Anticancer 3-Aryl-5-aryl-1,2,4-oxadiazoles
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 16 5221
) 5.1, 1H), 7.00 (d, J ) 9.0, 1H), 3.89 (s, 3H). Anal. (C13H9-
ClN2O2S) C, H, N.
removed and then the solution was stirred at room tempera-
ture for 2 h, and precipitates were observed. The mixture was
poured into water, and the organic phase was separated. The
organic phase was washed with 2 N HCl and with water, dried
over MgSO4, filtered, and distilled under vacuum (bp 35-40
°C) to yield 6.09 g (44.7%) of 8b as light yellow liquid: 1H NMR
(CDCl3) 7.36 (m, 1H), 7.30 (m, 1H), 6.33 (m, 1H).
5-(3-Chlorothiophen-2-yl)-3-(4-methylphenyl)-1,2,4-ox-
1
adiazole (4e): white solid (33%); H NMR (CDCl3) 8.04 (d, J
) 8.1, 2H), 7.59 (d, J ) 5.1, 1H), 7.30 (d, J ) 8.0, 2H), 7.12 (d,
J ) 5.1, 1H), 2.42 (s, 3H). Anal. (C13H9ClN2OS‚0.5H2O) C, H,
N.
3-Bromofuran-2-carboxylic Acid (9a). To a solution of
lithium diisopropylamide in tetrahydrofuran (26.2 mL, 1.4 M)
cooled at -78 °C was added dropwise a solution of 8a (5.0 g,
34 mmol) in tetrahydrofuran (26 mL). The solution was stirred
for 30 min at -78 °C and then poured into a solution of crushed
carbon dioxide in anhydrous ether (50 mL) and the mixture
was stirred for 10 min. The mixture was poured into water
(Caution: emission of a lot of gas could produce a violent
reaction) and the aqueous phase was separated. The aqueous
phase was acidified to pH 3 by 2 N HCl and extracted with
ethyl acetate (3 × 80 mL). The combined extracts were dried
over MgSO4, filtered, and concentrated to give a solid. The solid
was recrystallized from hexane and ethyl acetate to yield 4.21
g (65%) of 9a as a yellowish powder: 1H NMR (CDCl3) 7.58
(m, 1H), 6.66 (m, 1H).
3-Chlorofuran-2-carboxylic Acid (9b). Compound 9b
was prepared from 8b by a procedure similar to that described
for the preparation of compound 9a: white solid (51%); 1H
NMR (CDCl3) 7.57 (d, J ) 2.1, 1H), 6.59 (d, J ) 1.8, 1H).
5-(3-Bromofuran-2-yl)-3-(4-chlorophenyl)-1,2,4-oxadia-
zole (10a). A solution of 9a (74 mg, 1.0 mmol) and thionyl
chloride (0.5 mL) in benzene (5 mL) was stirred at 60 °C for 4
h and then evaporated to dryness. The residue was dissolved
in pyridine (10 mL) and to the solution was added 4-chloro-
N-hydroxybenzamidine (73 mg, 0.43 mmol). The solution was
refluxed for 10 h and then cooled to room temperature. Water
(20 mL) was added to the solution to produce a precipitate,
which was collected by filtration, washed with water, and then
dried to give 28 mg (22%) of 10a as white solid: 1H NMR
(CDCl3) 8.11 (d, J ) 9.0, 2H), 7.67 (d, J ) 2.1, 1H), 7.42 (d, J
) 9.0, 2H), 6.75 (d, J ) 1.8, 1H). Anal. (C12H6BrClN2O2) C, H,
N.
5-(3-Chlorothiophen-2-yl)-3-(4-dimethylaminophenyl)-
1,2,4-oxadiazole (4f): white solid (14%); 1H NMR (CDCl3)
8.01 (m, 2H), 7.56 (d, J ) 5.2, 1H), 7.10 (d, J ) 5.5, 1H), 6.76
(m, 2H), 3.04 (s, 6H). Anal. (C14H12ClN3OS) C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(3-trifluoromethylphenyl)-
1,2,4-oxadiazole (4g): white solid (72%); 1H NMR (CDCl3)
8.44 (s, 1H), 8.36 (d, J ) 7.7, 1H), 7.80 (d, J ) 8.5, 1H), 7.67
(d, J ) 8.0, 1H), 7.64 (d, J ) 5.2, 1H), 7.15 (d, J ) 5.2, 1H).
