Synthesis, crystal structure and antiproliferative activity of 6-adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles

Article abstract of DOI:10.1515/znb-2010-0214

A series of 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a - l bearing an adamantyl moiety were synthesized by condensation of 4-amino-5-aryl-2H-1,2,4-triazole-3(4H)-thiones 4a - l with adamantyl-1- carboxylic acid in the presence of POCl₃. The structures of the newly synthesized compounds were established using spectroanalytical techniques and verified further by the crystal structure determination of compounds 5a and 5j. The compounds were screened for their antiproliferative activity against a large panel of human cell lines.

Full text of DOI:10.1515/znb-2010-0214

Synthesis, Crystal Structure and Antiproliferative Activity of
6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
Mahmood-ul-Hassan Khana, Tashfeen Akhtara, Khawaja A. Yasina,
Najim A. Al-Masoudib, Peter G. Jonesc, and Shahid Hameeda
a Department of Chemistry, Quaid-I-Azam University, Islamabad-45320, Pakistan
b Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq
c Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig,
Hagenring 30, 38106 Braunschweig, Germany
Reprint requests to Dr. Shahid Hameed. Fax: +92 51 9064 2241. E-mail: shameed@qau.edu.pk or
shahidhameed@daad-alumni.de
Z. Naturforsch. 2010, 65b, 178 – 184; received November 6, 2009
A series of 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a – l bearing an adamantyl
moiety were synthesized by condensation of 4-amino-5-aryl-2H-1,2,4-triazole-3(4H)-thiones 4a – l
with adamantyl-1-carboxylic acid in the presence of POCl3. The structures of the newly synthesized
compounds were established using spectroanalytical techniques and verified further by the crystal
structure determination of compounds 5a and 5j. The compounds were screened for their antiprolif-
erative activity against a large panel of human cell lines.
Key words: Antiproliferative Activity, [1,2,4]Triazolo[3,4-b][1,3,4]thiadiazoles,
Adamantyl Derivatives
Introduction
Results and Discussion
Synthesis
Fused heterocycles have received significant at-
tention due to their synthetic and biological impor-
tance, and 1,2,4-triazole-3-thiones/thiols are excel-
lent candidates for their synthesis. A number of sig-
nificant activities, like antitumor and antimicrobial,
have been associated with these condensed hetero-
cycles [1 – 6]. Moreover, among various substituents,
adamantyl derivatives are gaining importance in well
known drugs like Rimantadine, Memantine, Adapa-
lene, Adatanserine and others in clinical trials [7, 8].
The adamantyl derivatives are also recognized for their
activity against influenza [9] and HI viruses [10].
Some other adamantyl derivatives have been used as
anti-inflammatory [11, 12], antimicrobial [13, 14], an-
timalarial [15], and antidepressant agents [16] as well
as inhibitors of 11β-hydroxysteroid dehydrogenase
type 1 (11β-HSD1) [17].
The synthesis of the adamantyl-bearing 3,6-di-
substituted
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
5a – l was carried out by treatment of 4-amino-
5-aryl-2H-1,2,4-triazole-3(4H)-thiones 4a – l with
adamantyl-1-carboxylic acid [6]. 4-Amino-5-aryl-
2H-1,2,4-triazole-3(4H)-thiones were prepared from
aryl hydrazides 3a – l by reaction with CS2 in the
presence of KOH, followed by cyclization with
hydrazine hydrate [18a]. The aryl hydrazides 3a – l
were synthesized from the corresponding aryl benzoic
acids 1a – l via esterification to 2a – l, by following
a reported procedure [18f]. The synthetic steps are
illustrated in Scheme 1.
The condensation of 4a – l with adamantyl-1-
carboxylic acid to 5a – l was achieved in 64 – 84 %
1
yield. The structures of 5a – l were confirmed by H-
and 13C-NMR, IR and mass spectra. The cyclization of
In continuation of our work on the synthesis
and biological evaluation of five-membered heterocy-
cles [18a – f], we have synthesized triazolothiadiazoles
bearing an adamantyl moiety and evaluated their an-
tiproliferative activities against a large panel of human
cell lines.
4a – l to [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a – l
was followed by the IR and H-NMR spectra, where
the NH/NH2 signals disappeared in comparison to
triazolethiones 4a – l. In the 1H-NMR spectra of 5a – l,
the adamantane protons resonated in the region δ =
1
c
0932–0776 / 10 / 0200–0178 $ 06.00 ꢀ 2010 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 10/29/17 4:04 PM

M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
179
Scheme 1. Synthesis of 3,6-disubstituted [1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles.
