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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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    New (arylalkyl)azole derivatives showing anticonvulsant effects could have VGSC and/or GABAAR affinity according to molecular modeling studies
    (Elsevier France-Editions Scientifiques Medicales Elsevier, 2016) Sari, Suat; Karakurt, Arzu; Uslu, Harun; Kaynak, F. Betul; Calis, Unsal; Dalkara, Sevim
    (Arylalkyl)azoles (AAAs) emerged as a novel class of antiepileptic agents with the invention of nafimidone and denzimol. Several AAA derivatives with potent anticonvulsant activities have been reported so far, however neurotoxicity was usually an issue. We prepared a set of ester derivatives of 1-(2-naphthyl)2-(1H-1,2,4-triazol-1-yeethanone oxime and evaluated their anticonvulsant and neurotoxic effects in mice. Most of our compounds were protective against maximal electroshock (MES)- and/or subcutaneous metrazol (s.c. MET)-induced seizures whereas none of them showed neurotoxicity. Nafimidone and denzimol have an activity profile similar to that of phenytoin or carbamazepine, both of which are known to inhibit voltage-gated sodium channels (VGSCs) as well as to enhance gamma-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and A type GABA receptors (GABA(A)Rs) we performed docking studies using homology model of Na+ channel inner pore and GABA(A)R as docking scaffolds. We found that our compounds bind VGSCs in similar ways as phenytoin, carbamazepine, and lamotrigine. They showed strong affinity to benzodiazepine (BZD) binding site and their binding interactions were mainly complied with the experimental data and the reported BZD binding model. (C) 2016 Elsevier Masson SAS. All rights reserved.