HTTP WWW - Arkat-Usa
HTTP WWW - Arkat-Usa
HTTP WWW - Arkat-Usa
Abstract
A new series of adamantanyl-1,3-thiazole and 1,3,4-oxadiazole derivatives (6a-l), bearing various
aryl groups has been synthesized from adamantan-1-nitrile in four steps. All the compounds were
evaluated, in vitro, for antiproliferative activity against a large panel of human tumor-derived cell
lines. Compounds 6e exhibited activity against human splenic B-lymphoblastoid (WIL-2NS) and
human acute B-lymphoblastic leukemia (CCRF-SB) cell lines with CC50 = 68 and 42 M,
respectively. Compound 6l showed activity against CCRF-SB cell lines with CC50 = 51 M. All the
other compounds were found inactive.
Key words: Adamantan-1-nitrile, antitumor activity, anti-HIV activity, thiazole, oxadiazoles.
Introduction
Amantadine hydrochloride 1 (1-adamantanamine hydrochloride, Symmetrel) was the first
adamantane derivative introduced in medicine as effective therapy1-3 against Asian A influenza
virus. Among various substituents a growing interest in adamantyl derivatives is gaining
prominence because of well known drugs like Rimantadine, Memantine, Adapalene, Adatanserin
and others in clinical trials.4,5 The pronounced central nervous stimulant and cardiovascular effects
of amantadine6 necessitated the search for newer more potent and less toxic agents for the control of
pandemic influenza viruses. N-1-adamantyl-4-aminophthalimide 2 was endowed with anti-HIV-1
and -HIV-2 activities in CEM cell cultures.6 Potent anti-HIV-1 activity was recently observed for a
series of ()-2-(1-adamantyl-3-alkyl/aryl)thiazolidin-4-ones where these compounds behaved as
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couplings with C-2 of the thiazole ring at C 183.8 and C-2 of the oxadiazole ring at 160.9 ppm.
Furthermore, a 2JC,H coupling of the same proton with C-4 of the thiazole ring at C 139.2 ppm was
also observed.
In vitro antiproliferative activity
Compounds 6a-l were tested, in vitro, against a large panel of human cell lines derived from
hematological [CD4+ human T-cells containing an integrated HTLV-1 genome (MT-4); CD4+
human acute T-lymphoblastic leukemia (CCRF-CEM); human splenic B-lymphoblastoid cells
(WIL-2NS); human acute B-lymphoblastic leukemia (CCRF-SB) and solid skin melanoma (SK-28);
breast adenocarcinoma (MCF-7); lung squamous carcinoma (SK-MES-1); hepatocellular carcinoma
(HepG-2); prostate carcinoma (DU-145)] or normal tissues [lung fibroblasts (MRC-5)]. For
comparative purposes, we evaluated the cytotoxic activities of the compounds relative to
Doxorubicin.
All compounds were inactive except 6e which showed activity against human splenic Blymphoblastoid cells (WIL-2NS) and human acute B-lymphoblastic leukemia (CCRF-SB) cell lines
with CC50 = 68 and 42 M, respectively. Compound 6l exhibited activity against CCRF-SB cell
lines with CC50 = 51 M.
Experimental Section
General Procedures. Melting points are uncorrected and were measured on a Gallenkamp melting
point apparatus (MP-D). The elemental analysis was performed on Leco CHNS-932 Elemental
Analyzer, Leco Corporation (USA). N MR spectra were recorded on a Bruker Avance 300 MHz
spectrometer with TMS as an internal standard and on the 75 MHz (13C) (scale in ). The
multiplicities are expressed as s = singlet, bs = broad singlet, d = doublet, dd = doublet of doublets,
dt = doublet of triplets, t = triplet and m = multiplet. Mass spectra were recorded on Agilent
technologies 6890N gas chromatograph and an inert mass selective detector 5973 mass
spectrometer. The Rf -values were determined employing pre-coated silica gel aluminium plates,
Kieslgel 60 F254 from Merck (Germany), using n-hexane: ethyl acetate (7:3) as an eluent unless
otherwise mentioned. Column chromatography was carried out using silica gel 60 (0.063-0.200
mm) purchased form Merck. The IR spectra were recorded on FTS 3000 MX, Bio-Rad Merlin
(Excalibur Model) spectrophotometer.