1.85 – 2.21 ppm as multiplets. Four aromatic protons
exhibited multiplicities depending on the position of
the substituent on the benzene ring. In addition, the
aromatic proton signals in 5d – f exhibited splittings
due to proton-fluorine coupling. In the 13C-NMR
spectra, adamantyl carbons appeared in the region δ =
21.2 – 28.5 ppm, whereas the signals in the aromatic
region of δ = 123.0– 140.0 ppm varied from four to
six due to different substitution patterns on the aryl
ring. The doublets at δ = 159.9, 162.8 and 163.8 ppm
with large JC,F values (254.2, 244.5, and 249.0 Hz)
were assigned to C-2, C-3 and C-4 of the aromatic
residues in compounds 5d, 5e, and 5f, respectively.
The signal of C-8 of the triazolothiadiazole unit
was observed in the region δ = 142.9– 149.9 ppm,
whereas C-3-triazole resonated in the region of
153.2– 154.8 ppm. The higher-field signals between
δ = 179.4 and 182.3 ppm were assigned to C-6-S.
The constitution of compounds 5a – l was further
confirmed by the single crystal X-ray studies of com-
Fig. 1. Structure of compound 5a in the crystal. Displacement
ellipsoids at the 50 % probability level.
S–C2–C10–C (−14.6◦ for 5a, −27.6, 42.7, −28.1,
14.9◦ for 5j, all involving C11 as the fourth atom).
In vitro antiproliferative activity
Compounds 5a – l were tested in vitro against
pounds 5a and 5j (Figs. 1 and 2). Compound 5j crystal- a large panel of human cell lines derived from
lizes with four independent molecules in the asymmet- hematological CD4+ human T cells containing an
ric unit, all of which differ in molecular conformation. integrated HTLV-1 genome (MT-4), CD4+ human
Molecular dimensions may be regarded as normal. The acute T-lymphoblastic leukaemia (CCRF-CEM), hu-
heterocyclic ring systems are planar within mean de- man splenic B-lymphoblastoid cells (WIL-2NS), hu-
˚
viations of 0.01 A. The relative ring orientations are man acute B-lymphoblastic leukemia (CCRF-SB) and
defined (i) by the interplanar angles between the hete- solid skin melanoma (SK-28), breast adenocarci-
rocycle and the phenyl rings (26.3◦ for 5a, 52.5, 57.0, noma (MCF-7), lung squamous carcinoma (SK-MES-
52.0, 55.7◦ for 5j) together with the torsion angles 1), hepatocellular carcinoma (HepG-2), prostate car-
N2–C1–C4–C5 (29.0◦) for 5a, N2–C1–C4–C9 (48.4, cinoma (DU-145) or normal tissues [lung fibrob-
52.4, −47.9, −52.3◦) for 5j, and (ii) the relative orien- lasts (MRC-5)]. The Microculture Tetrazolium As-
tation of the heterocycle and the adamantyl system, as say (MTT) method [19] was used for estimation of
indicated e. g. by the smallest absolute torsion angle the in vitro tumor-inhibiting activity of the tested
Unauthenticated
Download Date | 10/29/17 4:04 PM

180
M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
Fig. 2. Structure of com-
pound 5j (four independent
molecules) in the crystal. Dis-
placement ellipsoids at the
50 % probability level.
compounds. The cell lines of tumor subpanels were in- 5b, c, 5e – l). Thus, substitution of the aromatic ring by
cubated within five concentrations (0.01 – 100 g mL−1
chloro or bromo residues at ortho, meta or para posi-
)
of each test compound for 48 h. For comparative pur- tions (5g – l) did not show any activity. Similary, 3- or
poses, we evaluated the cytotoxic activities of the com- 4-methylphenyl (5b, c), or 3- or 4-fluorophenyl groups
pounds relative to Doxorubicin.
(5e, f) exhibited no activity as well.
