Synthesis, crystal structure, anti-HIV, and antiproliferative activity of new oxadiazole and thiazole analogs

Article abstract of DOI:10.1007/s00044-016-1669-9

A series of 2-adamantyl-5-arylthiazolyl-1,3,4-oxadiazoles 7a–x together with thiazoles 13 and 14 were synthesized. Compounds 7a–l, 13, and 14 were tested in vitro with the aim of identifying novel lead compounds active against human immunodeficiency virus type-1 and human immunodeficiency virus type-2 activity in MT-4 cells. Title compounds were also tested against representatives of Gram-positive and Gram-negative bacteria (Staphylococcus aureus, Salmonella spp.), various mycobacterial strains (Mycobacterium fortuitum and Mycobacterium smegmatis), yeast (Candida albicans), and mold (Aspergillus fumigatus). None of the compounds showed antiviral or antimicrobial activity, except compounds 13 and 14 exhibited anti-human immunodeficiency virus-1 activity with EC₅₀ values of 1.79 and 2.39 μM with Selectivity index = 18 and 4, respectively. On the other hand, compounds 7a and 7j showed a marked cytotoxicity against the human CD4⁺ lymphocytes (MT-4). Therefore, 7a and 7j were evaluated for their antiproliferative activity against two solid tumor-derived cell lines, which exhibited IC₅₀ values of 8.1 ± 0.10 μM and 4.8 ± 0.08 μM against Hep-G2 cell lines, respectively.

Full text of DOI:10.1007/s00044-016-1669-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1669-9
ORIGINAL RESEARCH
Synthesis, crystal structure, anti-HIV, and antiproliferative activity of
new oxadiazole and thiazole analogs
Mahmood-ul-Hassan Khan1 Shahid Hameed1 Tashfeen Akhtar1,2
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Najim A. Al-Masoudi3 Wasfi A. Al-Masoudi4 Peter G. Jones5
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Christophe Pannecouque6
Received: 22 November 2015 / Accepted: 4 July 2016
© Springer Science+Business Media New York 2016
Abstract A series of 2-adamantyl-5-arylthiazolyl-1,3,4-
oxadiazoles 7a–x together with thiazoles 13 and 14 were
synthesized. Compounds 7a–l, 13, and 14 were tested
in vitro with the aim of identifying novel lead compounds
active against human immunodeficiency virus type-1 and
human immunodeficiency virus type-2 activity in MT-4
cells. Title compounds were also tested against representa-
tives of Gram-positive and Gram-negative bacteria
(Staphylococcus aureus, Salmonella spp.), various myco-
bacterial strains (Mycobacterium fortuitum and Myco-
bacterium smegmatis), yeast (Candida albicans), and mold
(Aspergillus fumigatus). None of the compounds showed
antiviral or antimicrobial activity, except compounds 13 and
14 exhibited anti-human immunodeficiency virus-1 activity
with EC50 values of 1.79 and 2.39 μM with Selectivity
index = 18 and 4, respectively. On the other hand, com-
pounds 7a and 7j showed a marked cytotoxicity against the
human CD4+ lymphocytes (MT-4). Therefore, 7a and 7j
were evaluated for their antiproliferative activity against
two solid tumor-derived cell lines, which exhibited IC50
values of 8.1 0.10 µM and 4.8 0.08 µM against Hep-G2
cell lines, respectively.
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Keywords Anti-HIV activity Antiproliferative activity
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Adamantyl derivatives Oxadiazole Thiazoles
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1669-9) contains supplementary material,
which is available to authorized users.
Introduction
Najim A. Al-Masoudi’s present address: Am Tannenhof 8, 78464
Konstanz, Germany
Reverse transcriptase (RT) is a key enzyme that plays an
essential and multifunctional role in the replication of the
human immunodeficiency virus type-1 (HIV-1), and thus
constitutes an attractive target for the development of new
drugs useful in acquired immune deficiency syndrome
therapy (Jonckheere et al., 2000; De Clercq, 2009).
Thiourea is an important building block of a number of
heterocycles such as thiazoles (Dodson and King, 1945),
where several heterocyclic thioureas have been reported as a
new class of potent non-nucleoside reverse transcriptase
inhibitors (NNRTIs) (Ahgren et al., 1995; Heinisch et al.,
1997; Ren et al., 2000; D’Cruz et al., 2004; D’Cruz, 2006),
one example being phenethylthiazolylthiourea (PETT)
(Cantrell et al., 1996) (1). Uckun and Venkatachalam
(2005) described the synthesis of a series of thiazole
thioureas with alkyl, aryl, and heteroaryl substituents as
* Najim A. Al-Masoudi
Najim.al-masoudi@gmx.de
1
Department of Chemistry, Quaid-i-Azam University, Islamabad
45320, Pakistan
2
Department of Chemistry, Mirpur University of Science and
Technology (MUST), Mirpur, Azad Jammu & Kashmir, Pakistan
3
Department of Chemistry, College of Science, University of
Basrah, Basrah, Iraq
4
Department of Physiology, Pharmacology and Chemistry, College
of Veterinary Medicine, University of Basrah, Basrah, Iraq
5
Institut für Anorganische und Analytische Chemie, Technische
Universität Braunschweig, Hagenring 30, Braunschweig 38106,
Germany
6
Rega Institute for Medical Research, Katholieke Universiteit
Leuven, Leuven B-3000, Belgium

Med Chem Res
newly identified NNRTIs for HIV, including mutant strains
of HIV, and effective in the treatment of multi-drug resistant
HIV infection. However, significant resistance has been
developed against the current NNRTIs and there is an
urgent need to develop new anti-HIV agents that are
effective against these resistant mutants (Wainberg et al.,
2005; Imamichi, 2004). In this context, thiazolo thiourea
derivatives appear as a promising class of compounds, since
some 1,3-thiazole analogs exhibit remarkable anti-HIV
activity (Xu et al., 2014; Zia et al., 2012) besides many
other pharmacological activities such as anticancer
(Dawood et al., 2013). Thiazole-containing drug molecules
are currently being used in the treatment of various central
nervous system disorders (Mishra et al., 2015). Further-
more, the adamantyl group has been revealed as a promis-
ing pharmacophore and some adamantyl derivatives are
under clinical trial for 11β-hydroxysteroid dehydrogenase
type 1 (Yu et al., 2013). Many other investigations have
revealed the activity of its derivatives against HIV (Khan
et al., 2012), hepatitis (Maynard et al., 2006), cancer (Cai
et al., 2014), and some other biological disorders (Baxter
et al., 2003).
2-adamantyl/adamantylmethyl-5-arylthiazolyl-1,3,4-oxadia-
zoles and two new thiazole thioureido analogs (Fig. 1),
structurally similar to the powerful class of NNRTIs PETT
analogs. Our aim was to investigate their anti-HIV, anti-
fungal, and antibacterial activities, as well as anti-
proliferative activity against two solid-derived tumor cells.
Results and discussion
Chemistry
In the present work,
a series of 2-adamantyl/ada-
mantylmethyl-5-arylthiazolyl-1,3,4-oxadiazole derivatives
7a–x were synthesized from aryl nitriles 2a–l through a
multi-step reaction sequence (Scheme 1). Aryl nitriles were
converted to aryl thioamide derivatives 3a–l, which upon
cyclization with ethyl bromopyruvate, followed by hydra-
zinolysis yielded 2-aryl-1,3-thiazole-4-carbohydrazide ana-
logs 5a–l. Treatment of 5a–l with adamantyl-1-carboxylic
acid 6 in the presence of POCl3 afforded 7a–l (68–81 %).
