Design, synthesis and biological evaluation of novel substituted benzoylguanidine derivatives as potent Na+/H+ exchanger inhibitors

A novel series of substituted benzoylguanidine derivatives were designed and synthesized as potent NHE1 inhibitors. Most compounds can significantly inhibit NHE1-mediated platelet swelling in a concentration-dependent manner, among which compound 5f (IC50 = 3.60 nM) and 5l (IC50 = 4.48 nM) are 18 and 14 times respectively more potent than cariporide (IC50 = 65.0 nM). Furthermore, when tested in vivo and in vitro, compound 5f showed superior cardioprotective effects against SD rat myocardial ischemic-reperfusion injury over cariporide, representing a promising lead compound for further exploration.

Graphical abstractA novel series of substituted benzoylguanidine derivatives were designed and synthesized as potent NHE1 inhibitors and cardioprotective agents. Among these compounds, 5f was found to be the most potent NHE1 inhibitor, with a IC50 of 3.60 nM, being 18 times more potent than cariporide. Compound 5f showed superior cardioprotective efficacy in vivo and in vitro.Figure optionsDownload full-size imageDownload as PowerPoint slide