2-Adamantanethioamide (3). P4S10 (5.33 g, 12.00 mmol) was stirred at room temperature in EtOH
(25 mL) for 2 h. Adamantane-1-nitrile (1.0 g, 6.20 mmol) was added to the above solution and the
reaction mixture heated under reflux for 12 h. After completion of the reaction, the solution was
concentrated in vacuo, diluted with water and extracted with CH2Cl2 (3 x 50 mL). The combined
organic extracts were dried (Na2SO4), filtered and concentrated in vacuo and the yellow liquid was
refrigerated. The resulting white crystals were filtered, dried and recrystallized from aq. EtOH to
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give 3 (0.63 g, 52 %); mp 159-161 C; Rf: 0.54. IR (max, KBr, cm-1): 3424, 3323, 2907, 2848, 1656,
1449, 1384, 1181. 1H-NMR (CDCl3): 1.79 (m, 6H, CH2-4, CH2-6, CH2-10), 2.18 (m, 9H, CH2-2,
CH-3, CH-5, CH-7, CH2-8, CH2-9), 7.10 (bs, 1H, N-H), 7.95 (1H, bs, N-H). 13C-NMR (CDCl3):
28.4, 36.2, 41.7, 45.6 (Cadamant.); 218.9 (C=S). EI-MS (m/z, %): 195 (M+, 80), 135 (100), 121 (5),
107 (15), 93 (27), 60 (16). Anal. calcd. for C11H17NS: C, 67.64; H, 8.77; N, 7.17. Found: C, 67.54;
H, 8.72; N, 7.38.
Ethyl 2-adamantyl-1,3-thiazole-4-carboxylate (4). A mixture of 2-adamantanethioamide (3) (0.29
g, 1.5 mmol) and ethyl bromopyruvate (0.29 g, 1.5 mmol) in EtOH (25 mL) were heated under
reflux for 8 h. After cooling, the reaction mixture was concentrated in vacuo, diluted with water and
extracted with CH2Cl2 (3 x 25 mL). The combined organic layers were dried (Na2SO4), filtered and
concentrated in vacuo to afford 3 as a yellow oil (0.35 g, 80 %), Rf: 0.73. IR (max, film, cm-1):
3117, 2906, 2850, 1732, 1605, 1497, 1477, 1451, 1368, 1093. 1H-NMR (CDCl3): 1.40 (t, 3H, J =
7.2 Hz, OCH2CH3), 1.79 (m, 6H, CH2-4, CH2-6, CH2-10), 2.18 (m, 9H, CH2-2, CH-3, CH-5, CH-7,
CH2-8, CH2-9), 4.41 (2H, q, J = 7.2 Hz, OCH2CH3), 8.05 (1H, s, H-12). 13C-NMR (CDCl3): 14.4
(OCH2CH3); 28.5, 36.4, 39.8, 41.7 (Cadamant.); 61.2 (OCH2CH3); 125.9 (C5thiazole); 146.6 (C4thiazole);
161.7 (C=O); 182.3 (C2thiazole). EI-MS (m/z, %): 291 (M+, 90), 246 (100), 135 (45), 121 (3), 107
(9), 93 (15), 71, (50), 45 (10).
