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Öğe Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies(Wiley-V C H Verlag Gmbh, 2022) Sari, Suat; Akkaya, Didem; Zengin, Merve; Sabuncuoglu, Suna; Ozdemir, Zeynep; Alagoz, M. Abdullah; Karakurt, ArzuCholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.Öğe Azole derivatives inhibit wildtype butyrylcholinesterase and its common mutants(Wiley, 2023) Sari, Suat; Onder, Seda; Akkaya, Didem; Sabuncuoglu, Suna; Zengin, Merve; Barut, Burak; Karakurt, ArzuAzoles, which have been used for antifungal chemotherapy for decades, have recently been of interest for their efficacy against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). There is little known about the potential of azoles against BChE, however there is none regarding their inhibitory effects against mutants of BChE. In the current study, an azole library of 1-aryl-2-(1H-imidazol-1-yl)ethanol/ethanone oxime esters were tested against AChE and BChE, which yielded derivates more potent than the positive control, galantamine, against both isoforms. Kinetic analyses were performed for wildtype and mutant (A328F and A328Y) inhibition for the two most potent BChE inhibitors, pivalic and 3-bezoylpropanoic acid esters of 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanol, which were found to have great affinity to the wildtype and mutant BChE types with K-i values as low as 0.173 +/- 0.012 mu M. The compounds were identified to show linear competitive or mixed type inhibition. Molecular modeling confirmed these kinetic data and provided further insights regarding molecular basis of BChE inhibition by the active derivatives. Thus, current study suggests new azole derivatives with promising cholinesterase inhibitory effects and reveals the first set of information to promote our understanding for the inhibitory behavior of this class against the mutant BChE forms.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 CARDIOPROTECTIVE AND ANTIOXI DAN ACTIVITY OF BLUEBERRY ANTHOCYANINE AND POLYPHENOLS IN RATS(Elsevier Science Bv, 2009) Karakurt, Cemsit; Gursoy, Sule; Alagoz, Mehmet Abdullah; Karakurt, Arzu; Aktays, Goknur; Kocak, Gulendam[Abstract Not Available]Öğe Comparison of stereochemical structures of cholesterol from different sources by HPLC(Marmara Univ, Fac Pharmacy, 2012) Satilmis, Basri; Guldur, Tayfun; Karakurt, Arzu; Buyuktuncel, Ebru; Ertan, MevlutIt is known that only one stereoisomeric form, nat-cholesterol, naturally occurs. Nat-cholesterol and its enantiomer, ent-cholesterol, sometimes show enantiospecific interactions with biological molecules. If cholesterol is naturally found only one form, then the question of why does cholesterol show an enantiomeric selectivity? arises. For this purpose, stereoisomer analysis of cholesterol obtained from porcine liver and wool wax were carried out with three different high performance liquid chromatography (HPLC) systems including reversed-phase, reversed-phase with different cyclodextrins as a mobile phase modifier, and chiral. Results from HPLC analysis of both cholesterol samples by permethylated gamma-cyclodextrin and amylose tris-(3,5-dimethylphenylcarbamate) chiral columns showed that there was no stereoisomer of cholesterol present. However reversed-phase HPLC analysis of cholesterol samples from porcine liver carried out with various cyclodextrins as mobile phase modifiers presented a peak which was not observed in the analysis of cholesterol samples from wool wax. On the other hand, different storage conditions of cholesterol samples and addition of cyclodextrins as mobile phase modifiers produced almost identical alterations in chromatograms of fresh samples by reversed-phase HPLC. This could be attributed to catalytic properties of cyclodextrins. Cyclodextrins may not be suitable as a mobile phase modifier in the stereoisomer analysis of cholesterol with high performance liquid chromatography.Öğe Conventional and microwave prompted synthesis of aryl(alkyl)azole oximes, 1H-NMR spectroscopic determination of E/Z isomer ratio and HOMO-LUMO analysis(Elsevier, 2022) Bozbey, Irem; Uslu, Harun; Turkmenoglu, Burcin; Ozdemir, Zeynep; Karakurt, Arzu; Levent, SerkanIn this study, 12 oxime derivatives were synthesized by using with conventional method and microwave irradiation method. It was aimed to compare the effectiveness of the conventional method and microwave method. Their yields were determined for both methods, and the yields increased when the microwave method was used. The compounds which have oxime show geometric isomerism because they have carbon-nitrogen double bonds. Therefore, we have