Anal. (C13H6ClF3N2OS) C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(3,4-dichlorophenyl)-1,2,4-
oxadiazole (4h): white solid (69%); 1H NMR (CDCl3) 8.27
(d, J ) 1.4, 1H), 8.00 (dd, J ) 8.5, 1.5, 1H), 7.63 (d, J ) 5.5,
1H), 7.59 (d, J ) 8.2, 1H), 7.14 (d, J ) 5.2, 1H). Anal. (C12H5-
Cl3N2OS) C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(4-chloro-3-trifluorometh-
ylphenyl)-1,2,4-oxadiazole (4i): white solid (68%); 1H NMR
(CDCl3) 8.49 (d, J ) 1.6, 1H), 8.28 (dd, J ) 8.5, 1.9, 1H), 7.66
(m, 2H), 7.15 (d, J ) 5.2, 1H). Anal. (C13H5Cl2F3N2OS) C, H,
N.
3-(4-Chloro-2-methylphenyl)-5-(3-chlorothiophen-2-
yl)-1,2,4-oxadiazole (4j): white solid (46%); 1H NMR (CDCl3)
8.04 (d, J ) 8.0, 1H), 7.61 (dd, J ) 5.2, 1.4, 1H), 7.35-7.28
(m, 2H), 7.14 (dd, J ) 5.4, 1.2, 1H), 2.64 (s, 3H). Anal. (C13H8-
Cl2N2OS) C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(5-trifluoromethylpyridin-
2-yl)-1,2,4-oxadiazole (4k): white solid (77%); 1H NMR
(CDCl3) 9.09 (m, 1H), 8.36 (d, J ) 8.2, 1H), 8.14 (m, 1H), 7.66
(d, J ) 5.2, 1H), 7.16 (d, J ) 5.2, 1H). Anal. (C12H5ClF3N3OS)
C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-
oxadiazole (4l): white solid (85%); 1H NMR (CDCl3) 8.78 (dd,
J ) 2.5, 0.8, 1H), 8.18 (dd, J ) 8.4, 0.7, 1H), 7.86 (dd, J ) 8.5,
2.5, 1H), 7.64 (d, J ) 5.2, 1H), 7.14 (d, J ) 5.2, 1H). Anal.
(C11H5Cl2N3OS) C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(6-trifluoromethylpyridin-
3-yl)-1,2,4-oxadiazole (4m): white solid (80%); 1H NMR
(CDCl3) 9.49 (m, 1H), 8.63 (m, 1H), 7.85 (d, J ) 8.2, 1H), 7.66
(d, J ) 5.5, 1H), 7.17 (d, J ) 5.2, 1H). Anal. (C12H5ClF3N3OS)
C, H, N.
5-(3-Chlorothiophen-2-yl)-3-(6-chloropyridin-3-yl)-1,2,4-
oxadiazole (4n): white solid (27%); 1H NMR (CDCl3) 9.16 (d,
J ) 2.2, 1H), 8.39 (dd, J ) 8.2, 2.2, 1H), 7.65 (d, J ) 5.2, 1H),
7.49 (d, J ) 8.5, 1H), 7.15 (d, J ) 5.2, 1H). Anal. (C11H5Cl2N3-
OS) C, H, N.
The following compounds were prepared from the corre-
sponding 3-bromo- or 3-chlorofuran-2-carboxylic acid (9a or 9b)
and substituted N-hydroxybenzamidine or N-hydroxypyridine-
carboxamidine by a procedure similar to that described for the
preparation of compound 10a.
5-(3-Chlorofuran-2-yl)-3-(4-chlorophenyl)-1,2,4-oxadia-
1
zole (10b): white solid (45%); H NMR (CDCl3) 8.12 (d, J )
8.4, 2H), 7.68 (d, J ) 1.8, 1H), 7.49 (d, J ) 8.4, 2H), 6.69 (d, J
) 1.8, 1H). Anal. (C12H6Cl2N2O2) C, H, N.
5-(3-Bromofuran-2-yl)-3-(4-trifluoromethylphenyl)-1,2,4-
1
oxadiazole (10d): white solid (15%); H NMR (CDCl3) 8.33
(d, J ) 8.7, 2H), 7.79 (d, J ) 8.7, 2H), 7.68 (d, J ) 2.1, 1H),
6.76 (d, J ) 2.1, 1H). Anal. (C13H6BrF3N2O2) C, H, N.