2-Adamantyl-1,3-thiazole-4-carbohydrazide (5). Hydrazine hydrate 80% (5.2 mmol) was added
slowly to a stirred solution of ethyl 2-adamantyl-1,3-thiazole-4-carboxylate (4) (0.38 g, 1.3 mmol)
in MeOH (5 mL) and the reaction mixture heated under reflux for 4 h. After cooling, the mixture
was concentrated in vacuo, followed by addition of cold water. The precipitated solid was filtered,
dried (Na2SO4) and recrystallized from aq. EtOH to give (5) (0.27 g, 75%); mp 179-181 C; Rf 0.73
(petroleum ether : acetone; 2:3). IR (max, KBr, cm-1): 3424, 3323, 3184, 1663, 1541, 1491. 1HNMR (CDCl3): 1.79 (m, 6H, CH2-4, CH2-6, CH2-10), 2.04 (m, 9H, CH2-2, CH-3, CH-5, CH-7,
CH2-8, CH2-9), 4.08 (bs, 2H, NH2), 7.99 (s, 1H, H-12), 8.48 (bs, 1H, N-H). 13C-NMR (CDCl3):
28.4, 36.4, 39.6, 43.1 (Cadamant.); 121.8 (C5thiazole); 147.9 (C4thiazole); 162.2 (C=O); 182.1 (C2thiazole).
EI-MS (m/z, %): 277 (M+, 95), 246 (100), 219 (10), 179 (5), 135 (47), 121 (3), 107 (9), 93 (15).
Anal. calcd. for C14H19N3SO: C, 60.64; H, 6.88; N, 15.11. Found: C, 60.35; H, 6.66; N, 15.03.
General procedure for the synthesis of 2-(2-adamantyl-1,3-thiazol-4-yl)-5-aryl-1,3,4oxadiazoles (6a-l)
A mixture of 5 (0.50 g, 1.8 mmol) and substituted benzoic acid (1.8 mmol) was heated at 100-120
C in presence of excess polyphosphoric acid (PPA) for 4 h. After cooling, the mixture was poured
into crushed ice, and neutralized with 5% aq. NaHCO3 solution. The precipitated solid was filtered
and purified using column chromatography (petroleum ether : ethyl acetate; 9 : 1).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(4-methylphenyl)-1,3,4-oxadiazole
(6a).
From
4-1
methylbenzoic acid (0.25 g). Yield: 0.45 g (66%); mp 187-189 C, Rf: 0.57. IR (max, KBr, cm ):
1600, 1497, 1261. 1H-NMR (CDCl3): 1.84 (m, 6H, CH2-4, CH2-6, CH2-10); 2.17 (m, 9H, CH2-2,
CH-3, CH-5, CH-7, CH2-8, CH2-9); 2.46 (s, 3H, Ph-CH3); 7.35 (d, 2H, J2,3 = J5,6 = 9.0 Hz, Ar-H-3,
Ar-H-5); 8.07 (s, 1H, H5thiazole); 8.08 (d, 2H, Ar-H-2, Ar-H-6). 13C-NMR (CDCl3): 21.7 (Ph-CH3);
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28.5, 36.4, 39.9, 43.1 (Cadaman.); 120.7 (C5thiazole); 121.1, 127.1, 129.7 (Carom); 139.5 (C4thiazole); 142.3
(C1arom.); 160.6 (C2oxadiazole); 164.6 (C5oxadiazole); 183.5 (C2thiazole). EI-MS (m/z; %): 377 (M+, 100),
246 (10), 160 (33), 135 (15), 121 (10), 119 (25), 107 (3), 93 (7), 91 (27), 79 (15), 65 (10). Anal.
calcd. for C22H23N3SO: C, 69.90; H, 6.14; N, 11.10; S,8.49; Found: C, 69.95; H, 6.29; N, 10.81; S,
8.39.
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(3-methylphenyl)-1,3,4-oxadiazole
(6b).
