Design, synthesis, and evaluation of anti-inflammatory, analgesic, ulcerogenicity, and nitric oxide releasing studies of novel indomethacin analogs as non-ulcerogenic derivatives

Figures & data

Figure 1.  Pharmacophore.

Scheme 1.  Synthesis route for designed NCEs, 7a–7f.

Table 1.  Results for anti-inflammatory activity of synthesized compounds against carrageenan induced rat paw edema model in rats.

Compound/dose (mg/kg, p.o.)	Change in paw volume (mL) after drug treatment (± SEM)			Anti-inflammatory activity (% inhibition)
	1 h	2 h	3 h	1 h	2 h	3 h
Control	1.18 ± 0.08142	1.052 ± 0.08958	0.988 ± 0.0836	—	—	—
Indomethacin (10)	0.798 ± 0.0315	0.428 ± 0.699	0.276 ± 0.0422	32.38**	59.32**	72.93**
5 (8.20)	0.8511 ± 0.0621	0.7370 ± 0.0902	0.6725 ± 0.0901	27.87**	29.94**	31.93**
6c (11.96)	0.7223 ± 0.042	0.6300 ± 0.031	0.5742 ± 0.071	38.78*	40.11**	41.88**
7a (14.39)	0.936 ± 0.026	0.6 ± 0.02145	0.442 ± 0.0453	20.388*	42.97**	55.27**
7b (14.84)	0.856 ± 0.5075	0.506 ± 0.0463	0.372 ± 0.0307	20.68**	48.09**	62.35**
7c (14.84)	0.806 ± 0.0477	0.442 ± 0.0453	0.29 ± 0.0283	31.7**	57.98**	70.65**
7d (15.65)	0.926 ± 0.0668	0.61 ± 0.0620	0.454 ± 0.0633	21.53*	42.02**	50.41**
7e (15.65)	0.936 ± 0.026	0.634 ± 0.0479	0.444 ± 0.0646	20.68*	39.74**	47.37**
7f (16.07)	0.972 ± 0.08218	0.622 ± 0.0650	0.472 ± 0.06507	17.63	40.88**	46.36**

Note. Data analyzed by one way ANOVA followed by Dunnett’s t test (n = 6), *p < 0.05, **p < 0.01 significantly different from control.

Table 2.  Results for analgesic activity of synthesized compounds against acetic acid induced writhing test in mice.

Compound	Dose (mg/kg, p.o.)	No. of writhes in 5–15 min after treatment (mean ± SE)	% Inhibition
Control	Acetic acid (1%, v/v)	42.4 ± 2.421	—
Indomethacin	10	12.6 ± 1.72**	70.29
5	8.20	30.4 ± 4.363*	28.30
6c	11.96	29.2 ± 3.776*	31.13
7a	14.39	28.2 ± 4.363*	33.5
7b	14.84	21 ± 2.915**	50.48
7c	14.84	13.4 ± 2.337**	68.4
7d	15.65	28.6 ± 4.308*	32.55
7e	15.65	28.2 ± 4.576*	33.5
7f	16.07	28.6 ± 3.776*	32.55

Note. Data analyzed by one way ANOVA followed by Dunnett’s t test (n = 6), *p < 0.05, **p < 0.01 significantly different from control.

Table 3.  Ulcerogenic effects of synthesized compounds in comparison with diclofenac sodium.

Compound	Dose (mg/kg, p.o.)	Ratio of ulcerated animals	Ulcer index (mean ± SE)
Diclofenac	10	4/6	1.7 ± 0.2
	30	6/6	2.3 ± 0.3
	50	Not tested	—
7a	10	—	—
	30	—	—
	50	—	—
7b	10	—	—
	30	—	—
	50	—	—
7c	10	—	—
	20	—	—
	50	—	—

Note. —, no effect.

Figure 2.  Hematoxylin and eosin immunohistochemical staining of gastric ulcers after ulcer induction in rats. (a) Intact mucous membrane in control treated rat showing granular tissues composed of macrophages, fibroblasts, and endothelial cells forming microvessels. (b) Congestion of mucosal blood vessels observed in diclofenac treated group. (c–e) No damage to mucosa of rats treated with test compounds 7a, 7b, and 7c, respectively. These specimens were identical to that of the control (a). Original magnification ×200.

Table 4.  Nitric oxide releasing property of compounds 7a–7f.

Compound	NO release^a
7a	0.35%
7b	0.42%
7c	0.39%
7d	0.48%
7e	0.57%
7f	0.32%

^aPercentage of NO released (n = 2) relative to theoretical maximum release of 1 mol NO/mol test compound; determined by Griess reagent in presence of 5 mM l-cysteine, at pH 7.4.