Sterol 14α-Demethylase Structure-Based Design of VNI ((R)- N-(1-(2,4-Dichlorophenyl)-2-(1 H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)) Derivatives to Target Fungal Infections: Synthesis, Biological Evaluation, and Crystallographic Analysis

Laura Friggeri, Tatiana Y. Hargrove, Zdzislaw Wawrzak, Anna L. Blobaum, Girish Rachakonda, Craig W. Lindsley, Fernando Villalta, W. David Nes, Maurizio Botta, F. Peter Guengerich, Galina I. Lepesheva*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Scopus citations


Because of the increase in the number of immunocompromised patients, the incidence of invasive fungal infections is growing, but the treatment efficiency remains unacceptably low. The most potent clinical systemic antifungals (azoles) are the derivatives of two scaffolds: ketoconazole and fluconazole. Being the safest antifungal drugs, they still have shortcomings, mainly because of pharmacokinetics and resistance. Here, we report the successful use of the target fungal enzyme, sterol 14α-demethylase (CYP51), for structure-based design of novel antifungal drug candidates by minor modifications of VNI [(R)-N-(1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide)], an inhibitor of protozoan CYP51 that cures Chagas disease. The synthesis of fungi-oriented VNI derivatives, analysis of their potencies to inhibit CYP51s from two major fungal pathogens (Aspergillus fumigatus and Candida albicans), microsomal stability, effects in fungal cells, and structural characterization of A. fumigatus CYP51 in complexes with the most potent compound are described, offering a new antifungal drug scaffold and outlining directions for its further optimization.

Original languageEnglish (US)
Pages (from-to)5679-5691
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number13
StatePublished - Jul 12 2018


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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