Synthesis and biological evaluation of 5-substituted benzo[b]thiophene derivatives
449
8.64 (s, 1H, H-4), 11.5 (br s, NH), 11.91 (br s, 1H, COOH)
ppm; MS (70 eV): m/z = 322 (M?-2, 76), 295 (27), 265
(15), 237 (8), 209 (5), 181 (100), 154 (37), 105 (6), 97 (67).
NMR (270 MHz, DMSO-d6): d = 4.1 (s, 2H, –NHCH2),
7.32–7.41 (m, 4H, benzothiazole), 7.61, 7.74 (two dd, 2H,
H-6, H-7), 7.79 (br s, H, NH), 7.96 (s, 1H, H-3), 8.52 (s,
1H, H-4), 10.36 (br s, NH), 10.56 (br s, 1H, COOH) ppm;
MS (70 eV): m/z = 383 (M?, 1), 322 (2), 286 (15), 258
(9), 223 (4), 181 (100), 154 (17), 105 (6), 77 (27).
5-[2-(2-thioureido)acetamido]benzo[b]thiophene-2-
carboxylic acid (5, C12H11N3O3S2)
ꢀ
Yield 74%; M.p.: [300 °C; IR (KBr): m = 3,352 (COOH),
3,234, 3,198 (NH, NH2), 1,661 (C=O), 1,596 (C=O), 1,231
5-(2-(1H-Benzoimidazol-2-ylamino)acetamido)
benzo[b]thiophene-2-carboxylic acid (10, C18H14N4O3S)
1
(C=S) cm-1; H NMR (270 MHz, DMSO-d6): d = 3.93
ꢀ
(s, 2H, –NHCH2) 4.00 (br s, 2H, NH2), 7.29 (br s, H, NH),
7.67, 7.76 (two dd, 2H, H-6, H-7), 7.89 (s, 1H, H-3), 8.61
(s, 1H, H-4), 11.43 (br s, NH), 11.94 (br s, 1H, COOH)
ppm; MS (70 eV): m/z = 309 (M?, 3), 281 (33), 267 (5),
248 (69), 207 (100), 180 (35), 166 (34), 103 (6), 77 (44).
Yield 82%; M.p.: 290 °C; IR (KBr): m = 3,274 (COOH),
1
3,242, 3,087 (2NH), 1,692 (C=O), 1,613 (C=O) cm-1; H
NMR (270 MHz, DMSO-d6): d = 4.05 (s, 2H, –NHCH2)
6.87 (br s, 1H, NH), 7.34–7.43 (m, 4H, benzoimidazole),
7.60, 7.73 (two dd, 2H, H–6, H-7), 7.75 (br s, H, NH), 7.97
(s, 1H, H-3), 8.56 (s, 1H, H-4), 10.3 (br s, NH), 10.4 (br s,
1H, COOH) ppm; MS (70 eV): m/z = 366 (M?, 1), 333
(4), 319 (70), 277 (51), 246 (24), 207 (11), 181 (58), 154
(15), 105 (36), 102 (100), 77 (82).
5-(2-(4-Methylpiperazin-1-yl)acetamido)benzo[b]
thiophene-2-carboxylic acid (6, C16H19N3O3S)
ꢀ
Yield 84%; M.p.: 198–200 °C; IR (KBr): m = 3,298
(COOH), 3,102 (NH), 1,683 (C=O), 1,593 (C=O) cm-1
;
1H NMR (270 MHz, DMSO-d6): d = 2.12 (s, 3H, –NMe)
2.55 (t, 2H, –NHCH2), 2.60 (t, 2H, –NHCH2), 3.15 (s, 2H,
CH2), 7.58, 7.67 (two dd, 2H, H-6, H-7), 7.76 (br s, 1H,
NH, D2O– exchangeable), 7.94 (s, 1H, H-3), 8.57 (s, 1H,
H-4), 10.03 (br s, 1H, COOH) ppm; MS (70 eV):
m/z = 351 (M? ?18, 5), 333 (M?, 1) 280 (2), 237 (4),
223 (3), 181 (5), 141 (3), 113 (100), 70 (38).