Similarly, treatment of 5a–l with adamantylacetic acid 8
gave 7m–x in 71–80 % yields.
In continuation of our attempts to develop new potent
HIV-1 NNRTIs (Khan et al., 2010, 2012, 2015; Zahid et al.,
2009; Akhtar et al., 2008), we report herein a new series of
The structures of 7a–x were confirmed by infrared (IR),
1H, and 13C nuclear magnetic resonance (NMR) spectra.
Fig. 1 Potent anti-HIV agents
Scheme 1 Synthesis of 2-
adamantyl/adamantylmethyl-5-
arylthiazolyl-1,3,4-oxadiazole
derivatives 7a–x

Med Chem Res
Fig. 2 The molecular structure
of 7a in the crystal, showing
crystallographic numbering
scheme. Displacement ellipsoids
are drawn at 50 % probability
level
In the 1H NMR spectra, two signals integrating for 15
protons, in the region of δ 1.53–2.19 ppm, were assigned to
adamantyl moiety, whereas the two methylene protons in
7m–x appeared in the region of δ 2.69–2.76 ppm. H-5 of
thiazole backbone resonated in the range of δ 7.79–8.28
ppm. In 13C-NMR spectra, the resonances from δ 27.7 to
42.2 ppm were assigned to adamantyl carbon atoms,
whereas the methylene carbon atoms in compounds 7m–x
appeared in the region of δ 39.5–39.6 ppm. C-2, C-4, and
C-5 of the thiazole ring were observed in the regions δ
Compound 13 was selected for further NMR studies. The
gradient heteronuclear multiple bond correlation spectrum
3
(Willker et al., 1993) revealed a JCH coupling of NHCH2
protons at δH 3.83 ppm with C = S at δC 178.9 ppm.
In addition, the coupling between H-5 of thiazole ring
at δH 9.12 ppm and C = O at δC 165.9 ppm was observed
(Fig. 3).
In vitro anti-HIV activity
162.2–170.1, 140.1–141.6, and
δ
120.9–123.0 ppm,
Compounds 7a–l, 13, and 14 were tested for their in
vitro anti-HIV-1 and anti-HIV-2 activities in human
T-lymphocyte (MT-4) cells based on Microculture Tetra-
zolium Assay (MTT) method (Pannecouque et al., 2008).
The anti-HIV-1 activity was measured using strain IIIB,
while anti-HIV-2 activity was carried out on strain ROD.
The results are given in Table 1, where the data for nevir-
apine (Hargrave et al., 1991) is included for comparison
purposes. Compound‐induced cytotoxicity was also mea-
sured in MT‐4 cells parallel with the antiviral activity. All
the compounds were found to be inactive except com-
pounds 13 and 14, which showed remarkable anti-HIV-1
activity with EC50 values of 1.79 and 2.93 μM, and CC50
values of 33.22 and 11.72 μM, resulting in SI values of 18
and 4, respectively.
With respect to structure-activity relationship studies,
Bell et al. (1995) observed that meta and ortho substitutions
generally triggers better activities, when compared to para,
in the PETT analogs. As regards the electronic nature of the
ortho substituents, both small electron-donating and small
electron-withdrawing groups revealed good activities, and
among these the preferred groups are: fluoro, chloro, azido,
and methoxy (de Souza et al., 2011). Accordingly, the
combined four portions (o-chlorophenyl moiety, ethyl
group, thioureido residue, and thiazole scaffold) of com-
pound 13 are considered as the optimal substituents that
would give rise to the optimal activity. After proceeding
with docking studies, it was observed that compounds 13
and 14 are well tolerated in the hydrophobic region of HIV
RT and showed higher activity than those of 7a–x analogs.
In conclusion, compound 13 was found to be a potent agent
respectively. The C-2 and C-5 of oxadiazole ring resonated
in the regions δ 165.1–172.8 and 160.1–160.8 ppm,
respectively. The electron ionization mass spectrometery
(EI-MS) spectral data also supported the structures of 7a–x,
where molecular ion peaks were observed for all the syn-
thesized compounds.
The structures of the synthesized compounds were
unambiguously confirmed by single crystal X-ray diffraction
study of compound 7a as a representative molecule (Fig. 2);
colorless crystals of 7a were obtained from chloroform.
Next, our attention focused on synthesis of new thiazole
thioureido derivatives as potentially active anti-HIV agents.
Thus, treatment of acyl chloride 9 with NH4SCN in acetone,
following Kabbani’s approach (Kabbani et al., 2005)
afforded 10, which was directly treated with the amines 11
and 12 to give, after purification, the thiazole thioureido
derivatives 13 and 14 in 82 and 79 % yields, respectively.
The synthetic reactions are summarized in Scheme 2.
Structures of the newly synthesized compounds 13 and
1
14 were assigned using H, 13C-NMR, and mass spectral
1
data. The H NMR spectra showed similar patterns for the
phenyl protons, while the two triplets at δ 2.94 and δ 3.83
ppm were attributed to CH2Ph and CH2N methylene pro-
tons (J = 6.5 Hz), respectively. H-5 of the thiazole ring
appeared as a singlet at δ 9.12 and 9.09 ppm, respectively.
In the 13C-NMR spectra of 13 and 14, the resonances at δ
30.1, 29.6 ppm and δ 45.6, 46.1 ppm were attributed to
CH2Ph and CH2N methylene carbon atoms. Carbon atoms
of the thiazole and phenyl moieties have been fully ana-
lyzed (c.f. Experimental section).

Med Chem Res
Scheme 2 Reagents and
conditions: (i) NH4SCN,
acetone, reflux, 1 h; (ii) 11 or 12,
NaOH, reflux, 6 h
used to study antifungal activity. Antibacterial activity was
evaluated against six bacterial strains, i.e., Escherichia coli,
Bacillus subtillus, Shigella flexenari, Staphylococcus aur-
eus, Pseudomonas aeruginosa, and Salmonella typhi.
However, at nontoxic concentrations (10 µM), the activities
of the synthesized compounds were found to be non-
significant against the tested fungi and bacteria.
Fig. 3 JC,H correlations in the HMBC NMR spectrum of 13
Experimental
against HIV-1 and identified as a new candidate to act as a
NNRTI; it might be considered a promising agent for fur-
ther structural modifications and pharmacological
evaluation.
Chemistry
Melting points of the synthesized compounds were mea-
sured in open capillaries using Stuart SMP3 melting point
apparatus and are uncorrected. The IR spectra were recor-
ded on Schimadzu Fourier Transform Infra-red spectro-
photometer (Model 270), using KBr disks. 1H and 13C
NMR spectra were recorded on Bruker Avance 300 (1H)
and 75 MHz (13C) spectrometers, unless otherwise stated,
using CDCl3 solvent containing tetramethylsilane as an
internal standard (chemical shifts in δ, ppm). Micro-
analytical data were obtained with a Vario elemental
apparatus (Shimadzu, Japan). The EI-MS was carried out
using Agilent Technologies 6890N (GC) with an inert
selective detector 5973 mass spectrometer. The reagents
used were of analytical grade while the solvents were pur-
ified before use.
In-vitro antiproliferative activity
Due to the marked cytotoxicity of compounds 7a and 7j
against the human CD4+ lymphocytes (MT-4) (Vicini et al.,
2006), they were selected for their antiproliferative activity
in vitro against two solid tumor-derived cell lines consisting
Hep-G2 (human hepatocarcinoma) and MCF-7 (breast can-
cer) cell line using MTT assay (Alley et al., 1988). For
comparative purposes, we evaluated the cytotoxic activities
of the compounds relative to doxorubicin (Uyeki et al.,
1981). However, both compounds were inactive against
MCF-7 cell line (IC50 > 50 µM). On the other hand, com-
pound 7a with ortho methyl (IC50 = 8.1 0.10 µM) and 7j
with ortho bromo (IC50 = 4.8 0.08 µM) moieties exerted
cytotoxic effects towards Hep-G2 cell lines. Unfortunately,
both compounds did not show superior activity than doxor-
ubicin against Hep-G2 cell lines with IC50 value of 0.03 µM.
