title: Identification of Indole-Based Chalcones: Discovery of a Potent, Selective, and Reversible Class of MAO-B Inhibitors.
abstract: A series of 11 indole-based chalcones (IC1-11) with various electron donating and withdrawing groups at the para position of the phenyl ring B were synthesized. All the compounds were tested for their human monoamine oxidase (hMAO)-A and hMAO-B inhibitory potencies. Most of the synthesized candidates proved to be potent and selective inhibitors of MAO-B rather than MAO-A, with a reversible and competitive mode. Among them, compound IC9 was found to be a potent inhibitor of hMAO-B with Ki  = 0.01 ± 0.005 μM and a selectivity index of 120. It was found to be better than the standard drug, selegiline (hMAO-B with Ki  = 0.20 ± 0.020 μM) with a selectivity index of 30.55. PAMPA assays were carried out for all the compounds in order to evaluate the capacity of the compounds to cross the blood-brain barrier. Moreover, the most potent MAO-B inhibitor, IC9, was nontoxic at 5 and 25 μM, with 95.20 and 69.17% viable cells, respectively. The lead compound IC9 has an antioxidant property of 1.18 Trolox equivalents by ABTS assay. Molecular modeling studies were performed against hMAO-B to observe binding site interactions of the lead compound.
authors.affiliation: College of Pharmaceutical Science, Government T.D. Medical College, Alappuzha, Kerala, India.
authors.forename: Rani
authors.initials: R
authors.lastname: Sasidharan
authors.affiliation: Organic Chemistry Division, SAS, VIT University, Vellore, Tamil Nadu, India.
authors.forename: Sreedharannair Leelabaiamma
authors.initials: SL
authors.lastname: Manju
authors.affiliation: Faculty of Pharmacy, Department of Biochemistry, Hacettepe University, Sıhhiye, Ankara, Turkey.
authors.forename: Gülberk
authors.initials: G
authors.lastname: Uçar
authors.affiliation: Faculty of Pharmacy, Department of Biochemistry, Hacettepe University, Sıhhiye, Ankara, Turkey.
authors.forename: Ipek
authors.initials: I
authors.lastname: Baysal
authors.affiliation: Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala, India.
authors.forename: Bijo
authors.initials: B
authors.lastname: Mathew
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001812:Blood-Brain Barrier; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D062105:Molecular Docking Simulation; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000975:Antioxidants; D047188:Chalcones; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase
keywords: 3-Acetyl indole; Chalcones; MAO; MAO-B; Molecular docking