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    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, Ozlen
    Human 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.
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    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, Ozlen
    In 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.
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    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, Oezlen
    Introduction: 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.