title: Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors.
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.
authors.affiliation: Division of Drug Design and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, 678557, Kerala, India. bijovilaventgu@gmail.com.
authors.forename: Bijo
authors.identifier: http://orcid.org/0000-0002-6658-4497
authors.initials: B
authors.lastname: Mathew
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Abitha
authors.initials: A
authors.lastname: Haridas
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey. gulberk@hacettepe.edu.tr.
authors.forename: Gülberk
authors.initials: G
authors.lastname: Uçar
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey.
authors.forename: Ipek
authors.initials: I
authors.lastname: Baysal
authors.affiliation: School of Pure & Applied Physics, Mahatma Gandhi University, Kottayam, 686560, India.
authors.forename: Monu
authors.initials: M
authors.lastname: Joy
authors.affiliation: Department of Pharmacology, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Githa E
authors.initials: GE
authors.lastname: Mathew
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Baskar
authors.initials: B
authors.lastname: Lakshmanan
authors.affiliation: Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, Jharkhand, India.
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Jayaprakash
mesh_terms: D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D054879:Halogenation; D056945:Hep G2 Cells; D006801:Humans; D007700:Kinetics; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D047188:Chalcones; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase
keywords: chalcones; cytotoxicity; molecular docking; monoamine oxidases