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    Antifungal screening and in silico mechanistic studies of an in-house azole library
    (Wiley, 2019) Sari, Suat; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, Zeynep; Bozbey, Irem; Gencel, Melis
    Systemic Candida infections pose a serious public health problem with high morbidity and mortality. C. albicans is the major pathogen identified in candidiasis; however, non-albicans Candida spp. with antifungal resistance are now more prevalent. Azoles are first-choice antifungal drugs for candidiasis; however, they are ineffective for certain infections caused by the resistant strains. Azoles block ergosterol synthesis by inhibiting fungal CYP51, which leads to disruption of fungal membrane permeability. In this study, we screened for antifungal activity of an in-house azole library of 65 compounds to identify hit matter followed by a molecular modeling study for their CYP51 inhibition mechanism. Antifungal susceptibility tests against standard Candida spp. including C. albicans revealed derivatives 12 and 13 as highly active. Furthermore, they showed potent antibiofilm activity as well as neglectable cytotoxicity in a mouse fibroblast assay. According to molecular docking studies, 12 and 13 have the necessary binding characteristics for effective inhibition of CYP51. Finally, molecular dynamics simulations of the C. albicans CYP51 (CACYP51) homology model's catalytic site complexed with 13 were stable demonstrating excellent binding.
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    Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2019) Sari, Suat; Kart, Didem; Ozturk, Naile; Kaynak, F. Betul; Gencel, Melis; Taskor, Gulce; Karakurt, Arzu
    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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    Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening (vol 179, pg 634, 2019)
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2020) Sari, Suat; Kart, Didem; Ozturk, Naile; Kaynak, F. Betul; Gencel, Melis; Taskor, Gulce; Karakurt, Arzu
    [Abstract Not Available]
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    Synthesis, biological evaluation and molecular docking studies of bis-chalcone derivatives as xanthine oxidase inhibitors and anticancer agents
    (Academic Press Inc Elsevier Science, 2019) Burmaoglu, Serdar; Ozcan, Seyda; Balcioglu, Sevgi; Gencel, Melis; Noma, Samir Abbas Ali; Essiz, Sebnem; Ates, Burhan
    In this study, a series of B-ring fluoro substituted bis-chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and evaluated for their ability to inhibit xanthine oxidase (XO) and growth inhibitory activity against MCF-7 and Caco-2 human cancer cell lines, in vitro. According to the results obtained, the bis-chalcone with fluoro group at the 2 (4b) or 2,5-position (4g) of B-ring were found to be potent inhibitors of the enzyme with IC50 values in the low micromolar range. The effects of these compounds were about 7 fold higher than allopurinol. The binding modes of the bis-chalcone derivatives in the active site of xanthine oxidase were explained using molecular docking calculations. Also, compound 4g and 4h showed in vitro growth inhibitory activity against a panel of two human cancer cell lines 1.9 and 6.8 mu M of IC50 values, respectively.