General procedure for the preparation of 2-adamantyl/ada-
mantylmethyl-5-arylthiazolyl-1,3,4-oxadiazoles (7a–x)
Treatment of aryl nitriles 2 with 70 % NaSH in the presence
of MgCl2.6H2O afforded the corresponding aryl thioamides
3, which cyclized to the thiazole ester derivatives 4 on
treatment with ethyl bromopyruvate. Treatment of 4 with
hydrazine hydrate afforded the corresponding 2-aryl-1,3-
thiazole-4-carbohydrazides 5a–l (Zia et al., 2012). A sus-
pension of 5a–l (0.50 mmol), adamantyl-1-carboxylic
acid 6 (0.50 mmol) or adamantylacetic acid 8 (0.50 mmol)
In vitro antimicrobial activity
Compounds 7a–x were tested for their antifungal and
antibacterial activities. Six fungal strains viz. Trichphyton
longifusus, Candida albicans, Aspergillus flavus, Micro-
sporum canis, Fusarium solani, and Candida glabrata were

Med Chem Res
Table 1 In vitro anti-HIV-1 and HIV-2 activity of 2-adamantyl/
adamantylmethyl-5-arylthiazolyl-1,3,4-oxadiazoles 7a–l, and the
analogs 13 and 14
2-[(Adamantan-1-yl)-5-(2-(2-methylphenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7a) From 5a (117 mg). Yield: 141
mg (75 %); Mp 150–152 °C; FTIR (νmax, cm−1): 3097,
Compounds Virus strain EC50 (µM)a CC50 (µM)b SIc
1
2904, 2849, 1604, 1556, 1203. H NMR (CDCl3): δ = 1.83
(m, 6H, Hadamantane), 2.17 (m, 9H, Hadamantane), 2.64 (s, 3H,
Ar–Me), 7.29–7.42 (m, 3H, Harom.), 7.77 (m, 1H, Harom.),
7.79 (s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 21.4 (CH3),
27.7, 34.5, 36.3, 39.9 (10 × Cadamantane), 122.1 (C5thiazole),
126.2, 130.1, 130.2, 131.5, 132.1, 136.9 (6 × Carom.), 140.7
(C4thiazole), 160.4 (C5oxadiazole), 169.4 (C4thiazole), 172.7
(C2oxadiazole). EI-MS (m/z, %): 377 ([M]+, 100), 202 (27),
174 (9), 135 (57), 117 (12), 107 (7), 93 (18), 91 (24), 79
(25). Anal. Calcd. for C22H23N3OS: C, 70.00; H, 6.14; N,
11.13. Found: C, 69.85; H, 6.04; N, 10.93.
7a
IIIB
>10.50
>10.50
>125.00
>125.00
>105.70
>105.70
>97.60
>97.60
>125.00
>125.00
>75.20
>75.20
>125.00
>125.00
>125.00
>125.00
>125.00
>125.00
>10.90
>10.90
>125.00
>125.00
>110.00
>110.00
1.79
≥10.50
≥10.50
>125.00
>125.00
105.70
105.70
≥97.60
≥97.60
>125.00
>125.00
75.20
< or X1
< or X1
X1
ROD
IIIB
7b
ROD
IIIB
X1
7c
<1
ROD
IIIB
<1
7d
< or X1
< or X1
X1
ROD
IIIB
7e
ROD
IIIB
X1
7f
<1
2-[(Adamantan-1-yl)-5-(2-(3-methylphenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7b) From 5b (117 mg). Yield: 134
mg (71 %); Mp 183–184 °C; FTIR (νmax, cm−1): 3102,
ROD
IIIB
75.20
<1
7g
>125.00
>125.00
>125.00
>125.00
>125.00
>125.00
10.90
X1
1
2904, 2850, 1607, 1560, 1205. H NMR (CDCl3): δ = 1.84
ROD
IIIB
X1
(br s, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane), 2.46 (s,
3H, Ar–Me), 7.30 (m, 1H, Harom.), 7.38 (m, 1H, Harom.),
7.84 (m, 1H, Harom.), 7.91 (m, 1H, Harom.), 8.09 (s, 1H,
7h
X1
ROD
IIIB
X1
7i
X1
H
thiazole). 13C NMR (CDCl3): δ = 21.4 (CH3), 27.8, 34.5,
ROD
IIIB
X1
36.3, 40.0 (10 × Cadamantane), 121.3 (C5thiazole), 124.2, 127.5,
128.9, 131.7, 132.6, 138.9 (6 × Carom.), 141.3 (C4thiazole),
160.3 (C5oxadiazole), 170.1 (C2thiazole), 172.7 (C2oxadiazole).
EI-MS (m/z, %): 377 ([M]+, 100), 202 (13), 174 (9), 135
(31), 117 (12), 107 (10), 93 (11), 91 (7), 79 (20). Anal.
Calcd. for C22H23N3OS: C, 70.00; H, 6.14; N, 11.13.
Found: C, 69.79; H, 6.01; N, 10.88.
7j
<1
ROD
IIIB
10.90
<1
7k
>125.00
>125.00
≥110.00
≥110.00
32.22
X1
ROD
IIIB
X1
7l
< or X1
< or X1
18
ROD
IIIB
13
ROD
IIIB
>32.22
2.93
32.22
<1
2-[(Adamantan-1-yl)-5-(2-(4-methylphenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7c) From 5c (117 mg): Yield: 149
mg (79 %); Mp 196–198 °C; FTIR (νmax, cm−1): 3093,
14
11.72
4
ROD
IIIB
>11.72
0.05
11.72
<1
1
2915, 2849, 1601, 1552, 1203. H NMR (CDCl3): δ = 1.84
Nevirapine
>4
>80
<1
(br s, 6H, Hadamantane), 2.17 (m, 9H, Hadamantane), 2.43 (s,
3H, Ar–Me), 7.29 (d, 2H, J = 8.1 Hz, Harom.), 7.96 (d, 2H,
J = 8.1 Hz, Harom.), 8.06 (s, 1H, Hthiazole). 13C NMR
ROD
>4
>4
Anti-HIV-1 activity measured on strain IIIB
Anti-HIV-2 activity measured using strain ROD
aCompound concentration required to achieve 50 % protection of
MT-4 cells from HIV-1 and HIV-2-induced cytopathogenic effects
bCompound concentration that reduces the viability of mock-infected
MT-4 cells by 50 %
(CDCl3): δ = 21.5 (CH3), 27.8, 34.5, 36.3, 39.7 (10 × Cada-
5
(C thiazole), 125.8, 126.9, 129.7, 130.1 (6 ×
mantane), 120.9
C
arom.), 141.2 (C4thiazole), 160.3 (C5oxadiazole), 170.0
(C2thiazole), 172.6 (C2oxadiazole). EI-MS (m/z, %): 377 ([M]+,
100), 202 (22), 174 (7), 135 (36), 117 (13), 107 (8), 93 (15),
91 (12), 79 (23). Anal. Calcd. for C22H23N3OS: C, 70.00;
H, 6.14; N, 11.13. Found: C, 69.80; H, 6.03; N, 10.98.
cSelectivity index (SI) (CC50/EC50). Data represent mean values ( S.
