title: Monoamine Oxidase Inhibitory Activity: Methyl- versus Chlorochalcone Derivatives.
abstract: Numerous studies have shown that chalcones are promising scaffolds for the development of new monoamine oxidase-B (MAO-B) inhibitors. As a continuation of our ongoing research into the development of reversible human MAO-B (hMAO-B) inhibitors, two series of twenty chalcones containing electron-donating and electron-withdrawing substituents were synthesized. All compounds were found to be competitive, selective, and reversible inhibitors of hMAO-B except (2E)-1-(4-methylphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P7) and (2E)-1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (P17), which were found to be selective inhibitors of hMAO-A. The most potent hMAO-B inhibitor, (2E)-1-(4-chlorophenyl)-3-(4-ethylphenyl)prop-2-en-1-one (P16), showed a Kivalue of 0.11±0.01 μm. Molecular docking simulations were carried out to identify the hypothetical binding mode for the most potent compounds in the active sites of hMAO-A and B. The ability of the compounds to cross the blood-brain barrier was assessed by parallel artificial membrane permeability assay (PAMPA). Additionally, the most potent hMAO-B inhibitor P16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm.
authors.affiliation: Division of Drug Design and Medicinal Chemistry Research, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, 678557, Kerala, India.
authors.forename: Bijo
authors.initials: B
authors.lastname: Mathew
authors.affiliation: Department of Biochemistry, Faculty of Pharmacy, Hacettepe University, Sıhhiye, 06100, Ankara, Turkey.
authors.forename: Gülberk
authors.initials: G
authors.lastname: Uçar
authors.affiliation: Department of Pharmacology, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Githa Elizabeth
authors.initials: GE
authors.lastname: Mathew
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Sincy
authors.initials: S
authors.lastname: Mathew
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Praseedha
authors.initials: P
authors.lastname: Kalatharakkal Purapurath
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Fasil
authors.initials: F
authors.lastname: Moolayil
authors.affiliation: Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad, 678004, Kerala, India.
authors.forename: Smrithy
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, 33612, USA.
authors.forename: Sheeba
authors.initials: S
authors.lastname: Varghese Gupta
mesh_terms: D020134:Catalytic Domain; D047188:Chalcones / Q000737:chemistry* / Q000494:pharmacology; D002713:Chlorine / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008697:Methane / Q000737:chemistry; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000621091:1-(4-chlorophenyl)-3-(4-nitrophenyl)prop-2-en-1-one; D047188:Chalcones; D008996:Monoamine Oxidase Inhibitors; D002713:Chlorine; D008995:Monoamine Oxidase; D008697:Methane
keywords: Parkinson's disease; chalcones; docking; inhibitors; monoamine oxidase