Syntheses and evaluation of anti-inflammatory, analgesic and ulcerogenic activities of 1,3,4-oxadiazole and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives

Figures & data

Figure 1.  Chemical structures of some halogenated anti-inflammatory and analgesic agents.

Scheme 1.  Reagents and conditions: Synthetic route to target compounds 4a–f and 7a–f. (i) KBrO₃, 80°C; (ii) H₂SO₄ add over a period of 3 h; (iii) heat, 90°C−100°C, 2 h; (iv) CH₃OH, H₂SO₄, reflux for 4 h; (v) NH₂NH₂.H₂O, absolute C₂H₅OH, reflux for 6 h; (vi) POCl₃, Ar-COOH, reflux for 8–12 h; (vii) KOH, CS₂, absolute C₂H₅OH, reflux for 14 h, (viii) NH₂NH₂.H₂O, reflux for 2 h; (ix) POCl₃, Ar-COOH, reflux for 3–5 h. Where a, Ar= C₆H₅; b, Ar= 4-Cl-C₆H₄; c, Ar= 4-F-C₆H₄; d, Ar= 4-CH₃-C₆H₄; e, Ar= 4-OCH₃-C₆H₄; f, Ar= C₁₁H₉;

Table 1.  Anti-inflammatory activity of the synthesized compounds after oral administration (20 mg/kg).

Compound	Paw volume. ±SD				% inhibition ±SD			Potency
	0 h (Basal)	After 1 h	After 3 h	After 4 h	After 1 h	After 3 h	After 4 h
4a	0.84 ± 0.07	1.24 ± 0.07	1.74 ± 0.10	1.84 ± 0.10	12.91 ± 7.30	21.94 ± 6.36	23.75 ± 5.68^a	0.40
4b	0.82 ± 0.06	1.16 ± 0.07	1.54 ± 0.08	1.61 ± 0.09	18.65 ± 7.86	31.18 ± 4.55	33.03 ± 4.38^a	0.55
4c	0.84 ± 0.05	1.11 ± 0.09	1.55 ± 0.11	1.58 ± 0.11	22.44 ± 2.92	30.81 ± 4.32	34.66 ± 3.74^a	0.58
4d	0.81 ± 0.07	1.21 ± 0.09	1.73 ± 0.10	1.76 ± 0.09	14.92 ± 8.90	22.73 ± 3.58	26.97 ± 3.01^a	0.45
4e	0.83 ± 0.03	1.21 ± 0.06	1.69 ± 0.07	1.73 ± 0.08	15.28 ± 7.85	24.28 ± 5.65	28.19 ± 5.47^a	0.47
4f	0.84 ± 0.07	1.16 ± 0.07	1.53 ± 0.05	1.56 ± 0.06	18.54 ± 6.41	31.56 ± 1.81	35.36 ± 2.06^a	0.59
7a	0.81 ± 0.07	1.22 ± 0.07	1.63 ± 0.11	1.69 ± 0.11	14.12 ± 7.41	27.09 ± 6.36	29.95 ± 6.21^a	0.50
7b	0.81 ± 0.06	1.13 ± 0.06	1.25 ± 0.05	1.29 ± 0.05	20.72 ± 7.54	43.94 ± 3.47	46.61 ± 3.29^a	0.78
7c	0.81 ± 0.04	1.06 ± 0.04	1.12 ± 0.08	1.16 ± 0.10	25.49 ± 1.89	49.93 ± 3.35	51.86 ± 4.10	0.86
7d	0.83 ± 0.07	1.19 ± 0.05	1.60 ± 0.05	1.63 ± 0.04	16.11 ± 8.14	28.34 ± 4.47	32.17 ± 3.95^a	0.54
7e	0.82 ± 0.05	1.18 ± 0.05	1.55 ± 0.06	1.58 ± 0.05	17.44 ± 1.77	30.46 ± 5.03	34.25 ± 3.84^a	0.57
7f	0.84 ± 0.07	1.19 ± 0.05	1.44 ± 0.07	1.48 ± 0.08	16.22 ± 6.78	35.42 ± 4.45	38.42 ± 4.09^a	0.60
Ibuprofen	0.82 ± 0.06	0.89 ± 0.04	0.94 ± 0.04	0.96 ± 0.04	37.62 ± 0.90	57.78 ± 1.42	60.06 ± 1.66	1.00
Control	0.84 ± 0.08	1.43 ± 0.09	2.23 ± 0.07	2.41 ± 0.08	–	–	–	–

Data were given in mean ± SD and analyzed by ANOVA followed by Dunnett’s multiple comparison test, (n = 6)

^ap < 0.01 compared to the standard drug (ibuprofen).

Table 2.  Analgesic, ulcerogenic and lipid peroxidation activities of the synthesized compounds.

Compound	Analgesic activity ± SD			Ulcerogenic activity	Lipid peroxidation
	No. of writhes in 15 min ± SD	% inhibition	Potency
4a	59.25 ± 7.81	17.41 ± 4.19^b	0.29	–	–
4b	55.50 ± 7.94	22.77 ± 3.36^b	0.38	0.763 ± 0.19^a	5.103 ± 0.41^a
4c	53.75 ± 10.84	25.74 ± 4.33^b	0.43	0.850 ± 0.40^b	5.200 ± 0.51^a
4d	60.50 ± 7.55	15.65 ± 3.46^b	0.26	–	–
4e	53.25 ± 5.91	24.84 ± 13.12^b	0.41	–	–
4f	51.50 ± 5.26	27.71 ± 8.17^b	0.46	0.900 ± 0.48^b	5.615 ± 0.83^b
7a	53.25 ± 8.18	25.61 ± 9.43^b	0.42	–	–
7b	39.75 ± 5.56	44.48 ± 5.73^a	0.73	0.788 ± 0.17^a	5.008 ± 0.45
7c	36.75 ± 4.65	48.18 ± 9.11	0.80	0.763 ± 0.37^a	5.108 ± 0.58^a
7d	50.00 ± 6.22	29.75 ± 9.96^b	0.49	0.750 ± 0.39^a	5.095 ± 0.46^a
7e	45.00 ± 6.48	36.95 ± 8.71^b	0.61	0.875 ± 0.42^b	5.248 ± 0.65^a
7f	45.50 ± 6.60	35.83 ± 9.37^b	0.59	0.925 ± 0.41^b	5.358 ± 0.48^b
Ibuprofen	28.50 ± 5.20	60.48 ± 3.12	1.00	1.738 ± 0.13^b	7.375 ± 0.48^b
Control	72.00 ± 11.17	–	–	0.000 ± 0.00	3.978 ± 0.15

^bp < 0.01; ^ap < 0.05; compared to the standard drug (ibuprofen) for analgesic; compared to the control for ulcerogenic and lipid peroxidation studies.