All compounds were inactive except 5a and 5d which
showed activity against human CD4+ T cells contain-
Experimental Section
General
ing an integrated HTLV-1 genome (CD+) (CC50
=
45 µM and 47 µM, respectively) and human acute
T-lymphoblastic leukemia (CCRF-CEM) cell lines
(CC50 = 40 µM, for both compounds). Furthermore,
compounds 5a and 5d exhibited activity against human
acute B-lymphoblastic leukaemia (CCRF-SB) lines
(CC50 = 50 µM and 48 µM, respectively) and hu-
Melting points were measured using a Stuart SMP3 melt-
ing point apparatus and are uncorrected. The Rf values
were determined using pre-coated silica gel aluminium plates
with silica gel 60 F254 (Merck, Germany). Column chro-
matography was carried out using silica gel 60 (0.063 –
0.200 mm) obtained from Merck, Germany. The IR spectra
were recorded on an FTS 3000 MX, Bio-Rad Merlin spec-
trometer (Excalibur Model). 1H- and 13C-NMR spectra were
recorded on a Bruker Avance 300 MHz-NMR spectrome-
ter and signals calibrated to the residual signals of the sol-
vent. The EI mass spectra were carried out using an Agilent
man splenic lymphoblastoid (WIL-2NS) lines (CC50
=
52 µM and 44 µM, respectively).
Conclusion
A series of 3,6-disubstituted [1,2,4]triazolo[3,4-
b][1,3,4]thiadiazoles 5a – l were synthesized and char- Technologies 6890N (GC) mass spectrometer and an inert
selective detector 5973. 4-Amino-5-aryl-2H-1,2,4-triazole-
3(4H)-thiones 4a – l were prepared according to a reported
procedure [19].
acterized by spectral techniques. The structures of 5a
and 5j were further confirmed by single crystal X-ray
diffraction studies. Compounds 5a and 5d exhibited
antiproliferative activity against some selected human
cell lines. Introduction of methyl or fluoro residues
in the ortho position of the aromatic ring of 5 gener-
ally enhanced the potency: dramatic changes in activity
General procedure for the synthesis of 3,6-disubstituted
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5a – l)
A
mixture of the respective triazolethione 4a – l
were observed with the other congeners (compounds (0.90 mmol) and adamantane-1-carboxylic acid (0.90 mmol)
Unauthenticated
Download Date | 10/29/17 4:04 PM

M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
181
was heated under reflux for 4 h in the presence of POCl3 6H, adamant.-H), 2.10 (bs, 6H, adamant.-H), 2.17 (bs, 3H,
(5.0 mL). The reaction mixture was cooled to r. t., poured adamant.-H), 7.25 – 7.36 (m, 2H, Ar-H), 7.52 (m, 1H, Ar-
on ice and neutralized with solid K2CO3 until pH = 8. The H), 8.05 (dt, 1H, JH,F = 7.5, 1.8 Hz, Ar-H). – 13C-NMR
precipitated solid was filtered, washed with excess of water (CDCl3): δ = 28.1, 36.1, 39.9, 42.2 (C-adamant.), 114.3 (d,
and purified by column chromatography (n-hexane : ethyl JC−3F = 12.7 Hz, C-3-arom.), 116.6 (d, JC−1F = 20.2 Hz,
acetate 7 : 3).
C-1-arom.), 124.4 (d, JC−5F = 3.8 Hz, C-5-arom.), 130.2 (d,
JC−6F = 2.2 Hz, C-6-arom.), 132.1 (d, JC−4F = 8.3 Hz, C-4-
arom.), 142.9 (C-8), 154.5 (C-3-triazole), 159.9 (d, JC−2F
=
6-(1-Adamantyl)-3-(2-methylphenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5a)
254.2 Hz, C-arom.), 179.6 (C-6-S). – EIMS: m/z = 354 (100)
[M]+, 135 (11), 121 (34), 107 (9), 93 (7), 79 (13).
Yield: 76 %; m. p. 196 – 198 ◦C; Rf: 0.58 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3025, 2905, 2847, 1529,
6-(1-Adamantyl)-3-(3-fluorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5e)
1
1452. – H-NMR (CDCl3): δ = 1.81 (bs, 6H, adamant.-H),
2.08 (bs, 6H, adamant.-H), 2.15 (bs, 3H, adamant.-H), 2.58
(s, 3H, Ar-Me), 7.34 – 7.41 (m, 3H, Ar-H), 7.86 (m, 1H, Ar-
H). – 13C-NMR (CDCl3): δ = 21.2, 28.1, 36.1, 39.8, 42.2
(C-adamant.), 125.1, 125.8, 129.5, 130.0, 131.2, 138.1 (C-
arom.), 146.9 (C-8), 153.9 (C-3-triazole), 179.4 (C-6-S). –
EIMS: m/z (%) = 350 (100) [M]+, 215 (12), 135 (27), 117
(28), 107 (17), 93 (21), 79 (31).
