Monoamine oxidase inhibitory activity of methoxy-substituted chalcones

Abstract The MAO-B inhibitory activity of chalcone (1, 3- diphenyl-2-propen-1-one) based compounds arise from its structural similarity with 1, 4-diphenyl-2-butene, a known MAO-B inhibitor. Based on our previous report, the methoxy-substituted with fluorine containing chalcones are promising reversible MAO-B inhibitors, while in the present study, a series of methoxylated chalcones ( C1 - C9 ) bearing substitution on the para position of ring B was synthesized and evaluated for their human monoamine oxidase inhibitory activity. With the exception of (2 E )-1-(4-methoxyphenyl)-3-(4-nitrophenyl) prop-2-en-1-one ( C7 ), which is a nonselective inhibitor, the chalcones exhibited competitive, selective, and reversible inhibition of hMAO-B. The most potent compound, (2 E )-3-[4-(dimethylamino) phenyl]-1-(4-methoxyphenyl) prop-2-en-1-one ( C5 ), showed the best inhibitory activity towards hMAO-B (IC 50  = 0.29 ± 0.011 μM;  K i  = 0.14 ± 0.001 μM). The reversibility of MAO-B inhibition by compound C5 was demonstrated by the recovery of enzyme activity after dialysis of mixtures containing enzyme and inhibitor. The reversiblity of C5 was 25.38 ± 1.40 and 92.00 ± 3.87% before and after dialysis, respectively. PAMPA was carried out to evaluate the blood-brain barrier effects of the designated compounds. Moreover, the most potent MAO-B inhibitor, C5 , was found to be nontoxic towards cultured hepatic cells at 5 and 25 μM, with 97 and 90% viability. Molecular docking study was performed against hMAO-B to observe the binding site interactions of the lead compound.