also aimed to evaluate their E/Z isomer ratios in this study. While the synthesized pyrazole derivative compounds were mostly obtained in Z isomer in both synthesis methods, it was observed that some of the title compounds were almost completely obtained as E isomers when the conventional synthesis method was used in the synthesized imidazole derivative compounds. The structures of synthesized compounds were confirmed by IR, H-1-NMR, C-13-NMR and HRMS spectra. Additionally, in this study, the HOMO-LUMO energies and thermodynamic properties of the E/Z isomers of 12 oxime derivatives were performed using the 6-31 * G basis set and the Density Functional Theory (DFT) calculation using the B3LYP method three different environments (water, ethanol, vacuum). In addition, geometric parameters such as chemical hardness (eta), chemical potential (mu), electrophilicity index (omega), chemical softness (sigma) were calculated depending on the calculated HOMO-LUMO energies. (C) 2021 Elsevier B.V. All rights reserved.Öğe Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors synthesis molecular docking and anticonvulsant studies(Journal of Enzyme Inhibition and Medicinal Chemistry, 2016) Karataş, Mert Olgun; Uslu, Harun; Sarı, Suat; Alagöz, Mehmet Abdullah; Karakurt, Arzu; Alıcı, Bülent; Bilen, Çiğdem; Yavuz, Emre; Gençer, Nahit; Arslan, OktayAmong many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have antiseizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.Öğe Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies(Taylor & Francis Ltd, 2016) Karatas, Mert Olgun; Uslu, Harun; Sari, Suat; Alagoz, Mehmet Abdullah; Karakurt, Arzu; Alici, Bulent; Bilen, CigdemAmong many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.Öğe Cytotoxic effect of azole compounds bearing trifluorophenyl ring on MCF-7, MDA-MB-231, and HCT-116 cancer cell line(2022) Alagöz, Mehmet; Özdemir, Zeynep; Hepokur, Ceylan; Karakurt, ArzuCancer, a disease defined by rapid proliferation of cells, still remains one of the most feared diseases of the modern world. Many structurally different anti-carcinogenic drugs are used in several tumor types such as bladder, colon, ovary, breast, head and neck, testis, lung and prostate cancer. In this study, cytotoxic effects of the compounds with different linkers (ketone, oxime, alcohol, chlorine) between pyrazole and trifluoromethyl on MCF-7 (human breast adenocarcinoma), MDA-MB-231 (human breast adenocarcinoma), and HCT-116 (human colon cancer) cell lines were investigated. Compound a1 was observed to be the most potent compound with IC50 values of 5.84±0.76, 5.01±0.32, 5.57±0.02 µg.ml-1 against these cell lines, respectively. It was found that all compounds were very effective against all the tested cancer cell lines.Öğe Design, synthesis, and molecular modeling of new 3(2H)-pyridazinone derivatives as acetylcholinesterase/butyrylcholinesterase inhibitors(Springer Birkhauser, 2017) Ozdemir, Zeynep; Yilmaz, Hayriye; Sari, Suat; Karakurt, Arzu; Senol, Fatma Sezer; Uysal, MehtapInhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted benzalhidrazone) derivatives were designed, synthesized, and their inhibitory effects on acetylcholinesterase and butyrylcholinesterase were evaluated in pursuit of potent dual inhibitors. We obtained our compounds by the reaction of various substituted/nonsubstituted benzaldehydes with 6-[4-(3,4-dichlorophenyl)piperazine-1-yl]-3(2H)-pyridazinone-2-yl acetohydrazide and determined their anticholinesterase activities according to the Ellman's method. 5f and 5i showed 75.52 and 71.72% acetylcholinesterase inhibition at 100 A mu g/ml, respectively. 5h and 5f, on the other hand, were the best butyrylcholinesterase inhibitors with 67.16 and 62.03% inhibition at the same concentration, respectively. 5f emerged as a potent dual cholinesterase inhibitor. Through molecular docking studies we predicted the inhibition mechanism of 5f for both enzymes in comparison with our previous derivatives, which differ in inhibition potency, and tried to get insights into the factors that affect receptor affinity in molecular level.