Monoamine Oxidase Inhibitory Activity: Methyl‐ versus Chlorochalcone Derivatives. (30th November 2016)

• Record Type: Journal Article
• Authors: Mathew, Bijo; Uçar, Gülberk; Mathew, Githa Elizabeth; Mathew, Sincy; Kalatharakkal Purapurath, Praseedha; Moolayil, Fasil; Mohan, Smrithy; Varghese Gupta, Sheeba
• Is Part Of: ChemMedChem. Volume 11:Number 24(2016)
• Page Start: 2649
• Page End: 2655
• Publication Date: 2016-11-30
• Subjects: chalcones -- docking -- inhibitors -- monoamine oxidase -- Parkinson's disease; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600497
• Languages: English
• ISSNs: 1860-7179

Abstract

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 (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 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 inhibitorP16 showed no toxicity in cultured hepatic cells at concentrations of 5 and 25 μm . Abstract : Me versus Cl : Twenty chalcones containing methyl and chloro substituents were synthesized and evaluated for their hMAO inhibitory activities and capacity to cross the blood–brain barrier. Chloro substitution on the A ring is more favorable for MAO‐B inhibition than methyl substitution. hMAO inhibition by these chalcones was found to be reversible. The most potent inhibitor exhibited sub‐micromolar activity, and is nontoxic toward cultured hepatic cells at 5–25 μm .