New pyridazine derivatives as selective COX-2 inhibitors and potential anti-inflammatory agents; design, synthesis and biological evaluation

New pyridazinone and pyridazinthione derivatives were designed, synthesized and identified through performing H-1 NMR, C-13 NMR, IR and MS spectroscopic techniques. All the newly synthesized derivatives were evaluated for cyclooxygenase inhibitory activity and COX-2 selectivity using celecoxib and indomethacin, as reference drugs. All compounds showed highly potent COX-2 inhibitory activity with IC50 values in nano-molar range. Moreover, they demonstrated higher selectivity towards COX-2 inhibition compared to indomethacin. Compounds 3d, 3g and 6a exhibited significantly increased potency towards COX-2 enzyme compared to celecoxib with IC50 values of 67.23, 43.84 and 53.01 nM, respectively. They were 1.1-1.7 folds more potent than celecoxib (IC50 = 73.53 nM) and extremely much more potent than indomethacin (IC50 = 739.2 nM). Of particular interest, Compound 3g showed SI of 11.51 which was as high as that of celecoxib (SI 11.78). This compound was further challenged by in vivo anti-inflammatory activity assay and gastric ulcerogenic effect. It showed comparable anti-inflammatory activity to indomethacin as positive control. Moreover, the anti-inflammatory activity of compound 3g was found to be equipotent to celecoxib. Furthermore, the selective COX-2 inhibitor 3g exhibited a superior gastrointestinal safety profile compared to the reference drugs celecoxib and indomethacin with less number of ulcers and milder ulcer score. The molecular docking study of this compound with COX-2 protein revealed more favorable binding mode compared to celecoxib, explaining its remarkable COX-2 inhibitory potency.