From
3-1
methylbenzoic acid (0.25 g). Yield: 0.43 g (63%); mp 153-155 C; Rf: 0.55. IR (max, KBr, cm ):
1590, 1549, 1263. 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.17 (m, 9H, CH2-2,
CH-3, CH-5, CH-7, CH2-8, CH2-9); 2.47 (s, 3H, CH3); 7.37 (d, 1H, J = 7.5 Hz, Ar-H-4); 7.43 (t,
1H, J5,6 = 7.5 Hz, Ar-H-5); 7.98 (s, 1H, Ar-H-2); 8.02 (s, 1H, H5thiazole); 8.08 (d, 1H, Ar-H-6). 13CNMR (CDCl3): 22.3 (Ph-CH3); 28.6, 36.5, 39.9, 43.1 (Cadaman.); 120.8 (C5thiazole); 123.6, 124.3,
127.7, 128.9, 132.6 (Carom.); 139.5 (C4thiazole); 160.7 (C2oxadiazole); 164.5 (C5oxadiazole); 183.7 (C2thiazole).
EI-MS (m/z; %): 377 (M+, 100), 246 (10), 160 (20), 135 (10), 119 (15), 121 (3), 107 (2), 93 (6), 91
(17), 79 (10), 65 (5).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(2-methylphenyl)-1,3,4-oxadiazole
(6c).
From
2-1
methylbenzoic acid (0.25 g). Yield: 0.43 g (64%); mp 151-153 C; Rf: 0.61. IR (max, KBr, cm ):
1601, 1536, 1261. 1H-NMR (CDCl3): 1.84 (m, 6H, CH2-4, CH2-6, CH2-10); 2.17 (m, 9H, CH2-2,
CH-3, CH-5, CH-7, CH2-8, CH2-9); 2.78 (s, 3H, Ph-CH3); 7.34-7.45 (m, 3H, Ar-H-3, Ar-4, Ar-H5); 8.07 (m, 2H, Ar-H-6, H5thiazole). 13C-NMR (CDCl3): 22.1 (Ph-CH3); 28.5, 36.4, 39.9, 43.1
(Cadaman.); 120.7 (C5thiazole); 122.9, 126.1, 129.2, 131.2 (Carom.); 138.6 (C2arom.); 139.5 (C4thiazole);
160.4 (C2oxadiazole); 164.6 C5oxadiazole); 183.6 (C2thiazole). EI-MS (m/z; %): 377 (M+, 100), 246 (13),
160 (10), 135 (17), 121 (4), 119 (15), 107 (2), 93 (2), 91 (20), 65 (8).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (6d). From 4-chlorobenzoic acid (0.16 g). Yield: 0.26 g (64%); mp 181-183 C; Rf: 0.47. IR (max, KBr, cm-1): 1596,
1543, 1262, 1019. 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H, CH2-2,
CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.52 (d, 2H, J2,3 = J5,6 = 8.7 Hz, Ar-H-2, Ar-H-6); 8.09 (s, 1H,
H5thiazol); 8.13 (d, 2H, Ar-H-3, Ar-H-5). 13C-NMR (CDCl3): 28.5, 36.4, 39.9, 43.1 (Cadaman.); 121.1
(C5thiazole); 122.3, 128.4, 129.4 (Carom); 134.9 (C4arom.); 139.2 (C4thiazole); 160.9 (C2oxadiazole); 163.6
(C5oxadiazole); 183.8 (C2thiazole). EI-MS (m/z; %): 399 (M+2, 33), 397 (M+, 100), 246 (12), 217 (4),
182 (5), 180 (14), 141 (5), 139 (16), 135 (15), 121 (1), 113 (4), 111(12), 107 (2), 93 (12), 79 (15).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(3-chlorophenyl)-1,3,4-oxadiazole
(6e).
