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.
Many of the studies clearly revealed that most of the chalcones showed selective, reversible and potent MAO-B inhibition compared to MAO-A. Recent studies also showed that heteroaryl-based chalcones are potent MAO-A inhibitors.
For various neurodegenerative disorders like Alzheimer's and Parkinson's diseases, selective and reversible MAO-B inhibitors have a great therapeutic value. In our previous study, we have shown that a series of methoxylated chalcones with F functional group exhibited high binding affinity toward human monoamine oxidase-B (hMAO-B). In continuation of our earlier study and to extend the understanding of the structure-activity relationships, a series of five new chalcones were studied for their inhibition of hMAO. The results demonstrated that these compounds are reversible and selective hMAO-B inhibitors with a competitive mode of inhibition. The most active compound, (2E)-1-(4-hydroxyphenyl)-3-[4-(trifluoromethyl)phenyl]prop-2-en-1-one, exhibited a Ki value of 0.33 ± 0.01 μm toward hMAO-B with a selectivity index of 26.36. A molecular docking study revealed that the presence of a H-bond network in hydroxylated chalcone with the N(5) atom of FAD is crucial for MAO-B selectivity and potency.
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