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 Evaluation of the effects of novel nafimidone derivatives on thermal hypoalgesia in mice with diabetic neuropathy(Balkan Medical Journal, 2013) Kamışlı, Suat; Karakurt, Arzu; Uyumlu, Ayşe B.; Satılmış, Basri; Alagöz, Abdullah; Genç, Metin F.; Batcıoğlu, KadirÖz (İngilizce): Objective: Diabetic neuropathy (DN) is a common complication in Diabetes Mellitus. The streptozotocin-induced diabetic rodent is the most commonly used animal model of diabetes and increased sodium channel expression and activity were revealed in this model. At this study, we evaluated the effect of three different nafimidone derivatives which have possible anticonvulsant activity on disorders of thermal pain sensation in diabetic mice. Study Design: Randomized animal experiment. Material and Methods: Mice were divided randomly into five groups (5 mice per group): Control, Diabetes, Dibetes+C1, Diabetes+C2, Diabetes+C3. We used hot and cold plate, and tail-immersion tests for assessment of thermal nociceptive responses. Results: Compared with the control group, the hot-plate response time and the number of paw liftings on cold plate as important indicators of loss of sensation increased, but no significant difference (p>0.05) was found in tail-immersion response time test in diabetes group. C3 compound moved it back to control group levels in the all of three tests. C1 and C2 compounds were effective only in cold-plate test. Conclusion: Nafimidone derivatives may be effective in the cases where epilepsy and diabetes occur together since it has shown efficacy against loss of sensation which evolves in diabetic neuropathy over time as well as its antiepileptic effect.Öğe Histological assessment of liver and stomach damage caused by pyridazinone derivative antidepressant agents(Taylor & Francis Ltd, 2022) Ozdemir, Zeynep; Karakurt, Arzu; Taslidere, Elif; Vardi, Nigar; Alagoz, Mehmet Abdullah; Parlakpinar, Hakan; Uslu, HarunDepression is a serious psychological disorder that affects a significant population. We investigated the antidepressant activities of four pyridazinone derivatives that contain the hydrazide moiety using the forced swimming test (FST). The compounds tested exhibited good antidepressant activity compared to duloxetine. The most promising compound was compound 2, which reduced the duration of immobility during FST. The toxic effects of the four compounds on the histomorphology of the liver and stomach tissue also was evaluated.Öğe İlaç metabolizması ve farmasötik kimyada önemi(İnönü Üniversitesi Sağlık Bilimleri Dergisi, 2016) Özdemir, Zeynep; Karakurt, Arzuİlaçların, organizmadaki enzimlerin etkisiyle kimyasal değişikliğe uğrayarak genellikle daha polar yeni bileşiklere dönüşmesine biyotransformasyon ya da metabolizma denir. Metabolizma sonucu, vücuda alınan ilaç ve diğer yabancı maddeler daha az toksik bir şekle dönüştürülür ve polar hale getirilerek en kısa sürede vücuttan atılır. Ayrıca bazı ilaçların etkileri, metabolizma sonucu oluşan metabolitlerinin farmakolojik etkileri nedeniyle görülmektedir. Bir ilacın piyasaya girebilmesi için metabolitlerinin izole edilmesi ve toksik olup olmadıklarının mutlaka araştırılması gerekmektedir. İlaç tasarımında, daha etkin, toksisitesi azaltılmış, daha güvenli bileşiklere veya dağılım, absorbsiyon sorunları düzeltilmiş ilaçlara ulaşmak için önemli ipuçları sağlaması ilaç metabolizması çalışmalarını güncel kılmaktadır. Bu derleme ile metabolizma kavramına değinilmiş, metabolizmanın önemi vurgulanmış ve ilaç metabolizması çalışmalarından örnekler verilmiştir. Anahtar Kelimeler: İlaç Metabolizması, Biyotransformasyon, Metabolit, Ön İlaç, CYP-450.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 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.Öğe New Anti-Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies(Wiley-V C H Verlag Gmbh, 2017) Sari, Suat; Dalkara, Sevim; Kaynak, Filiz Betul; Reynisson, Johannes; Sarac, Selma; Karakurt, Arzu(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance -aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABA(A)Rs), was reported to be sensitive to Asn265 of the 2/3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure. We performed molecular docking studies for our active compounds using GABA(A)R and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABA(A)R in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABA(A)R is elucidated.Öğe New arylalkyl azole derivatives showing anticonvulsant effects could have VGSC and or GABAAR affinity according to molecular modeling studies(European Journal of Medicinal Chemistry, 2016) Sarı, Suat; Karakurt, Arzu; Uslu, Harun; Kaynak, Filiz Betül; Çalış, Ünsal; 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-yl)ethanone 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 g-aminobutiric acid (GABA)-mediated response. In order to get insights into the effects of our compounds on VGSCs and Atype GABA receptors (GABAARs) we performed docking studies using homology model of Naþ channel inner pore and GABAAR 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.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.