D.) for two independent determinations
2-[(Adamantan-1-yl)-5-(2-(2-fluorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7d) From 5d (119 mg). Yield: 130
mg (68 %); Mp 189–190 °C; FTIR (νmax, cm−1): 3080,
and POCl3 (5 mL) was heated under reflux for 4 h
(Khan et al., 2015). The reaction mixture was then cooled to
room temperature, poured onto crushed ice and neutralized
using solid K2CO3 and KOH to pH 8. The precipitated solid
was filtered, washed with excess water, and purified through
column chromatography (n-hexane-ethyl acetate; 7:3) to
afford thiazolyloxadiazoles 7a–x.
1
2919, 2881, 1577, 1552, 1203, 1195. H NMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane), 7.24
(m, 1H, Harom.), 7.33 (m, 1H, Harom.), 7.47 (m, 1H, Harom.),
8.18 (s, 1H, Hthiazole), 8.49 (m, 1H, Ar–H). 13C NMR
(CDCl3): δ = 27.8, 34.5, 36.3, 40.0 (10 × Cadamantane), 116.1

Med Chem Res
(d, JC-F = 21.8 Hz, C3arom.), 120.5 (d, JC-F = 11.3 Hz,
C1arom.), 121.3 (C5thiazole), 122.7 (d, JC-F = 9.8 Hz, C6arom.),
124.8 (d, JC-F = 3.0 Hz, C5arom.), 131.9 (d, JC-F = 9.0 Hz,
C4arom.), 140.3 (C4thiazole), 160.2 (d, JC-F = 251.3 Hz,
C2arom.), 160.3 (C5oxadiazole), 162.2 (C2thiazole), 172.7
(C2oxadiazole). EI-MS (m/z, %): 380/382 ([M]+, 100), 206
(28), 178 (9), 135 (88), 121 (8), 107 (16), 93 (13), 79 (14).
Anal. Calcd. for C21H20FN3OS: C, 66.12; H, 5.28; N,
11.02. Found: C, 65.94; H, 5.21; N, 10.93.
(C2oxadiazole). EI-MS (m/z, %): 397/399 ([M]+, 100), (69),
107 (5), 93 (9), 79 (11). Anal. Calcd. for C21H20ClN3OS: C,
63.39; H, 5.15; N, 10.56. Found: C, 63.18; H, 5.03; N,
10.33.
2-[(Adamantan-1-yl)-5-(2-(3-chlorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7h) From 5h (127 mg). Yield: 155
mg (78 %); Mp 198–200 °C; FTIR (νmax, cm−1): 3100,
1
2921, 2846, 1606, 1555, 1201, 1082. H NMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.19 (m, 9H, Hadamantane),
7.41–7.49 (m, 2H, Harom.), 7.92 (m, 1H, Harom.), 8.10 (m,
1H, Harom.), 8.14 (s, 1H, Hthiazole). 13C NMR (CDCl3):
2-[(Adamantan-1-yl)-5-(2-(3-fluorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7e) From 5e (119 mg). Yield: 137
mg (72 %); Mp 180–183 °C; FTIR (νmax, cm−1): 3080,
δ = 27.8, 34.5, 36.3, 39.9 (10 × Cadamantane), 121.8 (C5
thia-
1
(6 × Carom.), 141.6
zole), 125.1, 126.9, 130.3, 130.8, 134.2, 135.2
2906, 2847, 1590, 1549, 1204, 1155. H NMR (CDCl3): δ
(C4thiazole), 160.1 (C5oxadiazole), 168.1 (C2thiazole), 172.8
(C2oxadiazole). EI-MS (m/z, %): 397/399 ([M+2]+, 49),
397/399 ([M+, 100]), 224 (8), 222 (21), 196 (4), 194 (12),
135 (58), 107 (6), 93 (12), 79 (15). Anal. Calcd. for
C21H20ClN3OS: C, 63.39; H, 5.15; N, 10.56. Found: C,
63.22; H, 5.02; N, 10.40.
= 1.84 (m, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane), 7.19
(m, 1H, Harom.), 7.46 (m, 1H, Harom.), 7.80–7.84 (m, 2H,
H
arom.), 8.13 (s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 27.7,
34.5, 36.3, 39.9 (10 × Cadamantane), 113.8 (d, JC-F = 23.25
Hz, C4arom.), 117.7 (d, JC-F = 21.0 Hz, C2arom.), 121.8
(C5thiazole), 122.7 (d, JC-F = 3.0 Hz, C6arom.), 130.7 (d, JC-F
= 8.3 Hz, C1arom.), 134.6 (d, JC-F = 8.3 Hz, C5arom.), 141.6
(C4thiazole), 160.1 (C5oxadiazole), 163.1 (d, JC-F = 246.0 Hz,
2-[(Adamantan-1-yl)-5-(2-(4-chlorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7i) From 5i (127 mg). Yield: 161
mg (81 %); Mp 203–204 °C; FTIR (νmax, cm−1): 3081,
C3arom.),
168.2
(C2thiazole),
172.8
(C2oxadiazole).
EI-MS (m/z, %): 380/382 ([M]+, 100), 206 (22), 178 (11),
135 (35), 121 (14), 107 (9), 93 (10), 79 (12). Anal. Calcd.
for C21H20FN3OS: C, 66.12; H, 5.28; N, 11.02. Found: C,
65.89; H, 5.18; N, 10.82.
1
2910, 2845, 1604, 1557, 1206, 1079. HNMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane),
7.45–7.49 (m, 2H, Harom.), 7.99–8.03 (m, 2H, Harom.), 8.12
(s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 27.8, 34.5, 36.3,
39.9 (10 × Cadamantane), 121.5 (C5thiazole), 128.2, 129.3,
2-[(Adamantan-1-yl)-5-(2-(4-fluorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7f) From 5f (117 mg). Yield: 143
mg (75 %); Mp 204–205 °C; FTIR (νmax, cm−1): 3077,
131.2, 136.9 (6 × Carom.), 141.6 (C4thiazole), 160.1 (C5
oxadia-
zole), 168.4 (C thiazole), 172.7 (C2oxadiazole). EI-MS (m/z, %):
2
397/399 ([M+2]+, 36), 396/398 ([M+, 100]), 224 (6), 222
(16), 196 (4), 194 (11), 135 (41), 107 (4), 93 (6), 79 (11).
Anal. Calcd. for C21H20ClN3OS: C, 63.39; H, 5.15; N,
10.56. Found: C, 63.18; H, 5.00; N, 10.33.
1
2907, 2849, 1601, 1550, 1228, 1159. H NMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane),
7.18–7.21 (m, 2H, Harom.), 8.04–8.08 (m, 2H, Harom.), 8.09
(s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 27.7, 34.5, 36.3,
39.9 (10 × Cadamantane), 116.2 (d, JC-F = 22.5 Hz, C3
+
arom.
2-[(Adamantan-1-yl)-5-(2-(2-bromophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7j) From 5j (149 mg). Yield: 166
mg (75 %); Mp 138–141 °C; FTIR (νmax, cm−1): 3088,
C-5), 121.3 (C5thiazole), 129.0 (d, JC-F = 9.0 Hz, C2arom. + C-
6), 129.9 (d, JC-F = 3.0 Hz, C1arom.), 141.4 (C4thiazole), 160.2
(C5oxadiazole), 164.3 (d, JC-F = 250.5 Hz, C4arom.), 168.6
(C2thiazole), 172.7 (C2oxadiazole). EI-MS (m/z, %): 380/382
([M]+, 100), 206 (13), 178 (6), 135 (27), 121 (14), 107 (6),
93 (13), 79 (19). Anal. Calcd. for C21H20FN3OS: C, 66.12;
H, 5.28; N, 11.02. Found: C, 65.92; H, 5.15; N, 10.89.
