Design, synthesis and evaluation of benzotriazole derivatives as novel antifungal agents

• Published in: Bioorganic & medicinal chemistry letters 2015-09, Vol.25 (17), p.3730-3737
• Main Authors: Shah, Jay J., Khedkar, Vijay, Coutinho, Evans C., Mohanraj, Krishnapriya
• Format: Article
• Language: English
• Subjects: 14-alpha Demethylase Inhibitors - chemistry; 14-alpha Demethylase Inhibitors - pharmacology; Antifungal; Antifungal Agents - chemical synthesis; Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Benzotriazole derivatives; Candida albicans - drug effects; Chemistry Techniques, Synthetic; Docking; Drug Design; Drug Evaluation, Preclinical - methods; Ergosterol - analysis; Ergosterol quantification; Fungal Proteins - antagonists & inhibitors; Fungal Proteins - metabolism; Microbial Sensitivity Tests; Molecular Docking Simulation; Spectrophotometry, Ultraviolet; Sterol 14-Demethylase - chemistry; Sterol 14-Demethylase - metabolism; Structure-Activity Relationship; Tandem Mass Spectrometry; Triazoles - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.06.025

[Display omitted] Considering the need for discovery of new antifungal drugs with greater potency and broader spectrum of activity, a new series of 5-substituted benzotriazole derivatives were designed, through structure based design, as inhibitors of fungal cytochrome P450 lanosterol 14-α demethylase. These were further optimized by a combination of iterative medicinal chemistry principles and molecular docking. Based on the best docking scores, some benzotriazole derivatives were synthesized and characterized by IR, 1H NMR and MS/MS. The molecules were evaluated for their antifungal action against Candida albicans by cup plate method and ergosterol quantification method by UV spectroscopy. Reasonably good correlation between docking scores and antifungal activity were observed. The computational predictions were in consensus with the experimental results.