Design, Synthesis, And Biological Evaluation of 1-H Indazole Derivatives As Novel Target (CYP51) Antifungal Inhibitors

Abstract

The rise in drug-resistant fungal infections has intensified the need for novel antifungal agents, particularly those targeting cytochrome P450 51 (CYP51) a key enzyme in ergosterol biosynthesis. This study explores the design, synthesis, and biological evaluation of 1H-indazole derivatives as potential CYP51 inhibitors. Structure-based virtual screening identified seventeen indazole-based candidates, which were further assessed for pharmacokinetic properties including absorption, distribution, metabolism, excretion, and toxicity (ADMET) using computational approaches. Two lead compounds, 1aa and 2aa were synthesized and evaluated for their antifungal activity against Rhizopus oryzae. Among them, compound 1aa exhibited superior antifungal efficacy with a minimum inhibitory concentration (MIC) of 128 µg/mL, while 2aa displayed an MIC of 256 µg/mL. In vitro assays confirmed that 1aa effectively inhibited ergosterol biosynthesis correlating with its strong binding affinity to the heme group of CYP51, as demonstrated by molecular docking and molecular dynamics simulations. These findings highlight 1aa as a promising lead compound for further optimization offering a potential strategy to combat antifungal resistance in clinical settings.