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

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dc.authoridTaşkor Önel, Gülce/0000-0002-9375-2329
dc.authoridSARI, SUAT/0000-0002-8248-4218
dc.authoridOzturk, Naile/0000-0002-7617-8433
dc.authoridKarakurt, Arzu/0000-0003-2209-0871
dc.authoridEssiz, Sebnem/0000-0002-5476-4722
dc.authoridSARI, SUAT/0000-0002-8248-4218
dc.authorwosidTaşkor Önel, Gülce/T-6942-2017
dc.authorwosidSARI, SUAT/A-5249-2017
dc.authorwosidOzturk, Naile/F-3650-2017
dc.authorwosidKarakurt, Arzu/ABH-9340-2020
dc.authorwosidEssiz, Sebnem/JVZ-2123-2024
dc.authorwosidSARI, SUAT/JCD-8070-2023
dc.contributor.authorSari, Suat
dc.contributor.authorKart, Didem
dc.contributor.authorOzturk, Naile
dc.contributor.authorKaynak, F. Betul
dc.contributor.authorGencel, Melis
dc.contributor.authorTaskor, Gulce
dc.contributor.authorKarakurt, Arzu
dc.date.accessioned2024-08-04T20:46:01Z
dc.date.available2024-08-04T20:46:01Z
dc.date.issued2019
dc.departmentİnönü Üniversitesien_US
dc.description.abstractSystemic 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.en_US
dc.description.sponsorshipScientific and Technological Research Council of Turkey (TUBITAK) [1155387]; Hacettepe University Scientific Research Projects Coordination Unit [014 D09 301 001-703, TPT-2015-6794, TPT-2018-16666]en_US
dc.description.sponsorshipThis study was funded by grants from The Scientific and Technological Research Council of Turkey (11)BITAK) (1155387) and Hacettepe University Scientific Research Projects Coordination Unit (014 D09 301 001-703, TPT-2015-6794, TPT-2018-16666).en_US
dc.identifier.doi10.1016/j.ejmech.2019.06.083
dc.identifier.endpage648en_US
dc.identifier.issn0223-5234
dc.identifier.issn1768-3254
dc.identifier.pmid31279296en_US
dc.identifier.scopus2-s2.0-85068213658en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage634en_US
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2019.06.083
dc.identifier.urihttps://hdl.handle.net/11616/98850
dc.identifier.volume179en_US
dc.identifier.wosWOS:000486133100046en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherElsevier France-Editions Scientifiques Medicales Elsevieren_US
dc.relation.ispartofEuropean Journal of Medicinal Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectConsensus scoringen_US
dc.subjectAzolesen_US
dc.subjectCandida albicansen_US
dc.subjectBiofilmen_US
dc.subjectCytotoxicityen_US
dc.subjectMolecular dockingen_US
dc.subjectMolecular dynamics simulationsen_US
dc.titleDiscovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screeningen_US
dc.typeArticleen_US

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