Design and synthesis of novel benzoheterocyclic derivatives as human acrosin inhibitors by scaffold hopping

Human acrosin is an attracting target for the development of novel male contraceptives. Scaffold hopping was used to optimize the isoxazolecarbaldehyde human acrosin inhibitors and extend their structure–activity relationships. Four kinds of scaffolds, namely benzimidazole, benzothiazole, 3H-indazole, and 5-phenyl-1H-pyrazole, were designed and synthesized. Most of the synthesized compounds showed potent human acrosin inhibitory activity and their binding modes were investigated by molecular docking. The scaffold of the compounds was found to be important for the inhibitory activity. Several compounds were more active than the positive control TLCK, suggesting that they can serve as good starting points for the discovery of novel male contraceptive agents.

Graphical abstractScaffold hopping was used to optimize the isoxazolecarbaldehyde human acrosin inhibitors. A series of benzoimidazole, benzothiazole, pyrazole, and indazole derivatives were rationally designed and synthesized.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Scaffold hopping was used to design novel human acrosin inhibitors. ► The benzoimidazole derivative 5a showed good human acrosin inhibitory activity. ► The inhibitors formed hydrogen bonding and hydrophobic interactions with acrosin.