respectively. Moni-
toring 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 Fermen-
tation of Osaka (IFO), Osaka, Japan. The reference drugs Ampicillin
trihydrate (CAS 7177-48-2), Clotrimazole (CAS 23593-75-1) and
Indomethacin (CAS 53-86-1) were obtained from SigmaeAldrich
Chemie GmbH, Taufkirchen, Germany. The Sprauge-Dawley rats
were purchased from local animal house (Abu-Rawash, Giza, Egypt).
The animal experiments for the determination of the anti-inflam-
matory activity were carried out in agreement with the pertinent
legal and ethical standards of the international guidelines.
Comp. No.
Minimal Inhibitory Concentration (MIC,
m
g/ml)a
SA
BS
ML
EC
PA
CA
3
7
9
15b
ND
ND
ND
ND
ND
2
ND
2
4
4
2
2
0.5
ND
ND
ND
ND
ND
ND
2
0.5
ND
ND
ND
ND
0.5
2
2
ND
ND
ND
ND
ND
ND
ND
2
ND
ND
ND
ND
1
15c
Gentamicin
Ampicillin
Clotrimazole
2
ND
2
ND
2
ND
ND
a
ND: Not determined.
Table 4
Anti-inflammatory effect of intraperitoneal injection of (20
&
40 mg/kg) of
compounds 4a, 5b, 7, 9, 11 and Indomethacin (5 mg/kg) against carrageenan-induced
paw oedema in rats.
4.1. 5-(1-Adamantyl)-1,3,4-Thiadiazoline-2-Thione (3)
Comp. No.
Mean % Reduction of paw oedema from controla
Potassium N0-(1-adamantylcarbonyl)dithiocarbazate 2 (15.43 g,
0.05 mol) was added portion wise to 98% sulphuric acid (15 mL) and
the resulted clear solution was stirred at room temperature for 24 h.
The mixture was cautiously added to crushed ice (200 gm), stirred
for 1 h, refrigerated for 2 h, and the separated white precipitate was
filtered, washed with water, dried and crystallized from ethanol to
yield 7.8 gm (62%) of the title compound 3 (M.p. 155e6 ꢂC). 1H NMR
20 mg/kg
40 mg/kg
Controlb
4a
5b
7
9
11
0 (ꢀ0.036)
1.12 (ꢀ0.099)c
11.32 (ꢀ0.131)d
29.54 (ꢀ0.097)d
50.60 (ꢀ0.132)d
7.47 (ꢀ0.060)d
0.92 (ꢀ0.082)c
10.62 (ꢀ0.140)d
32.70 (ꢀ0.129)d
65.19 (ꢀ0.144)e
36.83 (ꢀ0.171)d
Indomethacin
(5 mg/kg)
52.79 (ꢀ0.044)
(CDCl3):
d 1.77e1.84 (m, 6H, Adamantane-H), 2.10 (s, 6H, Ada-
mantane-H), 2.14 (s, 3H, Adamantane-H), 6.14 (s, 1H, NH). 13C NMR:
28.36, 36.24, 38.86, 43.39 (Adamantane-C), 156.09 (C-5), 184.35
(C]S). ESI-MS, m/z (Rel. Int.): 252 (Mþ, 100), 209 (12), 195 (17), 135
(87), 119 (18), 59 (79).
a
Results are expressed as mean % inhibition ꢀ S.E.M. (n ¼ 5) and compared with
student “t” test.
b
The group was injected with 1 ml of 0.5% aqueous carboxymethyl cellulose
solution.
Inactive: Significantly different from Indomethacin at p < 0.05.
Activity comparable to Indomethacin (significantly different from Indomethacin
at p < 0.05.
c
d
4.2. 5-(1-Adamantyl)-3-(benzyl- or 4-substituted benzyl)-1,3,4-
thiadiazoline-2-thiones (4a-d)
e
Significantly different (higher than) Indomethacin at p < 0.05.