1
2917, 2844, 1600, 1559, 1212, 1044. H NMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.19 (m, 9H, Hadamantane), 7.34
(m, 1H, Harom.), 7.47 (m, 1H, Harom.), 7.74 (m, 1H, Harom.),
8.22 (m, 1H, Harom.), 8.27 (s, 1H, Hthiazole). 13C NMR
(CDCl3): δ = 27.7, 34.5, 36.3, 39.9 (10 × Cadamantane), 121.8
(C5thiazole), 123.1, 127.8, 131.3, 132.1, 133.2, 134.0 (6 ×
2-[(Adamantan-1-yl)-5-(2-(2-chlorophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7g) From 5g (127 mg). Yield:
159 mg (80 %); Mp 146–148 °C; FTIR (νmax, cm−1): 3088,
C
arom.), 140.3 (C4thiazole), 160.3 (C5oxadiazole), 166.6
(C2thiazole), 172.8 (C2oxadiazole). EI-MS (m/z, %): 443 ([M
+2]+, 96), 441/443 [M+, 100], 268 (8), 266 (10), 240 (6),
238 (7), 135 (48), 107 (12), 93 (5), 79 (13). Anal. Calcd. for
C21H20BrN3OS: C, 57.02; H, 4.56; N, 9.50. Found: C,
56.89; H, 4.48; N, 9.29.
1
2912, 2847, 1599, 1552, 1205, 1077. H NMR (CDCl3):
δ = 1.84 (m, 6H, Hadamantane), 2.19 (m, 9H, Hadamantane),
7.39–7.46 (m, 2H, Harom.), 7.54 (m, 1H, Harom.), 8.26 (s,
1H, Hthiazole), 8.42 (m, 1H, Harom.). 13C NMR (CDCl3): δ =
27.8, 34.5, 36.3, 39.9 (10 × Cadamantane), 123.0 (C5thiazole),
127.3, 130.6, 131.0, 131.1, 131.4, 132.1 (6 × Ar–C), 140.2
(C4thiazole), 160.3 (C5oxadiazole), 165.0 (C2thiazole), 172.7
2-[(Adamantan-1-yl)-5-(2-(3-bromophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7k) From 5k (149 mg). Yield: 168
mg (76 %); Mp 194–196 °C; FTIR (νmax, cm−1): 3078,

Med Chem Res
1
2911, 2847, 1602, 1551, 1218, 1052. H NMR (CDCl3):
δ = 1.84 (m, 6H, Hadamantane), 2.19 (m, 9H, Hadamantane),
7.37 (m, 1H, Harom.), 7.62 (m, 1H, Harom.), 7.97 (m, 1H,
42.2 (3 × Cadamantane), 121.3 (C5thiazole), 124.2, 127.5, 129.0,
131.7, 132.5, 139.0 (6 × Carom.), 141.1 (C4thiazole), 160.7
(C5oxadiazole), 165.0 (C2thiazole), 170.2 (C2oxadiazole). EI-MS
(m/z, %): 391 ([M]+, 28), 202 (19), 174 (4), 135 (100), 117
(3), 107 (7), 93 (18), 91 (11), 79 (10). Anal. Calcd. for
C23H25N3OS: C, 70.56; H, 6.44; N, 10.73. Found: C, 70.38;
H, 6.37; N, 10.48.
H
arom.), 8.14 (s, 1H, Hthiazole), 8.26 (m, 1H, Harom.). 13C
NMR (CDCl3): δ = 27.7, 34.5, 36.3, 39.9 (10 × Cadamantane),
121.9 (C5thiazole), 123.2, 125.6, 129.7, 130.6, 133.7, 134.4
(6 × Carom.), 141.6 (C4thiazole), 160.1 (C5oxadiazole), 167.9
(C2thiazole), 172.8 (C2oxadiazole). EI-MS (m/z, %): 443 ([M
+2]+, 98), 441/443 ([M]+, 100), 268 (10), 266 (12), 240 (4),
238 (3), 135 (79), 107 (6), 93 (14), 79 (14). Anal. Calcd. for
C21H20BrN3OS: C, 57.02; H, 4.56; N, 9.50. Found: C,
56.90; H, 4.50; N, 9.39.
2-[((Adamantan-1-yl)methyl)-5-(2-(4-methylphenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7o) From 5c (117 mg).
Yield: 141 mg (72 %); Mp 188–190 °C; FTIR (νmax, cm−1):
1
3108, 2901, 2847, 1585, 1562, 1222. H NMR (CDCl3): δ
= 1.61–1.74 (m, 12H, Hadamantane), 2.01 (br s, 3H,
2-[(Adamantan-1-yl)-5-(2-(4-bromophenyl)-1,3-thiazol-4-
yl)]-1,3,4-oxadiazole (7l) From 5l (149 mg). Yield: 179
mg (81 %); Mp 206–207 °C; FTIR (νmax, cm−1): 3091,
Hadamantane), 2.43 (s, 3H, Ar–Me), 2.76 (s, 2H, CH2), 7.29
(d, 2H, J = 8.1 Hz, Harom.), 7.95 (d, 2H, J = 8.1 Hz, Harom.),
8.07 (s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 21.5 (CH3),
28.5, 33.6, 36.6 (7 × Cadamantane), 39.6 (CH2), 42.2 (3 ×
1
2922, 2848, 1603, 1552, 1208, 1049. H NMR (CDCl3): δ
= 1.84 (m, 6H, Hadamantane), 2.18 (m, 9H, Hadamantane),
7.61–7.64 (m, 2H, Harom.), 7.93–7.96 (m, 2H, Harom.), 8.12
(s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 27.7, 34.5, 36.3,
39.9 (10 × Cadamantane), 121.6 (C5thiazole), 125.3, 128.4,
C
adamantane), 121.0 (C5thiazole), 126.9, 129.7, 130.0, 141.0
(6 × Carom.), 141.3 (C4thiazole), 160.8 (C5oxadiazole), 165.0
(C2thiazole), 170.2 (C2oxadiazole). EI-MS (m/z, %): 391 ([M]+,
16), 202 (11), 174 (3), 135 (100), 117 (3), 107 (8), 93 (25),
91 (14), 79 (32). Anal. Calcd. for C23H25N3OS: C, 70.56;
H, 6.44; N, 10.73. Found: C, 70.29; H, 6.36; N, 10.56.
131.6, 132.3 (6 × Carom.), 141.6 (C4thiazole), 160.1 (C5
oxadia-
2
zole), 168.5 (C thiazole), 172.7 (C2oxadiazole). EI-MS (m/z, %):
443/445 ([M+2]+, 98), 440/442 ([M]+, 100), 268 (10), 266
(11), 240 (3), 238 (3), 135 (45), 107 (4), 93 (7), 79 (6).
Anal. Calcd. for C21H20BrN3OS: C, 57.02; H, 4.56; N,
9.50. Found: C, 56.85; H, 4.47; N, 9.29.
2-[((Adamantan-1-yl)methyl)-5-(2-(2-fluorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7p) From 5d (119 mg).
Yield: 140 mg (71 %); Mp 173–175 °C; FTIR (νmax, cm−1):
3096, 2905, 2845, 1604, 1563, 1207, 1192. 1H NMR
(CDCl3): δ = 1.60–1.72 (m, 12H, Hadamantane), 2.00 (br s,
3H, Hadamantane), 2.74 (s, 2H, CH2), 7.18–7.32 (m, 2H,
2-[((Adamantan-1-yl)methyl)-5-(2-(2-methylphenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7m) From 5a (117 mg).