Yield: 64 %; m. p. 209 – 210 ◦C; Rf: 0.59 (n-hexane:
ethyl acetate 6 : 4). – IR (KBr, cm−1): ν = 3020, 2907,
2848, 1520, 1455, 998. – 1H-NMR (CDCl3): δ = 1.85
(bs, 6H, adamant.-H), 2.14 (bs, 6H, adamant.-H), 2.21 (bs,
3H, adamant.-H), 7.19 (m, 1H, Ar-H), 7.51 (m, 1H, Ar-
H), 8.09 (m, 1H, Ar-H), 8.17 (m, 1H, ArH). – 13C-NMR
(CDCl3): δ = 28.1, 36.1, 40.0, 42.3 (C-adamant.), 113.2 (d,
JC−2F = 24.0 Hz, C-2-arom.), 117.0 (d, JC−4F = 21.0 Hz, C-
4-arom.), 121.9 (d, JC−6,F = 3.0 Hz, C-6-arom.), 127.8 (d,
JC−5,F = 9.0 Hz, C-5-arom.), 136.6 (d, JC−1,F = 8.3 Hz, C-1-
6-(1-Adamantyl)-3-(3-methylphenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5b)
Yield: 68 %; m. p. 190 – 192 ◦C; Rf: 0.62 (n-hexane : ethyl
arom.), 145.1 (C-8), 154.8 (C-3-triazole), 162.8 (d, JC−3F
=
acetate 6 : 4). – IR (KBr, cm−1): ν = 3034, 2998, 2852, 1558,
244.5 Hz, C-arom.-F), 180.3 (C-6-S). – EIMS: m/z (%) = 354
1
1457. – H-NMR (CDCl3): δ = 1.85 (bs, 6H, adamant.-H),
(100) [M]+, 135 (13), 121 (49), 107 (8), 93 (9), 79 (16).
2.14 (bs, 6H, adamant.-H), 2.20 (bs, 3H, adamant.-H), 2.47
(s, 3H, Ar-Me), 7.30 (m, 1H, Ar-H), 7.43 (m, 1H, Ar-H),
8.15 – 8.17 (m, 2H, Ar-H). – 13C-NMR (CDCl3): δ = 21.5,
28.1, 36.1, 39.9, 42.3 (C-adamant.), 123.4, 125.7, 126.9,
128.7, 131.0, 138.6 (C-arom.), 146.3 (C-8), 154.4 (C-3-
triazole), 179.6 (C-6-S). – EIMS: m/z (%) = 350 (100) [M]+,
215 (10), 135 (9), 117 (31), 107 (16), 93 (12), 79 (13).
6-(1-Adamantyl)-3-(4-fluorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5f)
Yield: 70 %; m. p. 198 – 200 ◦C; Rf: 0.56 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3017, 2909, 2849,
1531, 1458, 1001. – 1H-NMR (CDCl3): δ = 1.85 (bs,
6H, adamant.-H), 2.14 (bs, 6H, adamant.-H), 2.20 (bs, 3H,
adamant.-H), 7.20 – 7.28 (m, 2H, Ar-H), 8.34 – 8.39 (m, 2H,
Ar-H). – 13C-NMR (CDCl3): δ = 28.1, 36.1, 39.9, 42.3 (C-
adamant.), 116.0 (d, JC−3F = JC−5,F = 21.7 Hz, C-3-arom.,
C-5-arom.), 122.2 (d, JC−1F = 3.0 Hz, C-1-arom.), 128.4 (d,
JC−2F = JC−6F = 8.2 Hz, C-2-arom., C-6-arom.), 145.4 (C-
8), 154.0 (C-3-triazole), 163.8 (d, JC−4F = 249.0 Hz, C-4-
arom.), 180.0 (C-6-S). – EIMS: m/z (%) = 354 (100) [M]+,
135 (14), 121 (57), 107 (8), 93 (10), 79 (15).