A mixture of 5-(1-adamantyl)-1,3,4-thiadiazoline-2-thione 3
(0.5 g, 2.0 mmol), the appropriate benzyl- or 4-substituted benzyl
chloride (2.0 mmol) and anhydrous potassium carbonate (0.28 g,
2.0 mmol), in ethanol (15 mL) was heated under reflux for 2 h, and
the solvent was distilled off under reduced pressure. Water (15 mL)
was added to the residue and the separated crude product was
filtered, washed with water, dried and crystallized from ethanol
(4c, 4d) or aqueous ethanol (4a, 4b). 4a: 1H NMR (CDCl3):
inhibition of the cyclooxygenase enzymes like other nonsteroidal
anti-inflammatory agents. In addition, the recently reported activity
of some adamantane derivatives as selective inhibitors of 11
hydroxysteroid dehydrogenase type 1 (11 -HSD1) [33,34] should be
taken into consideration. The 11 -hydroxysteroid dehydrogenase
b-
b
b
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 increasing
d
1.77e1.83 (m, 6H, Adamantane-H), 2.07 (s, 6H, Adamantane-H),
the intracellular cortisone level.
2.13 (s, 3H, Adamantane-H), 4.55 (s, 2H, ArCH2), 7.29e7.34 (m, 3H,
Ar-H), 7.44 (s, 2H, Ar-H). 13C NMR: 28.42, 36.35, 38.10, 43.40
(Adamantane-C), 38.34 (ArCH2), 127.78, 128.69, 129.27, 136.21
(Ar-C), 163.68 (C-5), 180.80 (C]S). ESI-MS, m/z (Rel. Int.): 343 (Mþ
þ1, 14), 342 (Mþ, 66), 309 (12), 148 (85), 135 (19), 105 (14), 91 (100),
3. Conclusion
In this study, new series of 5(1-adamanyl)-1,3,4-thiadiazole
were synthesized and their antimicrobial and anti-inflammatory
activity were determined. Several newly synthesized derivatives
displayed promising antimicrobial and anti-inflammatory activities
compared to known antibacterial, antifungal and anti-inflamma-
tory drugs. Though, the mechanism of the biological activity needs
further investigations, which are in progress.
77 (18). 4b: 1H NMR (CDCl3):
d 1.77e1.81 (m, 6H, Adamantane-H),
2.07 (s, 6H, Adamantane-H), 2.12 (s, 3H, Adamantane-H), 4.52 (s,
2H, ArCH2), 7.0 (t, 2H, Ar-H, J ¼ 8.5 Hz), 7.41e7.43 (m, 2H, Ar-H). 13
C
NMR: 28.41, 36.27, 38.36, 43.27 (Adamantane-C), 37.17 (ArCH2),
115.48,130.94,132.16,161.30 (Ar-C),163.33 (C-5),180.95 (C]S). ESI-
MS, m/z (Rel. Int.): 361 (Mþ þ1, 19), 360 (Mþ, 79), 345 (35), 327 (11),
166 (94), 135 (25), 123 (13), 109 (100). 4c: 1H NMR (CDCl3):
d 1.73 (s,
4. Experimental protocols
6H, Adamantane-H), 1.96 (s, 6H, Adamantane-H), 2.04 (s, 3H,
Adamantane-H), 4.52 (s, 2H, ArCH2), 7.38 (d, 2H, Ar-H, J ¼ 8.5 Hz),
7.45 (d, 2H, Ar-H, J ¼ 8.5 Hz), 13C NMR: 28.35, 36.25, 38.43, 43.31
(Adamantane-C), 38.0 (ArCH2), 129.06, 131.53, 132.74, 136.39 (Ar-C),
163.99 (C-5),180.84 (C]S). EI-MS, m/z (Rel. Int.): 378 (Mþ þ2,14), 376
(Mþ, 33), 343 (5),184(29),182(80),141 (4),139(11),135 (18),127 (39),
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

5010
A.A. Kadi et al. / European Journal of Medicinal Chemistry 45 (2010) 5006e5011
125 (100). 4d: 1H NMR (CDCl3):
d
1.76e1.83 (m, 6H, Adamantane-H),
38.59, 43.38 (Adamantane-C), 40.50 (NCH), 174.27 (C-5), 181.71
2.06 (s, 6H, Adamantane-H), 2.12 (s, 3H, Adamantane-H), 4.60 (s, 2H,
(C]S), 184.12 (C]O). ESI-MS, m/z (Rel. Int.): 325 (Mþ þ1, 13), 324
ArCH2), 7.64 (d, 2H, Ar-H, J ¼ 8.5 Hz), 8.17 (d, 2H, Ar-H, J ¼ 8.5 Hz), 13
C
(Mþ, 18), 323 (100). 11: 1H NMR (CDCl3):
d 1.73e1.83 (m, 8H, Ada-
NMR: 28.37, 36.29, 38.42, 43.40 (Adamantane-C), 36.59 (ArCH2),
123.83, 130.47, 144.44, 148.33 (Ar-C), 162.32 (C-5), 181.88 (C]S). ESI-
MS, m/z(Rel. Int.):388(Mþ þ1, 23), 387(Mþ,100), 354(6), 265 (4),193
(34), 182 (80), 150 (7), 136 (38), 135 (47), 121 (15).
