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Download fileSterol 14α-Demethylase Structure-Based Design of VNI ((R)‑N‑(1-(2,4-Dichlorophenyl)-2-(1H‑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
journal contribution
posted on 12.06.2018, 00:00 by 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. LepeshevaBecause
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.
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Keywords
antifungal drugsfumigatus CYP 51structure-based designAspergillus fumigatusTarget Fungal InfectionsCYP 51sterol 14α- demethylaseantifungal drug scaffoldimidazol -1-ylBiological Evaluationfungi-oriented VNI derivativescures Chagas diseaseCrystallographic Analysisnovel antifungal drug candidatesSterol 14α- Demethylase Structure-Based Designtreatment efficiencyimmunocompromised patientsCYP 51s