Yield: 143 mg (73 %); Mp 152–154 °C; FTIR (νmax, cm−1):
H
arom.), 7.44 (m, 1H, Harom.), 8.21 (s, 1H, Hthiazole), 8.46 (m,
1
3106, 2921, 2847, 1599, 1562, 1206. H NMR (CDCl3): δ
1H, Harom.). 13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 ×
= 1.61–1.74 (m, 12H, Hadamantane), 2.01 (br s, 3H,
Cadamantane), 39.6 (CH2), 42.2 (3 × Cadamantane), 116.1 (d,
H
adamantane), 2.65 (s, 3H, Ar–Me), 2.75 (s, 2H, CH2),
JC-F = 21.75 Hz, C3arom.), 120.4 (d, JC-F = 11.25 Hz,
C1arom.), 121.2 (C5thiazole), 122.7 (d, JC-F = 9.75 Hz,
7.29–7.42 (m, 3H, Harom.), 7.78 (m, 1H, Harom.), 8.19
(s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 21.5 (CH3),
28.5, 33.6, 36.5 (7 × Cadamantane), 39.5 (CH2), 42.2
(3 × Cadamantane), 122.1 (C5thiazole), 126.2, 130.1, 131.5,
131.6, 132.0, 136.9 (6 × Carom.), 140.5 (C4thiazole), 160.8
(C5oxadiazole), 165.1 (C2thiazole), 169.5 (C2oxadiazole). EI-MS
(m/z, %): 391 ([M]+, 16), 202 (9), 174 (13), 135 (100), 117
(4), 107 (12), 93 (29), 91 (16), 79 (29). Anal. Calcd. for
C23H25N3OS: C, 70.56; H, 6.44; N, 10.73. Found: C, 70.33;
H, 6.36; N, 10.54.
C6arom.), 124.8 (d, JC-F = 3.0 Hz, C5arom.), 132.0 (d, JC-F
=
9.0 Hz, C4arom.), 140.2 (C4thiazole), 160.2 (d, JC-F = 250.5
Hz, C2arom.), 160.8 (C5oxadiazole), 162.2 (C2thiazole), 165.1
(C2oxadiazole). EI-MS (m/z, %): 394/396 ([M]+, 12), 206 (18),
178 (3), 135 (100), 121 (3), 107 (12), 93 (31), 79 (64). Anal.
Calcd. for C22H22FN3OS: C, 66.81; H, 5.61; N, 10.62.
Found: C, 66.63; H, 5.58; N, 10.50.
2-[((Adamantan-1-yl)methyl)-5-(2-(3-fluorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7q) From 5e (119 mg).
Yield: 146 mg (74 %); Mp 156–158 °C; FTIR (νmax, cm−1):
3106, 2903, 2845, 1603, 1564, 1210, 1197. 1H NMR
(CDCl3): δ = 1.61–1.73 (m, 12H, Hadamantane), 2.01 (br s,
3H, Hadamantane), 2.76 (s, 2H, CH2), 7.18 (m, 1H, Harom.),
7.46 (m, 1H, Harom.), 7.80 (m, 1H, Harom.), 8.14 (s, 1H,
2-[((Adamantan-1-yl)methyl)-5-(2-(3-methylphenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7n) From 5b (117 mg).
Yield: 155 mg (79 %); Mp 163–165 °C; FTIR (νmax, cm−1):
1
3083, 2896, 2844, 1581, 1561, 1229. H NMR (CDCl3): δ
= 1.61–1.74 (m, 12H, Hadamantane), 2.01 (br s, 3H,
H
adamantane), 2.45 (s, 3H, Ar–Me), 2.75 (s, 2H, CH2),
H
thiazole). 13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 ×
7.31–7.39 (m, 2H, Harom.), 7.83 (m, 1H, Harom.), 7.91 (m,
1H, Harom.), 8.01 (s, 1H, Hthiazole). 13C NMR (CDCl3): δ =
21.3 (CH3), 28.5, 33.6, 36.5 (7 × Cadamantane), 39.6 (CH2),
Cadamantane), 39.6 (CH2), 42.2 (3 × Cadamantane), 113.8 (d,
JC-F = 23.3 Hz, C4arom.), 117.8 (d, JC-F = 21.8 Hz, C2arom.),
121.9 (C5thiazole), 130.8 (d, JC-F = 3.0 Hz, C6arom.), 134.5

Med Chem Res
(d, JC-F = 8.3 Hz, C1arom.), 135.6 (d, JC-F = 8.3 Hz, C5arom.),
141.3 (C4thiazole), 160.6 (C5oxadiazole), 163.0 (d, JC-F = 246.0
Hz, C3arom.), 165.1 (C2thiazole), 168.4 (C2oxadiazole). EI-MS
(m/z, %): 394/396 ([M]+, 11), 206 (14), 178 (3), 135 (100),
121 (3), 107 (12), 93 (30), 79 (41). Anal. Calcd. for
C22H22FN3OS: C, 66.81; H, 5.61; N, 10.62. Found: C,
66.60; H, 5.53; N, 10.48.
(C2thiazole), 168.1 (C2oxadiazole). EI-MS (m/z, %): 413/415
([M+2]+, 3), 411/413 [M+, 8], 224 (4), 222 (10), 135 (100),
107 (9), 93 (25), 79 (33). Anal. Calcd. for C22H22ClN3OS: C,
64.14; H, 5.38; N, 10.20. Found: C, 65.89; H, 5.29; N, 10.10.
2-[((Adamantan-1-yl)methyl)-5-(2-(4-chlorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7u) From 5i (127 mg).
Yield: 163 mg (79 %); Mp 184–187 °C; FTIR (νmax, cm−1):
3109, 2903, 2848, 1597, 1562, 1222, 1090. 1HNMR
(CDCl3): δ = 1.56–1.69 (m, 12H, Hadamantane), 1.96 (br s,
3H, Hadamantane), 2.71 (s, 2H, CH2), 7.41 (d, 2H, J = 8.7 Hz,
2-[((Adamantan-1-yl)methyl)-5-(2-(4-fluorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7r) From 5f (119 mg).
Yield: 146 mg (74 %); Mp 202–204 °C; FTIR (νmax, cm−1):
3109, 2899, 2849, 1601, 1565, 1206, 1191. 1H NMR
(CDCl3): δ = 1.58–1.71 (m, 12H, Hadamantane), 1.98 (br s,
3H, Hadamantane), 2.72 (s, 2H, CH2), 7.11–7.17 (m, 2H,
H
H
arom.), 7.94 (d, 2H, J = 8.7 Hz, Harom.), 8.06 (s, 1H,
thiazole). 13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 ×
Cadamantane), 39.5 (CH2), 42.2 (3 × Cadamantane), 121.6
H
arom.), 8.00–8.04 (m, 2H, Harom.), 8.06 (s, 1H, Hthiazole).
(C5thiazole), 128.1, 129.3, 131.1, 136.9 (6 × Carom.), 141.3
(C4thiazole), 160.5 (C5oxadiazole), 165.0 (C2thiazole), 168.5
(C2oxadiazole). EI-MS (m/z, %): 413/415 ([M+2]+, 4),
411/413 [M+, 10], 224 (3), 222 (8), 135 (100), 107 (8), 93
(23), 79 (32). Anal. Calcd. for C22H22ClN3OS: C, 64.14; H,
5.38; N, 10.20. Found: C, 65.90; H, 5.31; N, 9.98.
