Design and synthesis of antifungal benzoheterocyclic derivatives by scaffold hopping

The incidence of invasive fungal infections and associated mortality is increasing dramatically. Although azoles are first-line antifungal agents, cross-resistance and hepatic toxicity are their two major limitations. The discovery of novel non-azole lead compounds will be helpful to overcome these problems. On the basis of our previously reported benzopyran non-azole CYP51 inhibitor, scaffold hopping was used to design structurally diverse new compounds and expand the structure–activity relationships of the lead structure. Five kinds of scaffolds, namely benzimidazole, benzoxazole, benzothiazole, quinazolin-4-one and carboline, were chosen for synthesis. In vitro antifungal activity data and results from molecular docking revealed that the scaffold was important for the antifungal activity. Several compounds showed potent activity against both standard and clinically resistant fungal pathogens, suggesting that they can serve as a good starting point for the discovery of novel antifungal agents.

Scaffold hopping was used to design structurally diverse benzoheterocyclic antifungal derivatives. Several compounds showed potent activity against both standard and clinically resistant fungal pathogens. Figure optionsDownload as PowerPoint slideHighlights
► Staring from our previously designed non-azole lead structure, scaffold hopping was used to design structurally diverse antifungal benzoheterocyclic derivatives.
► The synthesized non-azole antifungal compounds bound with CYP51 through non-bond interactions without coordination to the iron atom, which is helpful to reduce the toxicity of azoles.
► Several compounds were active against fluconazole-resistant clinical isolates, which affords an opportunity to overcome the emerging severe resistance of azoles.
► As compared with the lead structure, several compounds showed improved antifungal activity, which can serve as a good starting point for further optimization.