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Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives
Author(s) -
Mathew Bijo,
Uçar Gülberk,
Mathew Githa Elizabeth,
Mathew Sincy,
Kalatharakkal Purapurath Praseedha,
Moolayil Fasil,
Mohan Smrithy,
Varghese Gupta Sheeba
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600497
Subject(s) - monoamine oxidase , chemistry , monoamine oxidase b , stereochemistry , docking (animal) , enzyme , monoamine neurotransmitter , membrane permeability , inhibitory postsynaptic potential , pharmacology , membrane , biochemistry , biology , medicine , nursing , receptor , serotonin
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 (2 E )‐1‐(4‐methylphenyl)‐3‐(4‐nitrophenyl)prop‐2‐en‐1‐one ( P7 ) and (2 E )‐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, (2 E )‐1‐(4‐chlorophenyl)‐3‐(4‐ethylphenyl)prop‐2‐en‐1‐one ( P16 ), showed a K i value of 0.11±0.01 μ m . 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 μ m .