Development of safe and antioxidant COX-2 inhibitors; Synthesis, molecular docking analysis and biological evaluation of novel pyrrolizine 5-carboxamides

[Display omitted] •A series of new pyrrolizine-5-carboxamide derivatives were developed as antioxidant COX-2 Inhibitors.•Compounds 9a, 9b, 9d, and 11b have higher COX-2 selectivity than celecoxib.•Compounds 9a and 11a showed good in vivo anti-inflammatory activity with a safety profile towards gastric mucosa.•Nitric oxide test revealed that compounds 10c,d & 12a,b can be used as nitric oxide donors to overcome cardiovascular side effect.•Pyrrolizine-5-carboxamide (9a) demonstrated high antioxidant and anti-inflammatory activity with lower ulcerogenicity. In the current study, a series of new pyrrolizine-5-carboxamide derivatives (5–8, 9a-d, 10a-d, 11a,b and 12a,b) were developed, synthesized and evaluated in terms of in vitro COX-2 enzyme inhibition. The in vivo anti-inflammatory evaluation was conducted on the most selective compounds (9a,b,d, 10b,c and 11a,b). For the most active five compounds (9a, 10b,c and 11a,b), ulcerogenic liability, histopathological examinations, physicochemical properties study and antioxidant activity were investigated. Also, nitric oxide donor activity was evaluated for compounds (6, 7, 10a-d and 12a,b), while, compounds (10c,d and 12a,b) showed a high significant result relative to the normal control. According to the findings of this study, 2,3-dihydro-1H-pyrrolizine-5-carboxamide (9a) demonstrated high antioxidant (highest beta-carotene concentration (10.825 µg/ml)) and anti-inflammatory activity (EIP = 63.6 %) with lower ulcerogenicity (ulcer index 13.67), presenting it as a promising candidate for treating inflammatory diseases which are complicated by oxidative tissue damage. Furthermore, MOE software tools docking software was used to carry out the in silico studies. Docking study for the most active compounds showed that all compounds made three to four H-bond interactions in COX-2 active site adopting excellent docking scores.