From
3-1
chlorobenzoic acid (0.16 g). Yield: 0.24 g (61%); mp 165-168 C; Rf: 0.52. IR (max, KBr, cm ):
1576, 1547, 1262, 1086. 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.31-7.55 (m, 2H, Ar-H-4, Ar-H-5), 8.00-8.21 (m, 3H,
Ar-H-2, Ar-H-6, H5thiazole). 13C-NMR (CDCl3): 28.6, 36.2, 39.9, 43.0 (Cadaman.); 121.3 (C5thiazole);
125.3, 125.4, 127.1, 130.4, 131.8, 135 (Carom.); (C3arom.); 139.1 (C4thiazole); 160.5 (C2oxadiazole); 163.2,
(C5oxadiazole); 183.8(C2thiazole). EI-MS (m/z; %): 399 (M+2, 33), 397 (M+, 100), 246 (10), 217 (2),
182 (2), 180 (7), 141 (5), 139 (16), 135 (15), 121 (1), 113 (4), 111(13), 107 (2), 93 (14), 79 (18).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(2-chlorophenyl)-1,3,4-oxadiazole
(6f).
From
2-1
chlorobenzoic acid (0.16 g). Yield: 0.24 g (62%); mp 148-150 C; Rf: 0.50. IR (max, KBr, cm ):
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1596, 1532, 1262, 1088. 1H-NMR (CDCl3): 1.82 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.44 (dt, 1H, J4,5 = J3,4 = 7.7 Hz, J4,6 = 1.5 Hz, Ar-H-4);
7.50 (m, 1H, Ar-H-5); 7.58 (dd, 1H, J3,4 = 7.7 Hz, J3,5 = 1.5 Hz, Ar-H-3), 8.09 (dd, 1H, J5,6 = 7.5
Hz, J4,6 = 1.8 Hz, H-6), 8.09 (s, 1H, H5thiazole). 13C-NMR (CDCl3): 28.5, 36.4, 39.9, 43.1 (Cadaman.);
121.3 (C5thiazole); 123.2, 127.1, 131.1, 131.5, 132.4 (Carom.); 133.3 (C1arom.); 139.3 (C4thiazole); 161.2
(C2oxadiazole); 162.7 C5oxadiazole); 183.8 (C2thiazole). EI-MS (m/z; %): 399 (M+2, 33), 397 (M+, 100),
246 (14), 182 (3), 180 (10), 141 (5), 139 (16), 135 (15), 121 (1), 113 (3), 111(10), 107 (2), 93 (15),
79 (18).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(4-bromophenyl)-1,3,4-oxadiazole
(6g).
From
4-1
bromobenzoic acid (0.20 g). Yield: 0.27 g (61%); mp 188-190 C; Rf: 0.53. IR (max, KBr, cm ):
1593, 1474, 1102, 1075; 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.15 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.67 (d, 2H, J2,3 = J5,6 = 8.6 Hz, Ar-H-2, Ar-H-6); 8.04
(s, 1H, H5thiazol); 8.04 (d, 2H, Ar-H-3, Ar-H-5). 13C-NMR (CDCl3): 28.5, 36.3, 39.9, 43.0,
(Cadaman.); 121.1 (C5thiazole); 122.7, 126.4, 128.5 (Carom); 132.3 (C4arom.); 139.2(C4thiazole); 160.9
(C2oxadiazole); 163.6 (C5oxadiazole); 183.7 (C2thiazole). EI-MS (m/z; %): 443 (M+2, 100), 441 (M+, 100),
362 (5), 246 (12), 217 (2), 185 (14), 183 (15), 157 (10), 155 (9), 135 (20), 121 (5), 107 (7), 93 (18),
79 (25).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(3-bromophenyl)-1,3,4-oxadiazole
(6h).
