Synthesis, Characterization, and Biological Evaluation of Novel Benzimidazole Derivatives as Potent Antifungal Agents.
Keywords:
Benzimidazole, Antifungal, Antimicrobial, Antioxidant, Molecular docking, CYP51, Lanosterol 14α-Demethylase, ADME, Drug-likeness, Structure-activity relationship.Abstract
The present study describes the design, synthesis, and biological evaluation of ten novel 1-acylbenzimidazole derivatives (T1–T10) bearing a 4-((3-hydroxyphenyl) amino)phenyl methanone scaffold with structurally diverse substituents at the 2-position of the benzimidazole ring, developed as potential antifungal, antimicrobial and antioxidant agents. Prior to synthesis, all designed compounds were screened through in silico drug-likeness assessment, ADME prediction, toxicity profiling, and molecular docking against Lanosterol 14α-Demethylase (CYP51, PDB ID: 5FSA), a validated antifungal target involved in fungal ergosterol biosynthesis. All derivatives satisfied Lipinski's Rule of Five with only a single violation, demonstrated favorable pharmacokinetic profiles, and returned inactive predictions across all toxicity endpoints, contrasting favorably with the hepatotoxic liability flagged for the reference drug posaconazole. Molecular docking revealed that compound T3 exhibited the highest binding affinity with a docking score of −7.90 kcal/mol, involving hydrogen bonding, halogen bonding, electrostatic, and hydrophobic interactions with key active site residues. All ten compounds were synthesized via a two-step route using Na₃AlF₆-catalyzed condensation followed by N-acylation, and characterized by FTIR, ¹H NMR, and mass spectrometry. Biological evaluation demonstrated that T3 surpassed ciprofloxacin against Staphylococcus aureus and exceeded posaconazole against Candida albicans at 100 μg/mL, while T4 exhibited the strongest antioxidant activity in both DPPH and ABTS assays. These findings establish T3 as a promising lead compound warranting further pharmacological development..
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