Pharmacology
Swiss mice weighing 20–30 g were purchased from the
animal house of the National Research Centre. The animals
were housed in standard metal cages in an air conditioned
room at 22 3 °C, 55 5% humidity, and provided with
standard laboratory diet and water ad libitum. Experiments
were performed between 0900 and 1500 hours. A group of
six mice was used for each experiment. All experimental
procedures were conducted in accordance with the guide
for care and use of laboratory animals and in accordance
with the Local Animal Care and Use Committee. Distilled
water was used as a vehicle for all tested compound and
5% sodium bicarbonate for indomethacin.
5-(2-Morpholinoacetamido)benzo[b]thiophene-2-
carboxylic acid (7, C15H16N2O4S)
ꢀ
Yield 90%; M.p.: 178–180 °C; IR (KBr): m = 3,272
(COOH), 3,082 (NH), 1,691 (C=O), 1,610(C=O) cm-1
;
1H NMR (270 MHz, DMSO-d6): d = 2.51 (t, 2H,
–NHCH2), 3.21 (s, 2H, CH2), 3.65 (t, 2H, –OCH2), 7.66,
7.81 (two dd, 2H, H-6, H-7), 7.78 (br s, 1H, NH, D2O
– exchangeable), 7.97 (s, 1H, H-3), 8.56 (s, 1H, H-4), 10.04
(br s, 1H, COOH) ppm; MS (70 eV): m/z = 338 (M? ?18,
5), 320 (M?, 1) 294 (3), 252 (3), 223 (2), 181 (4), 149 (3),
100 (100), 70 (4).
Anti-inflammatory activity
Anti-inflammatory activity in acute model was carried out
according to Winter et al. [19] and Obkowicz et al. [20].
Mice were divided into 15 groups each of six. They
received saline orally as control, tested compounds (50 mg/
kg) and indomethacin (25 mg/kg) orally, according to Rani
et al. [21], after induction of oedema by subplantar injec-
tion of 50 mm3 1% carrageenan (Sigma, USA) in saline
into the pad of right paw. The difference in hind footpad
thickness was measured before and 1, 2, 3, and 4 h after
carrageenan injection. The oedema was expressed as per-
centage of change from the control group (pre-drug)
values. The doses of the tested compounds and of indo-
methacin were based on the rate dose converted to that of
mice according to Paget et al. [22] and Souza et al. [23].
In the anti-inflammatory study, the percentage of
oedema inhibition was calculated from the mean effect in
the control and treated animals according to the equation:
5-(2-(2-Phenylhydrazinyl)acetamido)benzo[b]thiophene-2-
carboxylic acid (8, C17H15N3O3S)
ꢀ
Yield 88%; M.p.: 260 °C; IR (KBr): m = 3,341 (COOH),
3,234, 3,198, 3,123 (3NH), 1,696 (C=O), 1,643 (C=O)
1
cm-1; H NMR (270 MHz, DMSO-d6): d = 3.86 (s, 2H,
–NHCH2) 4.35 (br s, 1H, NH), 7.12–7.23 (m, 5H, Ph), 7.39
(br s, H, NH), 7.63, 7.80 (two dd, 2H, H-6, H-7), 7.93
(s, 1H, H-3), 8.55 (s, 1H, H-4), 10.32 (br s, NH), 10.45
(br s, 1H, COOH) ppm; MS (70 eV): m/z = 341 (M?, 6),
322 (6), 314 (9), 286 (39), 221 (11), 181 (100), 154 (23),
105 (6), 77 (42).
5-(2-(1H-Benzothiazol-2-ylamino)acetamido)benzo[b]thio-
phene-2-carboxylic acid (9, C18H13N3O3S2)
ꢀ
Yield 84%; M.p.: [300 °C; IR (KBr): m = 3,264 (COOH),
1
3,231, 3,194 (2NH), 1,694 (C=O), 1,633 (C=O) cm-1; H
123