From
3-1
bromobenzoic acid (0.20 g). Yield: 0.28 g (63%); mp 171-173 C; Rf: 0.57; IR (max, KBr, cm ):
1590, 1545, 1260, 1084; 1H-NMR (CDCl3): 1.84 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.42 (t, 1H, J5,6 = 7.8 Hz, Ar-H-5); 7.69 (m, 2H, Ar-H2, Ar-H-4); 8.10 (m, 1H, Ar-H-6); 8.12 (s, 1H, H5thiazole). 13C-NMR (CDCl3): 28.5, 36.4, 39.9, 43.0
(Cadaman.); 121.2 (C5thiazole); 123.0, 125.7, 129.9, 130.5, 134.6 (Carom.); 139.1 (C4thiazole); 161.0
(C2oxadiazole); 163.0 (C5oxadiazole); 183.8 (C2thiazole). EI-MS (m/z; %): 443 (M+2, 100), 441 (M+, 100),
362 (5), 246 (10), 217 (10), 185 (10), 183 (10), 157 (12), 155 (12), 135 (18), 121 (3), 107 (10), 93
(19), 79 (25).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(2-bromophenyl)-1,3,4-oxadiazole
(6i).
From
2-1
bromobenzoic acid (0.20 g). Yield: 0.28 g (64%); mp 186-188 C; Rf: 0.51. IR (max, KBr, cm ):
1592, 1489, 1262, 1013. 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.41 (m, 1H, Ar-H-4); 7.49 (m, 1H, Ar-H-5); 7.78 (m,
2H, Ar-H-3, Ar-H-6); 8.09 (s, 1H, H5thiazole). 13C-NMR (CDCl3): 28.5, 36.4, 39.9, 43.0 (Cadaman.);,
121.2 (C5thiazole); 121.8 (C2arom.); 125.3, 127.5, 131.8, 132.5 (Carom.); 134.4 (C1arom.); 139.2 (C4thiazole);
161.2 (C2oxadiazole); 163.6 (C5oxadiazole); 183.8 (C2thiazole). . EI-MS (m/z; %): 443 (M+2, 98), 441 (M+,
100), 362 (10), 246 (20), 217 (10), 185 (15), 183 (15), 157 (10), 155 (10), 135 (25), 121 (3), 107
(10), 93 (19), 79 (22).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(4-flourophenyl)-1,3,4-oxadiazole
(6j).
From
4-1
fluorobenzoic acid (0.14 g). Yield: 0.24 g (63%); mp 213-215 C; Rf: 0.47. IR (max, KBr, cm ):
1606, 1497, 1262, 1222. 1H-NMR (CDCl3): 1.83 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9); 7.23 (t, 2H, J = 8.4 Hz, Ar-H-3, Ar-H-5); 8.08 (s, 1H,
H5thiazol); 8.20 (dd, 2H, J2,3 = 9.0 Hz, J2,6 = 5.4 Hz, Ar-H-2, Ar-H-6). 13C-NMR (CDCl3): 28.5,
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36.4, 39.9, 43.0 (Cadaman.); 116.3 (d, JC,F = 22.5 Hz, C3,5arom.); 120.1 (C5thiazol.); 129.8 (d, JC,F = 9.0
Hz, C2,6arom.); 139.3 (C4thiazole); 161.0 (C2oxadiazole); 163.1 (C5oxadiazole); 163.7 (d, JC,F = 252.2 Hz,
C4arom.); 183.8 (C2thiazole). EI-MS (m/z; %): 381 (M+, 100), 246 (11), 217 (2), 164 (15), 135 (10),
121 (4), 107 (4), 95 (7), 93 (6), 79 (8).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(3-flourophenyl)-1,3,4-oxadiazole
(6k).