13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 × Cadamantane),
39.5 (CH2), 42.2 (3 × Cadamantane), 116.2 (d, JC-F = 22.5 Hz,
C3arom. + C-5), 121.4 (C5thiazole), 128.9 (d, JC-F = 9.0 Hz,
C2arom. + C-6), 129.9 (d, JC-F = 3.0 Hz, C1arom.), 141.2
(C4thiazole), 160.6 (C5oxadiazole), 164.3 (d, JC-F = 250.5 Hz,
C4arom.), 165.0 (C2thiazole), 168.7 (C2oxadiazole). EI-MS
(m/z, %): 395/396 ([M]+, 15), 206 (12), 178 (3), 135
(100), 121 (3), 107 (11), 93 (28), 79 (37). Anal. Calcd. for
C22H22FN3OS: C, 66.81; H, 5.61; N, 10.62. Found: C,
66.59; H, 5.55; N, 10.42.
2-[((Adamantan-1-yl)methyl)-5-(2-(2-bromophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7v) From 5j (149 mg).
Yield: 182 mg (80 %); Mp 185–187 °C; FTIR (νmax, cm−1):
3098, 2896, 2844, 1604, 1563, 1207, 1025. 1H NMR
(CDCl3) δ = 1.59–1.73 (m, 12H, Hadamantane), 2.00 (br s,
3H, Hadamantane), 2.75 (s, 2H, CH2), 7.32 (m, 1H, Harom.),
7.45 (m, 1H, Harom.), 7.72 (m, 1H, Harom.), 8.20 (m, 1H,
2-[((Adamantan-1-yl)methyl)-5-(2-(2-chlorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7s) From 5g (127 mg).
Yield: 165 mg (80 %); Mp 150–153 °C; FTIR (νmax, cm−1):
3088, 2911, 2844, 1600, 1560, 1206, 1076. 1H NMR
(CDCl3): δ = 1.56–1.68 (m, 12H, Hadamantane), 1.98 (br s,
3H, Hadamantane), 2.72 (s, 2H, CH2), 7.40–7.46 (m, 2H,
H
arom.), 8.26 (s, 1H, Hthiazole). 13C NMR (CDCl3): δ = 28.5,
33.6, 36.6 (7 × Cadamantane), 39.6 (CH2), 42.2 (3 ×
adamantane), 121.7 (C5thiazole), 123.1, 127.8, 131.3, 132.0,
C
133.1, 134.0 (6 × Carom.), 140.1 (C4thiazole), 160.7
(C5oxadiazole), 165.1 (C2thiazole), 166.7 (C2oxadiazole). EI-MS
(m/z, %): 457/459 ([M+2]+, 6), 454/457 (M+, 7), 268 (6),
266 (6), 135 (100), 107 (12), 93 (33), 79 (48). Anal. Calcd.
for C22H22BrN3OS: C, 57.90; H, 4.86; N, 9.21. Found:
C, 57.71; H, 4.77; N, 8.96.
H
arom.), 7.53 (m, 1H, Harom.), 8.27 (s, 1H, Hthiazole), 8.42 (m,
1H, Harom.). 13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 ×
adamantane), 39.6 (CH2), 42.2 (3 × Cadamantane), 121.4
(C5thiazole), 127.3, 130.4, 130.9, 131.0, 131.4, 132.6 (6 ×
arom.), 140.1 (C4thiazole), 160.3 (C5oxadiazole), 165.1
C
C
(C2thiazole), 168.8 (C2
2). EI-MS (m/z, %): 413/415
oxadiazole
([M+2]+, 7), 411/413 [M+, 23], 224 (5), 222 (15), 135
(100), 107 (11), 93 (25), 79 (56). Anal. Calcd. for
C22H22ClN3OS: C, 64.14; H, 5.38; N, 10.20. Found: C,
63.95; H, 5.30; N, 10.03 %.
2-[((Adamantan-1-yl)methyl)-5-(2-(3-bromophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7w) From 5k (149 mg).
Yield: 175 mg (77 %); Mp 172–173 °C; FTIR (νmax, cm−1):
3085, 2921, 2845, 1580, 1560, 1203, 993. 1H NMR
(CDCl3): δ = 1.60–1.74 (m, 12H, Hadamantane), 2.01 (br s,
3H, Hadamantane), 2.76 (s, 2H, CH2), 7.36 (m, 1H, Harom),
7.61 (m, 1H, Harom.), 7.95 (m, 1H, Harom.), 8.13 (s, 1H,
2-[((Adamantan-1-yl)methyl)-5-(2-(3-chlorophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7t) From 5h (127 mg).
Yield: 152 mg (74 %); Mp 166–168 °C; FTIR (νmax, cm−1):
3084, 2900, 2846, 1593, 1563, 1191, 1081. 1H NMR
(CDCl3): δ = 1.53–1.66 (m, 12H, Hadamantane), 1.93 (br s,
3H, Hadamantane), 2.69 (s, 2H, CH2), 7.28–7.38 (m, 2H,
H
thiazole), 8.24 (m, 1H, Harom.). 13C NMR (CDCl3): δ =
28.5, 33.6, 36.5 (7 × Cadamantane), 39.6 (CH2), 42.2 (3 ×
adamantane), 121.9 (C5thiazole), 123.2, 125.5, 129.7, 130.6,
C
133.7, 134.4 (6 × Carom.), 141.4 (C4thiazole), 160.5
(C5oxadiazole), 165.1 (C2thiazole), 168.1 (C2oxadiazole). EI-MS
(m/z, %): 457/459 ([M+2]+, 6), 454/457 (M+, 6), 268 (4),
266 (5), 135 (100), 107 (9), 93 (25), 79 (25). Anal. Calcd.
for C22H22BrN3OS: C, 57.90; H, 4.86; N, 9.21. Found: C,
57.79; H, 4.76; N, 9.02.
H
arom.), 7.81 (m, 1H, Harom.), 8.00 (m, 1H, Harom.), 8.09 (s,
1H, Hthiazole). 13C NMR (CDCl3): δ = 28.6, 33.4, 36.5 (7 ×
adamantane), 39.5 (CH2), 42.2 (3 × Cadamantane), 121.6
(C5thiazole), 125.0, 126.7, 130.3, 130.7, 134.0, 135.1 (6 ×
arom.), 141.2 (C4thiazole), 160.5 (C5oxadiazole), 165.1
C
C

Med Chem Res
Table 2 Summary of crystallographic data
2-[((Adamantan-1-yl)methyl)-5-(2-(4-bromophenyl)-1,3-
thiazol-4-yl)]-1,3,4-oxadiazole (7x) From 5l (149 mg).
Yield: 177 mg (78 %); Mp 190–192 °C; FTIR (νmax, cm−1):
3107, 2909, 2848, 1592, 1561, 1201, 989. 1H NMR
(CDCl3): δ = 1.59–1.73 (m, 12H, Hadamantane), 2.00 (br s,
3H, Hadamantane), 2.74 (s, 2H, CH2), 7.61 (d, 2H, J = 8.7 Hz,
Compound
7a
Formula
Mr
C22H23N3OS
377.49
Habit
Colorless block
0.4 × 0.35 × 0.25
Monoclinic
P21/c
Cryst. size (mm)
Crystal system
Space group
Temperature (°C)
Cell constants
a (Å)
H
H
arom.), 7.92 (d, 2H, J = 8.7 Hz, Harom.), 8.10 (s, 1H,
thiazole). 13C NMR (CDCl3): δ = 28.5, 33.6, 36.5 (7 ×
C
adamantane), 39.6 (CH2), 42.2 (3 × Cadamantane), 121.6
(C5thiazole), 125.3, 128.3, 131.5, 132.3 (6 × Carom.), 141.4
(C4thiazole), 160.6 (C5oxadiazole), 165.1 (C2thiazole), 168.7
(C2oxadiazole). EI-MS (m/z, %): 457/459 ([M+2]+, 6),
454/457 (M+, 6), 268 (5), 266 (6), 135 (100), 107 (8), 93
(20), 79 (32). Anal. Calcd. for C22H22BrN3OS: C, 57.90; H,
4.86; N, 9.21. Found: C, 57.67; H, 4.76; N, 8.88.
