Design and synthesis of 1,3-diarylurea derivatives as selective cyclooxygenase (COX-2) inhibitors

A group of 1,3-diarylurea derivatives, possessing a methylsulfonyl pharmacophore at the para-position of the N-1 phenyl ring, in conjunction with a N-3 substituted-phenyl ring (4-F, 4-Cl, 4-Me, 4-OMe), were designed and synthesized for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1/COX-2 isozyme inhibition structure–activity studies identified 1-(4-methylsulfonylphenyl)-3-(4-methoxyphenyl) urea (4e) as a potent COX-2 inhibitor (IC50 = 0.11 μM) with a high COX-2 selectivity index (SI = 203.6) comparable to the reference drug celecoxib (COX-2 IC50 = 0.06 μM; COX-2 SI = 405). The structure–activity data acquired indicate that the urea moiety constitutes a suitable scaffold to design new acyclic 1,3-diarylurea derivatives with selective COX-2 inhibitory activity.

Graphical abstractThe design, synthesis, and evaluation of a series of 1,3-diarylurea, possessing a methylsulfonyl pharmacophore, as potent and selective COX-2 inhibitors, are described.Figure optionsDownload full-size imageDownload as PowerPoint slide