6-(1-Adamantyl)-3-(4-methylphenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5c)
Yield: 80 %; m. p. 184 – 186 ◦C; Rf: 0. 58 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3033, 2907, 2846, 1540,
1
1455. – H-NMR (CDCl3): δ = 1.85 (bs, 6H, adamant.-H),
2.14 (bs, 6H, adamant.-H), 2.20 (bs, 3H, adamant.-H), 2.45
(s, 3H, Ar-Me), 7.35 (d, 2H, J = 8.1 Hz, Ar-H), 8.24 (d, 2H,
J = 8.1 Hz, Ar-H). – 13C-NMR (CDCl3): δ = 21.6, 28.1,
36.2, 39.9, 42.3 (C-adamant.), 123.1, 126.2, 129.6, 129.9,
140.0 (C-arom.), 143.2 (C-8), 153.2 (C-3-triazole), 179.5 (C-
6-S). – EIMS: m/z (%) = 350 (100) [M]+, 215 (16), 135 (13),
117 (42), 107 (10), 93 (13), 79 (16).
6-(1-Adamantyl)-3-(2-chlorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5g)
Yield: 84 %; m. p. 219 – 220 ◦C; Rf: 0.59 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3026, 2907, 2845,
1537, 1449, 1054. – 1H-NMR (CDCl3): δ = 1.80 (bs,
6H, adamant.-H), 2.08 (bs, 6H, adamant.-H), 2.15 (bs, 3H,
6-(1-Adamantyl)-3-(2-fluorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5d)
Yield: 66 %; m. p. 188 – 190 ◦C; Rf: 0.53 (n-hexane : ethyl adamant.-H), 7.41 – 7.51 (m, 2H, Ar-H), 7.57 (m, 1H, Ar-H),
acetate 6 : 4). – IR (KBr, cm−1): ν = 3029, 2906, 2854, 7.79 (m, 1H, Ar-H). – 13C-NMR (CDCl3): δ = 28.0, 36.1,
1540, 1455, 1020. – 1H-NMR (CDCl3): δ = 1.82 (bs, 39.9, 42.2 (C-adamant.), 125.3, 126.9, 130.5, 131.5, 131.9,
Unauthenticated
Download Date | 10/29/17 4:04 PM

182
M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
˚
Table 2. Selected bond lengths (A), and angles (deg) for 5a
Table 1. Crystal structure data for 5a and 5j.
and 5j.
5a
5j
5a
5j
Formula
Mr
C20H22N4S
350.48
0.3×0.2×0.2
monoclinic
P21/c
11.0863(3)
11.6370(3)
13.2322(4)
98.664(4)
1687.62
4
C19H19BrN4S
415.35
0.3×0.25×0.2
monoclinic
P21/c
18.9854(5)
18.1514(5)
20.8524(5)
103.982(4)
6973.1
16
1.58
2.5
3392
S–C(3)
S–C(2)
1.7295(12)
1.7707(12)
1.3096(14)
1.4002(14)
1.3235(15)
1.3583(15)
1.3789(12)
1.3792(14)
1.2976(15)
1.4660(16)
1.5043(15)
1.7340(17)
1.7771(17)
1.308(2)
1.4078(18)
1.3154(19)
1.3578(19)
1.3742(17)
1.3683(19)
1.2926(19)
1.466(2)
Crystal size, mm3
Crystal system
Space group
N(1)–C(3)
N(1)–N(2)
N(2)–C(1)
N(3)–C(3)
N(3)–N(4)
N(3)–C(1)
N(4)–C(2)
C(1)–C(4)
C(2)–C(10)
˚
a, A
˚
b, A
˚
c, A
β, deg
3
˚
V, A
Z
1.503(2)
Dcalcd, Mg m−3
µ(MoKα ), mm−1
F(000), e
1.38
0.2
744
C(3)–S–C(2)
87.85(5)
105.04(9)
109.72(9)
118.21(9)
106.02(9)
135.70(10)
108.28(9)
107.43(10)
127.95(10)
124.55(10)
121.83(10)
116.26(9)
121.83(8)
111.78(10)
138.81(9)
109.39(8)
87.68(8)
C(3)–N(1)–N(2)
C(1)–N(2)–N(1)
C(3)–N(3)–N(4)
C(3)–N(3)–C(1)
N(4)–N(3)–C(1)
C(2)–N(4)–N(3)
N(2)–C(1)–N(3)
N(2)–C(1)–C(4)
N(3)–C(1)–C(4)
N(4)–C(2)–C(10)
N(4)–C(2)–S
104.88(13)
109.14(12)
118.99(13)
105.85(13)
135.10(14)
107.97(13)
108.31(14)
126.27(14)
125.12(14)
121.98(14)
116.43(12)
121.45(12)
111.81(15)
139.35(14)
108.85(12)
2θmax, deg
Refl. meas. /
indep. /
58.3
35684 /
4520 /
58.3
155223 /
18653 /
0.055
901
0.045
0.793
0.67
Rint
0.045
Param. refined
wR (F2, all refl.)