−173
16.8868(5)
9.5584(3)
12.3345(4)
109.184(4)
1880.36
4
b (Å)
c (Å)
β (°)
V (Å3)
N-[(2-chlorophenethyl)carbamothioyl]-2-phenylthiazole-4-
carboxamide (13) To a stirred solution of 9 (112 mg, 0.50
mmol) in acetone (7 mL), NH4SCN (58 mg, 0.76 mmol)
was added and the reaction mixture heated under reflux for
2 h. After cooling and filtration, the amine 11 (156 mg, 0.39
mmol) and NaOH (20 mg, 0.51 mmol) were added directly
in dry form and the mixture heated under reflux for 6 h.
After cooling, the reaction mixture was filtered, and the
filtrate was evaporated to dryness. The residue was purified
on a column of silica gel (10 g), using, in gradient, MeOH
(0–10 %) and CHCl3 as eluent to give 13 (139 mg, 69 %);
Z
Dx (Mg m−3
)
1.333
μ (mm−1
F(000)
2θmax
)
0.19
800
62
Transmissions
Refl. measured
Refl. indep.
Rint
0.963–1.000
98225
5983
0.036
Parameters
wR(F2, all refl.)
R(F, >4σ(F))
S
245
1
Mp 159–162 °C. H NMR (600 MHz, CDCl3): δ = 2.95 (t,
0.096
2H, J = 6.5 Hz, CH2Ph), 3.84 (t, 2H, J = 6.5 Hz, CH2NH),
8.00–7.10 (m, 9H, Harom.), 9.12 (s, 1H, Hthiazole), 8.90 (br s,
1H, NH), 10.11 (br s, 1H, NH). 13C NMR (150.91 MHz,
CDCl3): δ = 30.1 (CH2Ph), 45.6 (CH2N), 126.0, 126.3,
0.033
1.07
max. Δρ (e Å−3
)
0.47
127.2, 128.0, 128.5, 128.8, 129.4, 132.8, 142.0 (Carom.
+
C5thiazole), 146.9 (C4thiazole), 165.0 (C2thiazole), 165.9 (C=O),
178.9 (C=S). FAB-MS (m/z, %): 401/403 [M, 78]+. Anal.
Calcd. for C19H16ClN3OS2: C, 56.78; H, 4.01; N, 10.45.
Found: C, 56.59; H, 3.95; N, 10.28.
for C20H19N3O2S2: C, 60.43; H, 4.82; N, 10.57. Found: C,
60.22; H, 4.61; N, 10.39.
N-[(2-methoxyphenethyl)carbamothioyl]-2-phenylthiazole-
4-carboxamide (14) This compound was prepared
according to the procedure of prepartion of compound 13,
from 9 (112 mg, 0.50 mmol), NH4SCN (58 mg, 0.76 mmol)
in acetone followed by treatment with the amine 12 (59 mg,
0.39 mmol) and NaOH (20 mg, 0.51 mmol). Yield: 145 mg
(73 %); Mp 149–151 °C. 1H NMR (600 MHz, CDCl3):
δ = 2.93 (t, 2H, J = 6.5 Hz, CH2Ph), 3.68 (s, 3H, OMe),
3.82 (t, 2H, J = 6.5 Hz, CH2NH), 8.01–7.43 (m, 5H,
X-ray structure determinations
A colorless block of compound 7a was mounted in inert oil
on a glass fiber and transferred to the cold gas stream of the
diffractometer (Oxford Diffraction Xcalibur E). Intensities
were registered using monochromated Mo Kα radiation
(λ = 0.71073 Å). Absorption corrections were based on
multi-scans. The structure was refined anisotropically on F2
using the program SHELXL-97. Hydrogen atoms were
included using a riding model starting from calculated posi-
tions. Table 2 presents the summary of crystallographic data.
Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplementary pub-
lication no. CCDC-864706. Copies of the data can be obtained
free of charge from www.ccdc.cam.ac.uk/data_request/cif.
H
arom.), 7.17–6.92 (m, 4H, Harom.), 9.09 (s, 1H, Hthiazole),
9.10 (br s, 1H, NH), 10.15 (br s, 1H, NH). 13C NMR
(150.91 MHz, CDCl3): δ = 29.6 (CH2Ph), 46.1 (CH2N),
55.0 (OMe), 111.8, 119.6, 126.3, 128.0, 128.5, 129.0,
130.4, 131.0 (Carom. + C5thiazole), 147.0 (C4thiazole), 157.2
(Carom.–OMe), 165.6 (C2thiazole), 166.3 (C=O), 181.1
(C=S). FAB-MS (m/z, %): 398 ([M+H]+, 88). Anal. Calcd.

Med Chem Res
Biological evaluation
and 14 showed significant inhibition of HIV-1 with EC50 of
1.79 and 2.39 μM (SI = 18 and 4), respectively. The anti-
HIV activity results suggest that compound 13 might act as
a new candidate for NNRTIs. Furthermore, compounds 7a
and 7j were tested against two solid tumor-derived cell lines
consisting Hep-G2 (human hepatocarcinoma) and MCF-7
(breast cancer). Compound 7j showed a moderate antitumor
activity against Hep-G2 and led to be promising agent for
further structural modification.
In vitro anti-HIV assay Evaluation of the antiviral activity
of compounds 7a–l, 13, and 14 against HIV-1 (IIIB) and
HIV-2 (ROD) strains in MT-4 cells was performed using an
MTT assay as described previously (Pannecouque et al.,
2008; Pauwles et al., 1988). In brief, stock solutions
(10 times final concentration) of test compounds were
added in 50-μl volumes to two series of triplicate wells to
allow simultaneous evaluation of their effects on mock and
HIV-infected cells at the beginning of each experiment.
Serial 5-fold dilutions of test compounds were made
directly in flat-bottomed 96-well microtiter trays using a
Biomek 3000 robot (Beckman instruments). Untreated
control, HIV-infected, and mock-infected cell samples were
included for each sample. HIV-1 (IIIB) (Popovic et al.,
1984) or HIV-2 (ROD) (Barré-Sinoussi et al., 1993) stock
(50 μl) at 100–300 CCID50 (50 % cell culture infectious
dose) or culture medium [10 % heat-inactivated Fetal Calf
Serum (FCS), 2 mM-glutamine, 0.1 % sodium bicarbonate,
and 20 μg/ml gentamicin] was added to either of the
infected or mock-infected wells of the microtiter tray.
Mock-infected cells were used to evaluate the effect of test
compound on uninfected cells in order to assess the cyto-
toxicity of the test compounds. Exponentially growing MT-
4 cells (Miyoshi et al., 1982) were centrifuged for 5 min at
1000 rpm (Minifuge T, rotor 2250; Heraeus, Germany), and
the supernatant was discarded. The MT-4 cells were
resuspended at 6 × 105 cells per ml, and 50 μl volumes were
transferred to the microtiter tray wells. Five days after
infection, the viability of the mock-infected and HIV-
infected cells was examined spectrophotometrically.
Acknowledgments This work was financially supported by Higher
Education Commission (HEC) of Pakistan through a Ph.D. fellowship
to Mahmood-ul-Hassan Khan under “Indigenous Ph.D 5000 Fellow-
ship Program”. Miss A. Friemel of the Chemistry Department, Uni-
versity of Konstanz, Germany, is highly acknowledged for the NMR
experiments.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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