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Öğe Antiviral Properties of 5-Sulfamoyl-1H-Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2(Marmara Univ, 2024) Trawally, Muhammed; Yilmaz, Fatima Nur; Ozbek Celik, Berna; Akdemir, Atilla; Guzel Akdemir, OzlenHuman parainfluenza viruses (HPIVs) are responsible for a wide range of respiratory infections in humans, particularly in children, the elderly, and immunocompromised individuals. This paper presents a study regarding the antiviral activity of a series of 3-phenyl-5-sulfamoyl-N-(7/8/9-(non)substituted-3-oxo-1-thia-4- azaspiro[4.4]non/[4.5]dec-4-yl)-1H-indole-2-carboxamide derivatives against HPIV-2. Our findings suggest the compounds displayed low potency against HPIV-2. Compounds 4 and 8 exhibited the most potent antiviral effects with inhibition of 95.46 and 90.90 % at 10 mg/mL, respectively. Molecular modeling studies were conducted on hemagglutinin-neuraminidase, a crucial druggable target for HPIV, to predict the binding modes of the compounds.Öğe In silico design, synthesis and antitubercular activity of novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones as enoyl-acyl carrier protein reductase inhibitors(Taylor & Francis Inc, 2024) Birgul, Serap Ipek Dingis; Kumari, Jyothi; Tamhaev, Rasoul; Mourey, Lionel; Lherbet, Christian; Sriram, Dharmarajan; Akdemir, AtillaMycobacteria regulate the synthesis of mycolic acid through the fatty acid synthase system type 1 (FAS I) and the fatty acid synthase system type-2 (FAS-II). Because mammalian cells exclusively utilize the FAS-I enzyme system for fatty acid production, targeting the FAS-II enzyme system could serve as a specific approach for developing selective antimycobacterial drugs. Enoyl-acyl carrier protein reductase enzyme (MtInhA), part of the FAS-II enzyme system, contains the NADH cofactor in its active site and reduces the intermediate. Molecular docking studies were performed on an in-house database (similar to 2200 compounds). For this study, five different crystal structures of MtInhA (PDB Code: 4TZK, 4BQP, 4D0S, 4BGE, 4BII) were used due to rotamer difference, mutation and the presence of cofactors. Molecular dynamics simulations (250 ns) were performed for the novel 2-acylhydrazono-5-arylmethylene-4-thiazolidinones derivatives selected by molecular docking studies. Twenty-three compounds selected by in silico methods were synthesized. Antitubercular activity and MtInhA enzyme inhibition studies were performed for compounds whose structures were elucidated by IR,H-1-NMR,C-13-NMR, HSQC, HMBC, MS and elemental analysis. Communicated by Ramaswamy H. SarmaÖğe Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies(Academic Press Inc Elsevier Science, 2024) Demir-Yazici, Kubra; Trawally, Muhammed; Bua, Silvia; Ozturk-Civelek, Dilek; Akdemir, Atilla; Supuran, Claudiu T.; Guzel-Akdemir, OzlenIn the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to similar to 340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (K-i) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; K-i: 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50: 53.32 +/- 7.74 mu M for HT-29; IC50: 74.64 +/- 14.15 mu M for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.Öğe Thiosemicarbazone-benzene Sulfonamide Derivatives as Human Carbonic Anhydrases Inhibitors: Synthesis, Characterization, and In silico Studies(Bentham Science Publ Ltd, 2024) Trawally, Muhammed; Demir-Yazici, Kuebra; Angeli, Andrea; Kaya, Kerem; Akdemir, Atilla; Supuran, Claudiu T.; Guezel-Akdemir, OezlenIntroduction: Carbonic anhydrases (CAs) are widespread metalloenzymes with the core function of catalyzing the interconversion of CO2 and HCO3(-). Targeting these enzymes using selective inhibitors has emerged as a promising approach for the development of novel therapeutic agents against multiple diseases. Methods: A series of novel thiosemicarbazone-containing derivatives were synthesized, characterized, and tested for their inhibitory activity against pharmaceutically important human CA I (hCA I), II (hCA II), IX (hCA IX), and XII (hCA XII) using the single tail approach. Results: The compounds generally inhibited the isoenzymes at low nanomolar concentrations, with compound 6b having Ki values of 7.16, 0.31, 92.5, and 375 nM against hCA I, II, IX and XII, respectively. Compound 6e exhibited Ki values of 27.6, 0.34, 872, and 94.5 nM against hCA I, II, IX and XII, respectively. Conclusion: To rationalize the inhibition data, molecular docking studies were conducted, providing insight into the binding mechanisms, molecular interactions, and selectivity of the compounds towards the isoenzymes.Öğe Yeşil Kimya Teknikleri ve Moleküler Docking Yöntemleri ile Yeni Florokinolon Hibrit Moleküllerin Sentezi, DNA Giraz, Topoizomeraz IV İnhibisyonu ve Antibakteriyel Aktivitelerinin Araştırılması(2021) Durukan, İnci; Kulabaş, Necla; Akdemir, Atilla; Faiz, Özlem; Ayvaz, Aslıhan; Kılıç, Ali Osman; Azafad, İmaneBu projede öncelikle, literatür verilerinden ve grubumuzun daha önceki çalışmalardan elde ettikleri sonuçlara (yapı-aktivite ilişkileri, SAR) dayanılarak DNA giraz ve topoizomeraz IV inhibisyonu göstermesi öngörülen ve florokinolon-heterohalka hibrit bileşikleri içeren sanal veribankası oluşturulmuştur. Daha sonra bu veribankasından ön çalışmalarımızda geliştirdiğimiz ve valide ettiğimiz sanal tarama yöntemleri ile E. coli veya S. aureas DNA giraz veya DNA topoizomeraz IV enzimlerini inhibe etme potansiyeline sahip olan 75 bileşik sentez için önerilmiştir. Sentezlenen bütün bileşikler enzim inhibisyonu ve antimikrobial aktivite deneylerinde test edilmiştir. Sentezlenen bileşiklerin bazılarının giraz ve topoizomeraz IV inhibisyonu göstermemesine karşılık bilinen antibakteriyel ilaçlar olan norfloksazin, siprofloksazin kadar veya onlara yakın derecede antibakteriyel aktivite göstermesi, bunların florokinolon antibiyotiklerinden farklı bir mekanizma üzerinden etki ettiklerini göstermektedir ki bu durum özellikle ilaç direnci probleminin üstesinden gelme çalışmalarına katkı sağlama potansiyeli göstermektedir. Sentez çalışmalarında geleneksel ısıtma veya karıştırma yöntemlerine ilaveten mikrodalga veya ultrasonik ışınlandırma tekniklerinin de denenmiş ve geleneksel yöntemlere üstünlük sağlayan sonuçların elde edilmiş olması, bu çalışmayı yeşil kimya tekniklerinin geliştirilmesi açısından da değerli kılmaktadır.