GoF (F2)
227
0.086
1.004
0.38
−3
˚
Max. ∆ρfin, e A
C(10)–C(2)–S
N(1)–C(3)–N(3)
N(1)–C(3)–S
133.9 (C-arom.), 145.0 (C-8), 154.4 (C-3-triazole), 179.5 (C-
6-S). – EIMS: m/z (%) = 372 (35) [M+2]+, 370 (100) [M]+,
137 (28), 135 (12), 107 (13), 93 (11), 79 (19).
N(3)–C(3)–S
6-(1-Adamantyl)-3-(3-chlorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5h)
6-(1-Adamantyl)-3-(2-bromophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5j)
Yield: 82 %; m. p. 208 – 210 ◦C; Rf: 0.65 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3025, 2901, 2848,
1539, 1457, 997. – 1H-NMR (CDCl3): δ = 1.85 (bs, 6H,
adamant.-H), 2.15 (bs, 6H, adamant.-H), 2.21 (bs, 3H,
adamant.-H), 7.46 – 7.48 (m, 2H, Ar-H), 8.26 (m, 1H, Ar-H),
8.38 (m, 1H, Ar-H). – 13C-NMR (CDCl3): δ = 28.1, 36.1,
40.0, 42.3 (C-adamant.), 124.3, 126.2, 127.5, 130.1, 130.2,
134.9 (C-arom.), 144.0 (C-8), 154.0 (C-3-triazole), 180.3 (C-
6-S). – EIMS: m/z (%) = 372 (35) [M+2]+, 370 (100) [M]+,
137 (41), 135 (15), 107 (9), 93 (13), 79 (20).
Yield: 74 %; m. p. 217 – 219 ◦C; Rf: 0.58 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3044, 2913, 2850,
1529, 1452, 643. – 1H-NMR (CDCl3): δ = 1.80 (bs, 6H,
adamant.-H), 2.07 (bs, 6H, adamant.-H), 2.14 (bs, 3H,
adamant.-H), 7.40 (m, 1H, Ar-H), 7.48 (m, 1H, Ar-H), 7.71 –
7.77 (m, 2H, Ar-H). – 13C-NMR (CDCl3): δ = 28.5, 36.1,
39.8, 42.2 (C-adamant.), 123.1, 127.4, 127.6, 131.7, 132.3,
133.7 (C-arom.), 146.0 (C-8), 154.3 (C-3-triazole), 179.5 (C-
6-S). – EIMS: m/z (%) = 416 (98) [M+2]+, 414 (100) [M]+,
281 (8), 279 (8), 183 (16), 181 (16), 135 (20), 107 (18), 93
(25), 79 (32).
6-(1-Adamantyl)-3-(4-chlorophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5i)
6-(1-Adamantyl)-3-(3-bromophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5k)
Yield: 84 %; m. p. 252 – 254 ◦C; Rf: 0.65 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3063, 2896, 2846,
Yield: 70 %; m. p. 229 – 230 ◦C; Rf: 0.62 (n-hexane : ethyl
1543, 1447, 1001. – 1H-NMR (CDCl3): δ = 1.85 (bs, acetate 6 : 4). – IR (KBr, cm−1): ν = 3035, 2899, 2845,
6H, adamant.-H), 2.14 (bs, 6H, adamant.-H), 2.21 (bs, 3H, 1540, 1456, 681. – 1H-NMR (CDCl3): δ = 1.85 (bs, 6H,
adamant.-H), 7.50 – 7.54 (m, 2H, Ar-H), 8.30–8.33 (m, 2H, adamant.-H), 2.15 (bs, 6H, adamant.-H), 2.21 (bs, 3H,
Ar-H). – 13C-NMR (CDCl3): δ = 27.6, 36.1, 40.0, 42.0 (C- adamant.-H), 7.42 (m, 1H, Ar-H), 7.62 (m, 1H, Ar-H), 8.31
adamant.), 124.7, 127.5, 129.2, 136.1 (C-arom.), 145.3 (C- (m, 1H, Ar-H), 8.54 (m, 1H, Ar-H). – 13C-NMR (CDCl3):
8), 154.7 (C-3-triazole), 180.2 (C-6-S). – EIMS: m/z (%) = δ = 28.1, 36.1, 40.0, 42.3 (C-adamant.), 123.0, 124.7,
372 (36) [M+2]+, 370 (100) [M]+, 137 (48), 135 (14), 107 127.7, 129.1, 130.4, 133.0 (C-arom.), 144.8 (C-8), 154.8
(11), 93 (12), 79 (19).
