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

7 Citations (Scopus)

Abstract

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
Volume61
Issue number13
DOIs
StatePublished - Jul 12 2018

Fingerprint

Sterol 14-Demethylase
Mycoses
Aspergillus fumigatus
14-alpha Demethylase Inhibitors
Pharmaceutical Preparations
Azoles
Ketoconazole
Chagas Disease
Fluconazole
Immunocompromised Host
Candida albicans
Fungi
Pharmacokinetics
Incidence
Enzymes
benzamide

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Friggeri, Laura ; Hargrove, Tatiana Y. ; Wawrzak, Zdzislaw ; Blobaum, Anna L. ; Rachakonda, Girish ; Lindsley, Craig W. ; Villalta, Fernando ; Nes, W. David ; Botta, Maurizio ; Guengerich, F. Peter ; Lepesheva, Galina I. / 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. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 13. pp. 5679-5691.
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abstract = "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.",
author = "Laura Friggeri and Hargrove, {Tatiana Y.} and Zdzislaw Wawrzak and Blobaum, {Anna L.} and Girish Rachakonda and Lindsley, {Craig W.} and Fernando Villalta and Nes, {W. David} and Maurizio Botta and Guengerich, {F. Peter} and Lepesheva, {Galina I.}",
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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. / Friggeri, Laura; Hargrove, Tatiana Y.; Wawrzak, Zdzislaw; Blobaum, Anna L.; Rachakonda, Girish; Lindsley, Craig W.; Villalta, Fernando; Nes, W. David; Botta, Maurizio; Guengerich, F. Peter; Lepesheva, Galina I.

In: Journal of Medicinal Chemistry, Vol. 61, No. 13, 12.07.2018, p. 5679-5691.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

T2 - Synthesis, Biological Evaluation, and Crystallographic Analysis

AU - Friggeri, Laura

AU - Hargrove, Tatiana Y.

AU - Wawrzak, Zdzislaw

AU - Blobaum, Anna L.

AU - Rachakonda, Girish

AU - Lindsley, Craig W.

AU - Villalta, Fernando

AU - Nes, W. David

AU - Botta, Maurizio

AU - Guengerich, F. Peter

AU - Lepesheva, Galina I.

PY - 2018/7/12

Y1 - 2018/7/12

N2 - 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.

AB - 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.

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