5-(3-Chlorofuran-2-yl)-3-(4-trifluoromethylphenyl)-1,2,4-
oxadiazole (10e): white powder (36%); 1H NMR (DMSO-d6)
8.29 (m, 3H), 7.99 (d, J ) 8.7, 2H), 7.16 (d, J ) 1.8, 1H). Anal.
(C13H6ClF3N2O2) C, H, N.
5-(3-Bromothiophen-2-yl)-3-(4-chlorophenyl)-1,2,4-oxa-
1
diazole (4o): white solid (98%); H NMR (CDCl3) 8.11 (d, J
) 8.7, 2H), 7.60 (d, J ) 5.4, 1H), 7.49 (d, J ) 8.4, 2H), 7.20 (d,
J ) 5.1, 1H). Anal. (C12H6BrClN2OS) H, N; C: calcd, 42.19;
found: C, 42.95.
5-(3-Bromofuran-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-
oxadiazole (10f): white solid (54%); 1H NMR (CDCl3) 8.81
(d, J ) 2.5, 1H), 8.22 (d, J ) 8.2, 1H), 7.90 (dd, J ) 8.3, 2.5,
1H), 7.71 (d, J ) 1.9, 1H), 6.79 (d, J ) 1.6, 1H). Anal. (C11H5-
BrClN3O2) H; C: calcd, 40.46; found: C, 41.15; N: calcd, 12.87;
found: N, 12.33.
5-(3-Bromofuran-2-yl)-3-(5-trifluoromethylpyridin-2-
yl)-1,2,4-oxadiazole (10g): white solid (85%); 1H NMR (CDCl3)
9.09 (m, 1H), 8.37 (d, J ) 8.2, 1H), 8.14 (dd, J ) 8.1, 2.3, 1H),
7.70 (d, J ) 1.9, 1H), 6.78 (d, J ) 1.9, 1H). Anal. (C12H5-
BrF3N3O2) C, H, N.
5-(3-Chlorofuran-2-yl)-3-(5-chloropyridin-2-yl)-1,2,4-
oxadiazole (10h): white solid (21%); 1H NMR (DMSO-d6)
8.87 (m, 1H), 8.28 (d, J ) 2.1, 1H), 8.19 (d, J ) 2.1, 1H), 8.18
(d, J ) 0.9, 1H), 7.15 (d, J ) 2.1, 1H). Anal. (C11H5Cl2N3O2) C,
H, N.
3-(4-Methylphenyl)-5-(thiophen-2-yl)-1,2,4-oxadi-
1
azole (4s): white solid (53%); H NMR (CDCl3) 8.04 (d, J )
8.4, 2H), 7.95 (d, J ) 3.6, 1H), 7.66 (d, J ) 5.1, 1H), 7.31 (d, J
) 8.7, 2H), 7.22 (m, 1H), 2.43 (s, 3H). Anal. (C13H10N2OS) C,
H, N.
5-(3-Chlorothiophen-2-yl)-3-(4-nitrophenyl)-1,2,4-oxa-
diazole (4v): white solid (80%); 1H NMR (CDCl3) 8.37 (s, 4H),
7.65 (d, J ) 5.4, 1H), 7.16 (d, J ) 5.4, 1H). Anal. (C12H6-
ClN3O3S): H, N; C: calcd, 46.84; found: C, 45.16.
3-Chlorofuran (8b). A solution of freshly distilled 3-bro-
mofuran (8a) (19.5 g, 132 mmol) in anhydrous THF (40 mL)
and anhydrous ether (70 mL) was cooled to -78 °C and stirred
for 20 min. To the solution was added n-butyllithium in
pentane (66 mL, 2.0 M) dropwise through an addition funnel.
The reaction mixture was stirred for 0.5 h at -78 °C and then
hexachloroethane (31.4 g, 133 mmol) in anhydrous THF (15
mL) was added dropwise to the stirring solution. The solution
was stirred for an additional 1 h at -78 °C. The ice bath was
Caspase Activation Assay (EC50). The potency of com-
pound 1d and its analogues as inducer of apoptosis was