mantane-H, NCH2), 1.94e1.96 (m, 8H, Adamantane-H, CH2CO), 2.05
(s, 3H, Adamantane-H), 11.85 (br. s, 1H, COOH). 13C NMR: 27.85,
36.15, 38.60, 42.23 (Adamantane-C), 28.14 (NCH2), 40.49 (CH2CO),
174.29 (C-5), 183.91 (C]S), 188.92 (C]O). ESI-MS, m/z (Rel. Int.):
325 (Mþ þ1, 20), 324 (Mþ, 23), 323 (100).
4.3. 5-(1-Adamantyl)-3-(4-substituted-1-piperazinylmethyl)-1,3,4-
thiadiazoline-2-thiones (5aec)
4.5. 5-(1-Adamantyl)-2-amino-1,3,4-thiadiazole (14)
A mixture of 5-(1-adamantyl)-1,3,4-thiadiazoline-2-thione 3
(0.5 gm, 2.0 mmol), the N-substituted piperazine (2.0 mmol) and
37% formaldehyde solution (1 mL), in ethanol (8 mL), was heated
under reflux for 2 h and stirred at room temperature for 24 h. The
crude product was separated in case of compound 5c, while in
case of compounds 5a and 5b it was necessary to add water
(5 ml) to precipitate the products. The crude products were
filtered, washed with water, dried and crystallized from ethanol
Method A [29]: 98% Sulphuric acid (20 mL) was added to
1-(1-adamantylcarbonyl)-3-thiosemicarbazide 12 (12.67 gm,
0.05 mol), and the mixture was stirred for 24 h at room tempera-
ture. The mixture was then poured onto crushed ice (200 gm),
neutralized with concentrated ammonium hydroxide solution and
stirred for 20. The separated crude product was filtered, washed
with water, dried and crystallized from aqueous ethanol to yield
5.65 g (48%) of the title compound 14 (M.p. 201e3 ꢂC) [29]. Method
B: Phosphorus oxychloride (20 ml) was added to adamantane-1-
carboxylic acid 13 (9 gm, 0.05 mol) and the mixture was stirred for
20 min at room temperature. Thiosemicarbazide (4.56 gm,
0.05 mol) was added and the mixture was heated under reflux for
1 h. On cooling, water (50 mL) was added dropwise and cautiously
with continuous stirring to decompose the excess phosphorus
oxychloride. The mixture was then heated under reflux for 4 h. On
cooling, the mixture was neutralized by addition of potassium
hydroxide pellets and refrigerated overnight. The precipitated
crude product was filtered, washed with water, dried and crystal-
lized from aqueous ethanol to yield 6.94 g (59%) of the title
(5c) or aqueous ethanol (5a, 5b). 5a: 1H NMR (CDCl3):
d 1.73e1.80
(m, 6H, Adamantane-H), 1.94 (s, 3H, Adamantane-H), 2.05 (s, 6H,
Adamantane-H), 2.34 (s, 3H, CH3), 2.61e2.78 (m, 4H, Piperazine-
H), 2.99 (s, 4H, Piperazine-H), 5.25 (s, 2H, CH2). 13C NMR: 27.98,
36.05, 38.43, 42.11 (Adamantane-C), 46.52 (CH3), 50.12, 52.68
(Piperazine-C), 70.13 (CH2), 168.33 (C-5), 186.75 (C]S). ESI-MS, m/
z (Rel. Int.): 364 (Mþ, 1), 252 (9), 135 (46), 113 (100), 98 (7). 5b: 1H
