Molecular hybridization strategy for the design of benzimidazolyl-retrochalcone derivatives as antifungal agents: Synthesis, characterization, and CYP51-based computational evaluation

Abstract

Abstract The growing resistance of Candida species highlights the need for antifungal agents targeting validated fungal enzymes. In this study, a series of benzimidazole-based retrochalcone derivatives was designed, and evaluated as potential inhibitors of lanosterol 14α-demethylase (CYP51). The design strategy combined benzimidazole with a retrochalcone scaffold to improve the predicted binding within the CYP51 active site. The compounds were tested in vitro against Candida species using a microdilution assay. Several derivatives showed significant, strain-dependent activity compared to ketoconazole. Compounds 4c, 4h exhibited outstanding potency against C. glabrata (up to 71-fold improvement), while compound 4e showed remarkable activity against C. albicans. Compounds 4g and 4i displayed balanced activity across multiple strains. Molecular docking provided a computational rationale for the observed antifungal activity. Enhanced activity was linked to improved hydrogen bonding, hydrophobic interactions, aromatic stacking, and, in some cases, interactions with heme cofactor. Overall, these results identify benzimidazole–retrochalcone hybrids as promising antifungal scaffolds. Graphical AbstractDiagram of benzimidazole-retrochalcone hybrid design showcasing antifungal activity and structural highlights.This multi-panel diagram details the design and antifungal activity of benzimidazole-retrochalcone hybrids. It starts with a 'HYBRID DESIGN' panel illustrating the molecular combination aimed at inhibiting CYP51. The central section lists potent compounds (4c, 4h, 4e) with minimum inhibitory concentrations (MICs) against C. albicans, C. glabrata, and C. tropicalis. The 'PROPOSED MECHANISM' shows interactions with lanosterol 14a-demethylase. Key findings emphasize hybridization benefits, potency comparisons to ketoconazole, and crucial structural insights like electron-withdrawing groups enhancing effectiveness.