(C-3-triazole), 180.3 (C-6-S). – EIMS: m/z (%) = 416 (98)
Unauthenticated
Download Date | 10/29/17 4:04 PM

M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
183
[M+2]+, 414 (100) [M]+, 281 (5), 279 (5), 183 (34), 181 X-Ray structure determinations
(34), 135 (30), 107 (15), 93 (24), 79 (36).
Crystal data and refinement details are presented in Ta-
ble 1. Data collection and reduction: Crystals were mounted
in inert oil on glass fibers and transferred to the cold gas
stream of an Oxford Diffraction Xcalibur S diffractometer.
Measurements were performed with monochromated MoKα
6-(1-Adamantyl)-3-(4-bromophenyl)-[1,2,4]triazolo[3,4-
b][1,3,4]thiadiazole (5l)
Yield: 76 %; m. p. 252 – 254 ◦C; Rf: 0.60 (n-hexane : ethyl
acetate 6 : 4). – IR (KBr, cm−1): ν = 3040, 2907, 2849,
1521, 1447, 679. – 1H-NMR (CDCl3): δ = 1.85 (bs, 6H,
adamant.-H), 2.14 (bs, 6H, adamant.-H), 2.21 (bs, 3H,
adamant.-H), 7.66 – 7.70 (m, 2H, Ar-H), 8.23 – 8.26 (m, 2H,
Ar-H). – 13C-NMR (CDCl3): δ = 28.1, 36.1, 39.9, 42.3 (C-
adamant.), 124.5, 124.8, 127.7, 132.1 (C-arom.), 145.4 (C-
8), 154.7 (C-3-triazole), 180.3 (C-6-S). – EIMS: m/z (%) =
416 (98) [M+2]+, 414 (100) [M]+, 281 (7), 279 (7), 183 (43),
181 (43), 135 (27), 107 (18), 93 (23), 79 (34).
˚
radiation (λ = 0.71073 A). Absorption corrections were per-
formed on the basis of multi-scans. Structure refinement: The
structures were refined anisotropically against F2 (program
SHELXL-97) [20]. Methyl groups were refined as idealized
rigid groups allowed to rotate but not tip; other hydrogen
atoms were included with a riding model. For 5j, restraints to
displacement parameters were employed to improve stability
of refinement. Table 2 lists some selected bond lengths and
angles.
CCDC 743335 (5a) and 743336 (5j) contain the sup-
plementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data
request/cif.
Cytotoxicity assays
Cell cultures were seeded at 1 × 105 cells per mL in
96 multiwell plates in specific media supplemented with
◦
10 % FCS and antibiotics and incubated at 37 C in a hu-
midified CO2 (5 %) atmosphere in the absence or presence
of serial dilutions of test compounds. Cell viability was de-
termined after 96 h at 37 ◦C by the 3-(4,5-dimethylthiazol-2-
yl)-2,5-diphenyl-tetrazolium bromide (MTT) method. Com-
pounds were dissolved in DMSO at 100 mM and then diluted
into culture medium.
Acknowledgement
This work was financially supported by Higher Education
Commission (HEC) of Pakistan through a Ph. D. fellowship
to Mahmood-ul-Hassan Khan under the “Indigenous Ph. D.
5000 Fellowship Program”.
[1] T. Karabasanagouda, A. V. Adhikari, N. S. Shetty, Eur.
J. Med. Chem. 2007, 42, 521 – 529.
[2] D. J. Prasad, M. Ashok, P. Karegoudar, B. Poojary,
B. S. Holla, N. S. Kumari, Eur. J. Med. Chem. 2009,
44, 551 – 557.
lou-Litina, P. Eleftheriou, Eur. J. Med. Chem. 2009, 44,
1198 – 1204.
[12] A. A. Kadi, N. R. El-Brollosy, O. A. Al-Deeb, E. E.
Habib, T. M. Ibrahim, A. A. El-Emam, Eur. J. Med.
