A new series of co-drugs was designed based on hybridising the dihydropteroate synthase (DHPS) inhibitor sulphonamide scaffold with the COX-2 inhibitor salicylamide pharmacophore through biodegradable linkage to achieve compounds with synergistic dual inhibition of COX-2/PGE2 axis and DHPS enzyme to enhance antibacterial activity for treatment of septicaemia. Compounds 5 b, 5j, 5n and 5o demonstrated potent in vitro COX-2 inhibitory activity comparable to celecoxib. 5j and 5o exhibited ED 50 lower than celecoxib in carrageenan-induced paw edoema test with % PGE2 inhibition higher than celecoxib. Furthermore, 5 b , 5j and 5n showed gastric safety profile like celecoxib. Moreover, in vivo antibacterial screening revealed that, 5j showed activity against S.aureus and E.coli higher than sulfasalazine. While, 5o revealed activity against E.coli higher than sulfasalazine and against S.aureus comparable to sulfasalazine. Compound 5j achieved the target goal as potent inhibitor of COX-2/PGE2 axis and in vivo broad-spectrum antibacterial activity against induced septicaemia in mice.

New selective COX-2 inhibitors were designed and synthesized by tethering 1,2,3-triazole and benzenesulfonamide pharmacophores to some NSAIDs. Compounds 6b and 6j showed higher in vitro COX-2 selectivity and inhibitory activity (IC50 = 0.04 µM and S.I. = 329 and 312, respectively) than celecoxib (IC50 = 0.05 µM and S.I. = 294). Compound 6e revealed equipotent in vitro COX-2 inhibitory activity to celecoxib. Furthermore, 6b and 6j expressed more potent relief of carrageenan-induced paw edema thickness in mice than celecoxib, with ED50 values of 11.74 µmol/kg and 13.38 µmol/kg vs. 16.24 µmol/kg, respectively. Compounds 6b and 6j inhibited the production of PGE2 with a % inhibition of PGE2 production of 90.70% and 86.34%, respectively, exceeding celecoxib’s percentage (78.62%). Moreover, 6b and 6j demonstrated a gastric safety profile comparable to celecoxib. In conclusion, compounds 6b and 6j better achieved the target goal as more potent and selective COX-2 inhibitors than celecoxib in vitro and in vivo.