NMR (CDCl3):
d
1.08 (t, 3H, CH3CH2, J ¼ 7.0 Hz), 1.71e1.80 (m, 6H,
Adamantane-H), 1.88 (s, 3H, Adamantane-H), 1.92 (s, 6H, Ada-
mantane-H), 2.48 (q, 2H, CH3CH2, J ¼ 7.0 Hz), 2.58 (br. s, 4H,
Piperazine-H), 2.93 (s, 4H, Piperazine-H), 5.24 (s, 2H, CH2). 13C
NMR: 11.22 (CH3CH2), 28.12, 36.15, 38.99, 42.08 (Adamantane-C),
49.71 (CH3CH2), 51.98, 52.23 (Piperazine-C), 70.01 (CH2), 169.26
(C-5), 188.01 (C]S). ESI-MS, m/z (Rel. Int.): 378 (Mþ, 1), 266 (3),
compound 14 (M.p. 201e3 ꢂC). 1H NMR (CDCl3):
d 1.79 (s, 6H,
Adamantane-H), 2.04 (s, 6H, Adamantane-H), 2.11 (s, 3H, Ada-
mantane-H), 5.25 (s, 2H, NH2). 13C NMR: 28.46, 36.45, 38.11, 43.24
(Adamantane-C), 166.82 (C-5), 171.34 (C-2). ESI-MS, m/z (Rel. Int.):
235 (Mþ, 92), 202 (9), 178 (32), 135 (100).
252 (30), 135 (100), 127 (56). 5c: 1H NMR (CDCl3):
d 1.73e1.80 (m,
6H, Adamantane-H), 2.10 (s, 6H, Adamantane-H), 2.14 (s, 3H,
Adamantane-H), 3.03 (s, 4H, Piperazine-H), 3.20 (s, 4H, Pipera-
zine-H), 5.31 (s, 2H, CH2), 6.93e7.28 (m, 5H, Ar-H). 13C NMR:
28.36, 36.25, 38.86, 43.39 (Adamantane-C), 49.47, 50.42 (Pipera-
zine-C), 70.33 (CH2), 116.35, 120.04, 129.14, 151.27 (Ar-C), 165.85
(C-5), 184.34 (C]S). ESI-MS, m/z (Rel. Int.): 426 (Mþ, 1), 263 (2),
265 (1), 252 (100), 195 (7), 175 (66), 135 (65).
4.6. N-[5-(1-Adamantyl)-1,3,4-thiadiazol-2-yl]-N0-arylthioureas
(15aec)
The appropriate arylisothiocyanate (2.0 mmol) was added to
a
solution of 5-(1-adamantyl)-2-amino-1,3,4-thiadiazole 14
(0.47 gm, 2.0 mmol) in dry DMF (10 mL) and the mixture was
heated under reflux for 6 h. On cooling, the mixture was poured
onto cold water (15 mL) and the separated precipitate was filtered,
washed with water and crystallized from ethanol (15b, 15c) or
aqueous ethanol (15a) to yield compounds 15aec. 15a: 1H NMR
4.4. 2-[5-(1-Adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]acetic
acid (7), (ꢀ)-2-[5-(1-Adamantyl)-2-thioxo-1,3,4-thiadiazolin-3-yl]-
propionic acid (9), and 3-[5-(1-Adamantyl)-2-thioxo-1,3,4-
thiadiazolin-3-yl]propionic acid (11)
(DMSO-d6): d 1.72 (s, 6H, Adamantane-H), 1.91 (s, 6H, Adamantane-
A mixture of 5-(1-adamantyl)-1,3,4-thiadiazoline-2-thione 3
(0.5 gm, 2.0 mmol), the appropriate ethyl bromoester (2.0 mmol)
and anhydrous potassium carbonate (0.28 gm, 2.0 mmol), in
ethanol (15 mL), was heated under reflux for 2 h, and the solvent
was distilled off under reduced pressure. 10% Aqueous sodium
hydroxide (15 mL) was added to the residue and the mixture was
heated under reflux for 1 h and filtered hot. The cold filtrate was
acidified with hydrochloric acid to pH 2e3 and allowed to stand for
