Sulfonyl hydrazones derived from 3-formylchromone as non-selective inhibitors of MAO-A and MAO-B: Synthesis,molecular modelling and in-silico ADME evaluation |
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| Affiliation: | 1. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad 22060, Pakistan;2. Department of Chemistry, Forman Christian College (A Chartered University), Ferozepur Road, Lahore 54600, Pakistan;3. Department of Chemistry, COMSATS Institute of Information Technology, Defence Road, Off Raiwind Road, Lahore 54000, Pakistan;4. Department of Chemistry, College of Science and Humanity Studies, Prince Sattam Bin Abdulaziz University, P.O. Box 83, Alkharj 11942, Saudi Arabia;1. Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany;2. Leibniz Institut für Katalyse an der Universität Rostock e.V. (LIKAT), Albert-Einstein-Str. 29a, 18059 Rostock, Germany;3. Centre for Advanced Drug Research, COMSATS Institute of Information Technology, Abbottabad, Pakistan;4. Département de Microbiologie-infectiologie et d''immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 0A6, Canada;5. Centre de Recherche du CHU de Québec – Université Laval, Québec, QC, G1V 4G2, Canada;1. Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan;2. Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan;3. Department of Physics, University of Sargodha, Sargodha, Pakistan;4. Sustainable Energy Technologies Center, College of Engineering, PO-Box 800, King Saud University, Riyadh 11421, Saudi Arabia;1. Department of Chemistry, Faculty of Science, Gazi University, Ankara 06500, Turkey;2. Department of Molecular Biology and Genetics, Faculty of Science, Bartın University, Bartın 74100, Turkey;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;2. Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Ege University, 35040 Izmir, Turkey;3. Institute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany;1. Department of Pharmacy, “G. D’Annunzio” University of Chieti-Pescara, Via Dei Vestini 31, 66100 Chieti, Italy;2. Dipartimento di Scienze Della Salute, University “Magna Graecia” of Catanzaro, Campus “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy;3. Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom 2520, South Africa;4. Dipartimento di Chimica e Tecnologie Del Farmaco, “Sapienza” University of Rome, P.le A. Moro 5, 00185 Rome, Italy;5. Selcuk University, Science Faculty, Department of Biology, Konya, Turkey;1. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro, 14-gil, Seongbuk-gu, Seoul 136-791, Republic of Korea;2. Department of Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea;3. Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 130-701, Republic of Korea;4. Department of Biological Chemistry, University of Science and Technology, Daejeon 305-350, Republic of Korea |
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| Abstract: | A series of sulfonyl hydrazones derived from 3-formylchromone was synthesized and discovered to be effective, non-selective inhibitors of monoamine oxidases (MAO-A and MAO-B). The compounds are easily (synthetically) accessible in high yields, by simple condensation of 4-methylbenzenesulfonohydrazide with different (un)substituted 3-formylchromones. All compounds had IC50 values in lower micro-molar range (IC50 = 0.33–7.14 μM for MAO-A, and 1.12–3.56 μM for MAO-B). The most active MAO-B inhibitor was N′-[(E)-(6-fluoro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3e) with IC50 value of 1.12 ± 0.02 μM, and N′-[(E)-(6-chloro-4-oxo-4H-chromen-3-yl)methylidene]-4-methylbenzenesulfonohydrazide (3f) was the most active MAO-A inhibitor with IC50 value of 0.33 ± 0.01 μM. From enzyme kinetic studies, the mode of inhibition against MAO-B was found to be competitive, whereas against MAO-A, it was found to be non-competitive. Molecular docking studies indicated a new binding pocket for non-competitive MAO-A inhibitors. The activity of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability. |
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| Keywords: | Sulfonohydrazide 3-Formylchromones Molecular docking Oral bioavailability |
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