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dc.contributor.authorKarakurt, Arzu
dc.contributor.authorKart, Didem
dc.contributor.authorÖztürk, Naile
dc.contributor.authorKaynak, F. Betül
dc.contributor.authorGencel, Melis
dc.contributor.authorTaşkor, Gülce
dc.contributor.authorKarakurt, Arzu
dc.contributor.authorSaraç, Selma
dc.contributor.authorEşsiz, Şebnem
dc.contributor.authorDalkara, Sevim
dc.date.accessioned2020-04-22T13:35:50Z
dc.date.available2020-04-22T13:35:50Z
dc.date.issued2020
dc.identifier.issn0223-5234
dc.identifier.urihttps://hdl.handle.net/20.500.12469/2829
dc.identifier.urihttps://doi.org/10.1016/j.ejmech.2020.112130
dc.description.abstractSystemic candidiasis is a rampant bloodstream infection ofCandidaspp. andC. albicansis the majorpathogen isolated from infected humans. Azoles, the most common class of antifungals which sufferfrom increasing resistance, and especially intrinsically resistant non-albicans Candida(NAC) species, actby inhibiting fungal lanosterol 14a-demethylase (CYP51). In this study we identified a number of azolecompounds in 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol/ethanone oxime ester structurethrough virtual screening using consensus scoring approach, synthesized and tested them for theirantifungal properties. We reached several hits with potent activity against azole-susceptible and azole-resistantCandidaspp. as well as biofilms ofC. albicans.5i's minimum inhibitor concentration (MIC) was0.125mg/ml againstC. albicans, 0.5mg/ml againstC. kruseiand 1mg/ml against azole-resistantC. tropicalisisolate. Considering the MIC values offluconazole against these fungi (0.5, 32 and 512mg/ml, respec-tively),5iemerged as a highly potent derivative. The minimum biofilm inhibitor concentration (MBIC) of5c,5j, and5pwere 0.5mg/ml (and5iwas 2mg/ml) againstC. albicansbiofilms, lower than that ofamphotericin B (4mg/ml), afirst-line antifungal with antibiofilm activity. In addition, the active com-pounds showed neglectable toxicity to human monocytic cell line. We further analyzed the dockingposes of the active compounds inC. albicansCYP51 (CACYP51) homology model catalytic site andidentified molecular interactions in agreement with those of known azoles with fungal CYP51s andmutagenesis studies of CACYP51. We observed the stability of CACYP51 in complex with5iin moleculardynamics simulations.©2019 Elsevier Masson SAS. All rights reserved.1. IntroductionSystemic candidiasis is a major public health issue, especiallywith immune-suppressed cases reaching high mortality rates. Themembers of the genusCandidaare the most frequently recoveredfrom human fungal infection andCandida albicans, so far, is theleading pathogen identified in nosocomial candidiasis [1]. Inaddition to increasing drug-resistant strains ofC. albicans, emer-gence of non-albicans Candidaspp. (NAC) complicate the treatmentof mycoses [2].C. tropicalisis among the NACs that show reducedsusceptibility tofirst-line antifungals reportedly leading to break-through fungemia among high-risk patients [3,4]. Also,C. kruseiisknown to be intrinsically resistant to a number of azoles includingfluconazole [5]. One of the several mechanisms of therapy-resistance is formation of biofilms, which are complex microor-ganism colonies enclosed in an exopolysaccharide matrix on bioticand non-biotic surfaces. Persistent biofilms make fungi much lesssusceptible to antifungal drugs compared to their planktonic formsfor a number of reasons [6e8]. Therefore it is essential to design*Corresponding author. Hacettepe University Faculty of Pharmacy, Departmentof Pharmaceutical Chemistry, 06100, Sihhiye, Ankara, Turkey.E-mail addresses:suat.sari@hacettepe.edu.tr,suat1039@gmail.com(S. Sari).Contents lists available atScienceDirectEuropean Journal of Medicinal Chemistryjournal homepage:http://www.elsevier.com/locate/ejmechhttps://doi.org/10.1016/j.ejmech.2019.06.0830223-5234/©2019 Elsevier Masson SAS. All rights reserved.European Journal of Medicinal Chemistry 179 (2019) 634e648en_US
dc.language.isoEnglishen_US
dc.publisherElsevieren_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.titleDiscovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screeningen_US
dc.typeCorrectionen_US
dc.identifier.startpage634-648en_US
dc.relation.journalEuropean Journal of Medicinal Chemistryen_US
dc.identifier.issueen_US
dc.identifier.wosWOS:000518870100029en_US
dc.identifier.doi10.1016/j.ejmech.2020.112130en_US
dc.contributor.khasauthorEşsiz, Şebnemen_US


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