Chem. 2007, 42, 235 – 242.
[13] O. A. Al-Deeb, M. A. Al-Omar, N. R. El-Brollosy,
E. E. Habib, T. M. Ibrahim, A. A. El-Emam, Arzneim.-
Forsch. Drug Res. 2006, 56, 40 – 47.
[14] A. A. Kadi, N. R. El-Brollosy, O. A. Al-Deeb, E. E.
Habib, T. M. Ibrahim, A. A. El-Emam, Eur. J. Med.
Chem. 2007, 42, 235 – 242.
[3] D. A. Ibrahim, Eur. J. Med. Chem. 2009, 44, 2776 –
2781.
[4] J. Mohan, V. Kumar, Ind. J. Chem. 1998, 37B, 183 –
186.
[5] J. Mohan, Ind. J. Chem. 2002, 41B, 403 – 406.
[6] L.-X. Zhang, A.-J. Zhang, X.-X. Chen, X.-X. Lei, X.-
Y. Nan, D.-Y. Chen, Z.-Y. Zhang, Molecules 2002, 7,
681 – 689.
[15] S. A. F. Rostom, M. A. Shalaby, M. A. El-Demellawy,
Eur. J. Med. Chem. 2003, 38, 959 – 974.
[7] T. W. Moody, R. T. Jensen, J. Pharmacol. Exp. Ther.
2001, 299, 1154 – 1160.
[8] Y. Ru, R. W. Marquis, D. F. Veber, U.S. Patent 2002,
6,369,077.
[9] N. Kolocouris, G. Zoidis, G. B. Foscolos, G. Fytas,
R. S. Prathalingham, J. M. Kelly, L. Naesens, E. De-
Clereq, Bioorg. Med. Chem. Lett. 2007, 17, 4358 –
4362.
[10] A. A. El-Emam, O. A. Al-Deeb, M. Al-Omar, J. Leh-
mann, Bioorg. Med. Chem. 2004, 12, 5107 – 5113.
[11] O. Kouatly, A. Geronikaki, C. Kamoutsis, D. Hadjipav-
[16] V. L. J. Narayanan, J. Med. Chem. 1972, 15, 682 – 684.
[17] R. S. Bitner, K. E. Browman, M. E. Brune, Y. Chen,
S. Fung, P. B. Jacobson, H. Jae, J. T. Link, J. R. Patel,
M. A. Pliushchev, J. J. Rohde, L. E. Rueter, Q. Shuai,
B. K. Sorensen, M. I. Strakhova, J. Wang, M. Winn,
D. Wodka, H. Yong, US2009192141-A1, 2009.
[18] a) T. Akhtar, S. Hameed, K. M. Khan, M. I. Choud-
hary, Med. Chem. 2008, 4, 539 – 543; b) T. Akhtar,
S. Hameed, N. A. Al-Masoudi, R. Loddo, P. La
Colla, Acta Pharm. 2008, 58, 135 – 149; c) T. Akhtar,
S. Hameed, N. A. Al-Masoudi, K. M. Khan, Het-
Unauthenticated
Download Date | 10/29/17 4:04 PM

184
M.-u.-H. Khan et al. · 6-Adamantyl-3-aryl[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles
eroat. Chem. 2007, 18, 316 – 322; d) M. Zahid,
[19] M. C. Alley, D. A. Scudiero, A. Monks, M. L. Hursey,
M. J. Czerwinski, D. L. Fine, B. J. Abbott, J. G. Mayo,
R. H. Schoemaker, R. Boyd, Cancer Res. 1988, 48,
589 – 601.
[20] G. M. Sheldrick, SHELXL-97, Program for the Refine-
ment of Crystal Structures, University of Go¨ttingen,
Go¨ttingen (Germany) 1997. See also: G. M. Sheldrick,
Acta Crystallogr. 2008, A64, 112 – 122.
K. A. Yasin, T. Akhtar, S. Hameed, N. H. Rama,
N. A. Al-Masoudi, R. Loddo, P. La Colla, Arkivoc
2009, xi, 85 – 93; e) M.-u.-H. Khan, S. Hameed,
M. N. Tahir, T. H. Bokhari, I. U. Khan, Acta
Crystallogr. 2009, E65, o1437; f) M. Serwar,
T. Akhtar, S. Hameed, K. M. Khan, Arkivoc 2009, vii,
210 – 221.
Unauthenticated
Download Date | 10/29/17 4:04 PM