Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening

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Date

2019

Authors

Sari, Suat
Kart, Didem
Ozturk, Naile
Kaynak, F. Betul
Gencel, Melis
Taskor, Gulce
Karakurt, Arzu

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Elsevier France-Editions Scientifiques Medicales Elsevier

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Abstract

Systemic candidiasis is a rampant bloodstream infection of Candida spp. and C. albicans is the major pathogen isolated from infected humans. Azoles, the most common class of antifungals which suffer from increasing resistance, and especially intrinsically resistant non-albicans Candida (NAC) species, act by inhibiting fungal lanosterol 14 alpha-demethylase (CYP51). In this study we identified a number of azole compounds in 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol/ethanone oxime ester structure through virtual screening using consensus scoring approach, synthesized and tested them for their antifungal properties. We reached several hits with potent activity against azole-susceptible and azoleresistant Candida spp. as well as biofilms of C albicans. 5i's minimum inhibitor concentration (MIC) was 0.125 mu g/ml against C. albicans, 0.5 mu g/ml against C. krusei and 1 mu g/ml against azole-resistant C. tropicalis isolate. Considering the MIC values of fluconazole against these fungi (0.5, 32 and 512 mu g/ml, respectively), 5i emerged as a highly potent derivative. The minimum biofilm inhibitor concentration (MBIC) of 5c, 5j, and 5p were 0.5 mu g/ml (and 5i was 2 mu g/ml) against C. albicans biofilms, lower than that of amphotericin B (4 mu g/ml), a first-line antifungal with antibiofilm activity. In addition, the active compounds showed neglectable toxicity to human monocytic cell line. We further analyzed the docking poses of the active compounds in C. albicans CYP51 (CACYP51) homology model catalytic site and identified molecular interactions in agreement with those of known azoles with fungal CYP51s and mutagenesis studies of CACYP51. We observed the stability of CACYP51 in complex with 5i in molecular dynamics simulations. (C) 2019 Elsevier Masson SAS. All rights reserved.

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Keywords

General Force-Field, Antifungal Activity, Molecular-Dynamics, Accurate Docking, Derivatives, Protein, Design, Glide, Cyp51, Constraints, General Force-Field, Antifungal Activity, Molecular-Dynamics, Accurate Docking, Consensus scoring, Derivatives, Azoles, Protein, Candida albicans, Design, Biofilm, Glide, Cytotoxicity, Cyp51, Molecular docking, Constraints, Molecular dynamics simulations

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Citation

17

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Q1

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Q1

Source

European Journal of Medicinal Chemistry

Volume

179

Issue

Start Page

634

End Page

648