3 h. The separated crude product was filtered, washed with water,
dried and crystallized from aqueous ethanol. 7: 1H NMR (CDCl3):
H), 2.02 (s, 3H, Adamantane-H), 6.97 (s, 3H, Ar-H), 7.34e7.45 (m, 2H,
Ar-H), 11.05 (br. s, 2H, NH). 13C NMR: 28.38, 36.45, 37.72, 43.27
(Adamantane-C), 122.19, 125.15, 129.07, 136.58 (Ar-C), 168.0 (C-5),
172.44 (C-2), 186.42 (C]S). ESIeMS, m/z (Rel. Int.): 370 (Mþ, 3), 235
(94), 220 (4), 135 (59), 91 (100). 15b: 1H NMR (DMSO-d6):
d 1.75 (s,
6H, Adamantane-H), 1.99 (s, 6H, Adamantane-H), 2.06 (s, 3H,
Adamantane-H), 6.82e6.86 (m, 2H, Ar-H), 7.22e7.36 (m, 2H, Ar-H),
11.0 (br. s, 2H, NH). 15c: 1H NMR (DMSO-d6):
d 1.74e1.82 (m, 6H,
Adamantane-H), 2.03 (s, 6H, Adamantane-H), 2.10 (s, 3H, Ada-
mantane-H), 7.02 (d, 2H, Ar-H, J ¼ 7.5 Hz), 7.31 (d, 2H, Ar-H,
J ¼ 7.5 Hz), 10.87 (br. s, 2H, NH). 13C NMR: 28.03, 36.44, 38.10, 43.22
(Adamantane-C), 122.96, 128.85, 129.05, 138.55 (Ar-C), 167.48 (C-5),
171.99 (C-2), 188.59 (C]S).
d
1.71e1.82 (m, 6H, Adamantane-H), 1.94e1.96 (m, 6H, Ada-
mantane-H), 2.05 (s, 3H, Adamantane-H), 2.12 (s, 2H, NCH2), 11.80
(br. s, 1H, COOH). 13C NMR: 28.14, 36.15, 38.64, 42.24 (Adamantane-
C), 40.49 (NCH2), 174.33 (C-5), 183.13 (C]S), 188.85 (C]O). ESI-MS,
m/z (Rel. Int.): 311 (Mþ þ1, 11), 310 (Mþ, 18), 319 (100). 9: 1H NMR
4.7. 5-(1-Adamantyl)-1,3,4-thiadiazoline-2-one (16)
(CDCl3):
d 1.69e1.85 (m, 9H, Adamantane-H, CH3), 1.93 (s, 6H,
Adamantane-H), 2.04 (s, 3H, Adamantane-H), 2.14e2.16 (m, 1H,
10% Aqueous sodium nitrite solution (10 mL) was added drop-
wise to an ice-cooled suspension of 5-(1-adamantyl)-2-amino-
NCH), 11.78 (br. s, 1H, COOH). 13C NMR: 17.11 (CH3), 27.85, 36.43,

A.A. Kadi et al. / European Journal of Medicinal Chemistry 45 (2010) 5006e5011
5011
1,3,4-thiadiazole 14 (2.35 gm, 0.01 mol) and hydrochloric acid
Acknowledgements
(5 mL) in cold water (20 mL), with continuous stirring over a period
of 20 min. The temperature was then allowed to rise to room
temperature and the mixture was heated to boiling for 10 min,
cooled and allowed to stand overnight. The separated crude
product was filtered, washed with water, dried and crystallized
from aqueous ethanol to yield 1.44 gm (61%) of compound 16. 1H
The financial support of the Research Center of the College of
Pharmacy, King Saud University is greatly appreciated.
NMR (CDCl3):
d 1.74e1.82 (m, 6H, Adamantane-H), 2.01 (s, 3H,
References
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ESI-MS, m/z (Rel. Int.): 236 (Mþ, 17), 235 (Mþþꢃ1, 43), 220 (100),
163 (25), 135 (83), 100 (8).
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