article · Synthetic Communications
Candida infections are becoming harder to treat due to growing resistance, creating a demand for new treatments targeting proven fungal enzymes. A series of hybrid molecules combining benzimidazole and retrochalcone scaffolds was designed and synthesised to inhibit lanosterol 14α-demethylase (CYP51). In laboratory tests using microdilution assays against Candida species, several derivatives demonstrated significant, strain-dependent antifungal activity compared to the conventional drug ketoconazole. Specific compounds, designated 4c and 4h, showed up to a 71-fold improvement in potency against Candida glabrata, whereas compound 4e demonstrated strong activity against Candida albicans. Other derivatives, namely 4g and 4i, exhibited balanced effects across multiple strains. Computational docking indicated that this enhanced activity results from stronger hydrogen bonding, hydrophobic contacts, aromatic stacking, and interactions with the enzyme heme cofactor.
Rising antimicrobial resistance among Candida fungal species threatens healthcare outcomes and limits existing treatment options. Developing new chemical scaffolds that target validated fungal enzymes like CYP51 is essential to counter resistant strains. These hybrid molecules provide alternative structural templates that outperform standard drugs like ketoconazole in laboratory assays, offering valuable insights for future drug design against fungal infections.
These compounds are early-stage drug candidates relevant to pharmaceutical companies and biotechnology firms developing novel antifungal therapeutics. The findings are based entirely on computational docking and in vitro microdilution assays, placing the technology at an early discovery stage. Significant further evaluation, including selectivity assays, pharmacokinetic profiling, and in vivo animal testing, is required before these scaffolds could advance toward preclinical development.
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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.
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DOI: 10.1080/00397911.2026.2725883
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