2-Amino-2,3-dihydro-1H-2λ5-[1,3,2]diazaphospholo[4,5-b]pyridin-2-one-based urea and thiourea derivatives: synthesis, molecular docking study and evaluation of anti-inflammatory and antimicrobial activities

Abstract

A series of new class of P-heterocycle encompassing urea and thiourea derivatives, N-(substitutedphenyl)-N′-(2-oxo-2,3-dihydro-1H-2λ5-[1,3,2]diazaphospholo[4,5-b]pyridin-2-yl)ureas 11a–e/thioureas 11f–k, was accomplished from the precursor intermediate, 2-amino-2,3-dihydro-1H-2λ5-[1,3,2]diazaphospholo[4,5-b]pyridin-2-one, 9. The compound 9 was obtained by cyclization of pyridine-2,3-diamine, 6 with POCl3 followed by amidation with NaNH2. The products were tested for their in vitro and in vivo anti-inflammatory activity, and in vitro antimicrobial activity including minimum inhibitory concentration. Compounds 11a, 11d and 11j exhibited comparable anti-inflammatory activity to the standard drug, diclofenac, both in in vitro and in vivo assays, which might be due to the presence of lipophilic functional groups, F, NO2 and CF3. The compounds 11c and 11j exhibited potential growth of inhibition against selected bacterial and fungal strains at lower minimum inhibitory concentrations, while most of the thiourea-linked analogues exhibited good antimicrobial activity. A molecular modelling study was performed on cyclooxygenase isoenzyme (COX-2) to investigate the hypothetical binding mode of the most active anti-inflammatory agents, and binding conformers were proposed.