Design, synthesis, and pharmacological evaluation of novel oxadiazole and oxadiazoline analogs as anti-inflammatory agents

Figures & data

Figure 1.  Indomethacin: structural features.

Scheme 1.  Synthesis of oxadiazole and oxadiazoline analogs. Reagents and conditions: (a) ClCH₂COOC₂H₅, K₂CO₃, acetone, reflux for 12 h; (b) NH₂NH₂, ethanol, reflux for 8 h; (c) aldehydes, ethanol, reflux for 6 h; (d) Br, CH₃COONa, CH₃COOH, 2 h stirring; (e) (CH₃CO)₂O, reflux for 1 h.

Figure 2.  Structure of compounds 1–10.

Figure 3.  Structure of compounds 11–20.

Table 1.  Anti-inflammatory activity^a of the synthesized oxadiazoles and oxadiazolines (100 mg/kg p.o.) using carrageenan-induced rat paw edema method and cotton pellet-induced granuloma method.

Compound	Carrageenan-induced rat paw edema method		Cotton pellet-induced granuloma method
	Mean increase in paw volume^b ± SEM (mL)	% Protection	Weight of moist cotton pellet^c ± SEM (mg)	% Inhibition	Weight of dry cotton pellet^d ± SEM (mg)	% Inhibition
1	0.22 ± 0.007**	62.71	144.69 ± 0.60**	29.88	25.39 ± 0.74**	46.46
2	0.25 ± 0.008**	57.62	157.76 ± 0.61**	23.55	26.61 ± 0.43**	43.89
3	0.31 ± 0.003**	47.45	157.81 ± 0.57**	23.52	25.46 ± 0.53**	46.32
4	0.38 ± 0.002*	35.59	—	—	31.81 ± 0.14**	32.93
5	020 ± 0.008**	66.10	139.69 ± 0.79**	32.30	23.39 ± 0.24**	50.68
6	0.34 ± 0.003**	42.37	160.80 ± 0.17**	22.07	36.47 ± 0.26*	23.18
7	0.43 ± 0.007*	27.11	175.79 ± 0.70*	14.81	37.57 ± 0.59*	20.78
8	0.43 ± 0.005*	27.11	167.00 ± 0.69*	19.07	35.39 ± 0.36*	25.38
9	0.33 ± 0.003**	44.06	170.79 ± 0.18*	17.23	—	—
10	0.29 ± 0.008**	50.84	170.65 ± 0.64*	17.30	26.44 ± 0.28**	44.25
11	0.29 ± 0.008**	50.84	170.65 ± 0.64*	17.30	26.44 ± 0.28**	44.25
12	0.38 ± 0.001*	35.59	172.47 ± 0.71*	16.42	31.35 ± 0.53**	33.90
13	0.26 ± 0.006**	55.93	172.41 ± 0.63*	16.45	35.17 ± 0.50*	25.84
14	0.43 ± 0.005*	27.11	—	—	—	—
15	0.26 ± 0.01**	55.93	151.82 ± 0.48*	26.42	25.00 ± 0.58**	47.29
16	0.33 ± 0.007**	44.06	158.31 ± 0.45*	23.28	28.15 ± 0.45**	40.64
17	0.47 ± 0.003*	20.33	182.14 ± 0.62*	11.73	—	—
18	0.44 ± 0.008*	25.42	170.47 ± 0.61*	17.39	—	—
19	0.34 ± 0.003**	42.37	160.80 ± 0.17**	22.07	—	—
20	0.31 ± 0.003**	47.45	155.58 ± 0.21**	24.60	27.66 ± 0.07**	41.68
Indomethancin	0.11 ± 0.004***	81.35	102.38 ± 0.46***	50.38	21.72 ± 0.30***	54.20
Control	0.59 ± 0.003	—	208.11 ± 0.46	—	46.34 ± 0.32	—

^aSignificance level considered with respect to control as follows: *p < 0.05, **p < 0.01, and ***p < 0.0001.

^bThe mean increase in paw volume in rats treated with indomethacin (10 mg/kg) observed in this experiment was 0.11 ± 0.004 mL with percentage protection of 81.35 (p < 0.0001).

^cThe mean increase in the weight of moist cotton pellets in rats treated with indomethacin (10 mg/kg) observed in this experiment was 102.38 ± 0.46 mg with percentage protection of 50.38 (p < 0.0001).

^dThe mean increase in the weight of dry cotton pellets in rats treated with indomethacin (10 mg/kg) observed in this experiment was 21.72 ± 0.30 mg with percentage protection of 54.20 (p < 0.0001).

Table 2.  Ulcerogenicity index of the synthesized oxadiazole and oxadiazoline analogs (20 mg/kg i.p.).

Compound	Ulcer index^a
1	0.83 ± 1.65*
2	0.72 ± 1.82*
3	0.68 ± 1.71*
4	0.61 ± 1.58*
5	0.81 ± 1.72*
6	0.79 ± 1.56*
7	0.75 ± 1.62*
8	0.73 ± 1.83*
9	0.70 ± 1.92*
10	0.69 ± 1.77*
11	0.72 ± 1.52*
12	0.78 ± 1.74*
13	0.65 ± 1.61*
14	0.57 ± 1.47*
15	0.85 ± 1.89*
16	0.83 ± 1.44*
17	0.79 ± 1.68*
18	0.74 ± 1.43*
19	0.80 ± 1.35*
20	0.63 ± 1.58*
Aspirin	1.86 ± 0.64**
Control	0.17 ± 0.63

^aSignificance level considered with respect to control as follows: *p < 0.05 and **p < 0.01.