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Öğe Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies(Wiley, 2020) Sari, Suat; Avci, Ahmet; Kocak, Ebru; Kart, Didem; Sabuncuoglu, Suna; Dogan, Inci Selin; Ozdemir, ZeynepAzole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria,Enterococcus faecalisandStaphylococcus aureus.Compound73's minimum inhibitory concentration (MIC) value less than 1 mu g/ml againstS. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistantS. aureus(MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.Öğe 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, MelisSystemic 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.Öğe Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms ofCandidaspp.: an in vitro and in silico study(Springer, 2021) Sari, Suat; Kocak, Ebru; Kart, Didem; Ozdemir, Zeynep; Acar, M. Fahir; Sayoglu, Burcu; Karakurt, ArzuCandidainfections pose a serious public health threat due to increasing drug resistance. Azoles are first-line antifungal drugs for fungal infections. In this study, we tested an in-house azole collection incorporating naphthalene ring to find hits against planktonic and biofilm forms of resistantCandidaspp. In the collection, potent derivatives were identified against the susceptible strains ofCandidawith minimum inhibitory concentration (MIC) values lower than those of the reference drug, fluconazole. MIC values of 0.125 mu g/ml againstC. albicans, 0.0625 mu g/ml againstC. parapsilosis, and 2 mu g/ml againstC. krusei, an intrinsically azole-resistant non-albicans Candida, were obtained. Some of the derivatives were highly active against fluconazole-resistant clinical isolate ofC. tropicalis. Inhibition ofC. albicansbiofilms was also observed at 4 mu g/ml similar as amphotericin B, the reference drug known for its antibiofilm activity. Through molecular docking studies, affinities and key interactions of the compounds with fungal lanosterol 14 alpha-demethylase (CYP51), the target enzyme of azoles, were predicted. The interactions of imidazole with heme cofactor and of the naphthalene with Tyr118 were highlighted in line with the literature data. As a result, this study proves the importance of naphthalene for the antifungal activity of azoles againstCandidaspp. in both planktonic and biofilm forms.Öğe Azoles containing naphthalene with activity against Gram-positive bacteria: in vitro studies and in silico predictions for flavohemoglobin inhibition(Taylor & Francis Inc, 2022) Sari, Suat; Sabuncuoglu, Suna; Aslan, Ebru Kocak; Avci, Ahmet; Kart, Didem; Ozdemir, Zeynep; Acar, M. FahirAzoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 mg/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 mg/ml, respectively). Six more were active against S. aureus with MIC <= 4 mg/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials.Öğe Conventional and Microwave Assisted Synthesis of New Triazole Derivatives and Evaluation of Their Antimicrobial Activities(2019) Özdemir, Zeynep; Alagöz, Mehmet; Doğan, İnci Selin; Sellitepe, Hasan Erdinç; Kart, DidemAbstract: In this study, four new oxime ether derivatives were synthesized and their antimicrobial activities were evaluated. At the same time, a comparison of the efficiency of the conventional method of synthesis with the microwave method was inves-tigated. The structures of synthesized compounds were confirmed by their IR, 1H-NMR, and HRMS spectra. Antimicrobial activity of the compounds was tested against two Gr (+) bacteria (S. aureus, E. faecalis), two Gr (-) bacteria (P. aeruginosa, E. coli), and three yeast-like fungi (C. albicans, C. krusei, C. parapsilosis) by modified agar dilution method.Öğe 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, ArzuSystemic 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.Öğe 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]Öğe İmidazol Halkası Taşıyan Yeni Oksim Eter Bileşiklerinin Sentez, Biyolojik Aktivite Ve Moleküler Modelleme Çalışmaları(2019) Dalkara, Sevim; Tarhan, Selma Saraç; Özdemir, Zeynep; Kart, Didem; Karakurt, ArzuEnfeksiyon hastalıkları, dünya genelinde ciddi bir sağlık sorunudur ve insan morbiditesi ve mortalitesinin ana nedenlerinden biridir. Mevcut ilaçların dar aktivite spektrumu, toksisitesi, zayıf farmakokinetik özellikleri ve ilaçlara karşı direnç gelişmesinden dolayı etkili antifungal ve antibakteriyel bileşikler geliştirmek için yoğun çalışmalar yapılmaktadır. Bu çalışmada azol grubu antifungal ilaçların yapısı esas alınarak tasarlanan bir seri yeni bileşik, 1-(4- triflorometilfenil)-2-(1H-imidazol-1-il)etanon oksim esterlerin antifungal ve antibakteriyel etkilerinin incelenmesi amaçlanmıştır. Bu çalışmada 15 yeni bileşiğin sentezi yapılmış ve bileşiklerin yapıları spektral analiz verileriyle aydınlatılmıştır. Sentezlenen bileşiklerin antifungal aktiviteleri üç Candida türüne karşı incelenmiştir. Yapılan çalışmalar sonucunda bileşikler Candida türlerine karşı etkili bulunmuştur. 15 yeni bileşiğin sentezi yapılıp, antifungal etkileri incelenmiştir. Elde edilen sonuçlara göre antifungal aktivitesi daha yüksek bileşikler tasarlanacaktır.Öğe p-Trifluoroacetophenone Oxime Ester Derivatives: Synthesis, Antimicrobial and Cytotoxic Evaluation and Molecular Modeling Studies(Bentham Science Publ Ltd, 2020) Bozbey, Irem; Sari, Suat; Salva, Emine; Kart, Didem; Karakurt, ArzuBackground: Azole antifungals are among the first-line drugs clinically used for the treatment of systemic candidiasis, a deadly type of fungal infection that threatens mostly immune-compromised and hospitalized patients. Some azole derivatives were also reported to have antiproliferative effects on cancer cells. Objective: In this study, 1-(4-trifluoromethylphenyl)-2-(1H-imidazol-1-yl)ethanone (3), its oxime (4), and a series of its novel oxime ester derivatives (5a-v) were synthesized and tested for their in vitro antimicrobial activities against certain ATCC standard strains of Candida sp. fungi and bacteria. The compounds were also tested for their cytotoxic effects against mouse fibroblast and human neuroblastoma cell lines. Molecular modeling studies were performed to provide insights into their possible mechanisms for antifungal and antibacterial actions. Methods: The compounds were synthesized by the reaction of various oximes with acyl chlorides. Antimicrobial activity of the compounds was determined according to the broth microdilution method. For the determination of cytotoxic effect, we used MTS assay. Molecular docking and QM/MM studies were performed to predict the binding mechanisms of the active compounds in the catalytic site of C. albicans CYP51 (CACYP51) and S. aureus flavohemoglobin (SAFH), the latter of which was created via homology modeling. Results: 5d, 5l, and 5t showed moderate antifungal activity against C. albicans, while 3, 5c, and 5r showed significant antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Most of the compounds showed approximately 40-50% inhibition against the human neuroblastoma cells at 100 mu M. In this line, 3 was the most potent with an IC50 value of 82.18 mu M followed by 5a, 5o, and 5t. 3 and 5a were highly selective to the neuroblastoma cells. Molecular modelling results supported the hypothesis that our compounds were inhibitors of CAYP51 and SAFH. Conclusion: This study supports that oxime ester derivatives may be used for the development of new antimicrobial and cytotoxic agents.
