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Synthesis,Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors
Authors:Bijo Mathew  Abitha Haridas  Prof. Dr. Gülberk Uçar  Ipek Baysal  Monu Joy  Githa E. Mathew  Dr. Baskar Lakshmanan  Dr. Venkatesan Jayaprakash
Affiliation:1. Division of Drug Design and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala, India;2. Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, Kerala, India;3. Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey;4. School of Pure & Applied Physics, Mahatma Gandhi University, Kottayam, India;5. Department of Pharmacology, Grace College of Pharmacy, Palakkad, Kerala, India;6. Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
Abstract:A series of (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(para‐substituted phenyl)prop‐2‐en‐1‐ones ( TB1 – TB11 ) was synthesized and tested for inhibitory activity toward human monoamine oxidase (hMAO). All compounds were found to be competitive, selective, and reversible toward hMAO‐B except (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( TB7 ) and (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐(4‐chlorophenyl)prop‐2‐en‐1‐one ( TB8 ), which were selective inhibitors of hMAO‐A. The most potent compound, (2E)‐1‐(5‐bromothiophen‐2‐yl)‐3‐[4‐(dimethylamino)phenyl]prop‐2‐en‐1‐one ( TB5 ), showed the best inhibitory activity and higher selectivity toward hMAO‐B, with Ki and SI values of 0.11±0.01 μm and 13.18, respectively. PAMPA assays for all compounds were carried out in order to evaluate the capacity of the compounds to cross the blood–brain barrier. Moreover, the most potent MAO‐B inhibitor, TB5 , was found to be nontoxic at 5 and 25 μm , with 95.75 and 84.59 % viability among cells, respectively. Molecular docking simulations were carried out to understand the crucial interactions responsible for selectivity and potency.
Keywords:chalcones  cytotoxicity  molecular docking  monoamine oxidases
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