Synthesis, Biochemistry, and Computational Studies of Brominated Thienyl Chalcones: A New Class of Reversible MAO-B Inhibitors

Abstract

A series of (2E)-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 Ki 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.

Keywords: chalcones; cytotoxicity; molecular docking; monoamine oxidases.