From
3-1
fluorobenzoic acid (0.14 g). Yield: 0.25 g (66%); mp 158-160 C; Rf: 0.52. IR (max, KBr, cm ):
1587, 1551, 1259, 1225; 1H-NMR (CDCl3): 1.82 (m, 6H, CH2-4, CH2-6, CH2-10); 2.16 (m, 9H,
CH2-2, CH-3, CH-5, CH-7, CH2-8, CH2-9);, 7.26 (dt, 1H, J4,5 = 8.1 Hz, J4,6 = 2.4 Hz, J4,F = 8.3 Hz,
Ar-H-4), 7.52 (m, 2H, Ar-H-2, Ar-H-5), 7.88 (s, 1H, H5thiazol); 7.99 (m, 1H, Ar-H-6). 13C-NMR
(CDCl3): 28.5, 36.4, 39.9, 43.0 (Cadaman.); 113.6 (C5thiazole); 114.1 (d, JC2,F = 24.0 Hz, C2arom.);
115.3 (d, JC4,F = 21.0 Hz, C4arom.); 122.9 (d, JC6,F = 3.0 Hz, C6arom.); 125.6 (d, JC5,F = 8.2 Hz, C5arom.);
130.8 (d, JC1,F = 7.1 Hz, C1arom..); 161.1 (C2oxadiazole); 162.8 (d, JC2,F = 246.0 Hz, C3arom.); 163.3
(C5oxadiazole); 183.8 (C2thiazole). EI-MS (m/z; %): 381 (M+, 100), 246 (11), 217 (2), 164 (15), 135 (10),
121 (4), 107 (4), 95 (7), 93 (6), 79 (8).
2-(2-Adamantyl-1,3-thiazol-4-yl)-5-(2-flourophenyl)-1,3,4-oxadiazole (6l). From 2-flurobenzoic
acid (0.14 g). Yield: 0.25 g (65%); mp 175-177 C; Rf: 0.53. IR (max, KBr, cm-1): 1596, 1467, 1256,
1228. 1H-NMR (CDCl3): 1.82 (m, 6H, CH2-4, CH2-6, CH2-10); 2.15 (m, 9H, CH2-2, CH-3, CH-5,
CH-7, CH2-8, CH2-9); 7.24-7.34 (m, 2H, Ar-H-3, Ar-H-5); 7.59 (m, 1H, Ar-H-4), 8.09 (s, 1H,
H5thiazole); 8.17 (t, 1H, JH6,F = 8.4 Hz, Ar-H-6). 13C-NMR (CDCl3): 28.5, 36.4, 39.9, 43.0,
(Cadaman.); 112.3 (C5thiazole); 116.9 (d, JC3,F = 21.0 Hz, C3arom.); 124.6 (d, JC1,F = 21.2 Hz, C1arom.);
130.0 (d, JC5,F = 3.7.0 Hz, C5arom.); 133.5 (d, JC6,F = 9.0 Hz, C6arom.); 139.2 (d, JC4,F = 9.2 Hz,
C4arom.); 160.0 (d, JC2,F = 257.2 Hz, C2arom.); 161.0 (C2oxadiazole); 161.1 (C5oxadiazole); 183.7 (C2thiazole).
EI-MS (m/z; %): 381 (M+, 100), 246 (11), 217 (2), 164 (15), 135 (10), 121 (4), 107 (4), 95 (7), 93
(6), 79 (8).
Cytotoxicity assays
Cell cultures were seeded at 1x105 cells/mL in 96 multiwell plates in specific media supplemented
(5%) atmosphere supplemented with 10% FCS and antibiotics then incubated atand antibiotics and
incubated at 37 C in a humidified CO2 in the absence or presence of serial dilutions of test
compounds. Cell viability was determined after 96 hrs at 37 C by the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) method.25
Compounds were dissolved in DMSO at 100 mM and then diluted into culture medium.
References
1. Davies, W. L.; Grunnert, R. R.; Haff, R. F.; McGahen, J. W.; Neumeyer, E. M.; Paulshock, M.;
Watts, J. C.; Wood, T. R.; Hermann, E. C.; Hoffmann, C. E. Science 1964, 144, 862.
2. Togo, Y.; Hornick, R. B.; Dawkins. A. T. J. Am. Med. Assoc. 1968, 203, 1089.
3. Wendel, H. A.; Snyder, M. T.; Pell. S. Clin. Pharmacol. Therap. 1966, 7, 38.
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