Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO‐B Inhibitors. (9th May 2016)

• Record Type: Journal Article
• Authors: Mathew, Bijo; Haridas, Abitha; Uçar, Gülberk; Baysal, Ipek; Joy, Monu; Mathew, Githa E.; Lakshmanan, Baskar; Jayaprakash, Venkatesan
• Is Part Of: ChemMedChem. Volume 11:Number 11(2016)
• Page Start: 1161
• Page End: 1171
• Publication Date: 2016-05-09
• Subjects: chalcones -- cytotoxicity -- molecular docking -- monoamine oxidases; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600122
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: A series of (2 E )‐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 K i 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. Abstract : No more MAO : Brominated thienyl chalcones were synthesized and tested for inhibitory activity toward human monoamine oxidase (MAO) and for their capacity to cross the blood–brain barrier. The most potent inhibitor exhibited sub‐micromolar activity and was found to be nontoxic at higher concentrations. Molecular docking simulations were used to determine critical interactions for selectivity and potency. In addition, single‐crystal X‐ray diffraction was performed for lead compoundTB5 .