Effect of halogens on 3-[4-(dimethylamino) phenyl]-1-phenylprop-2-en-1-ones: development of a new class of monoamine oxidase-B inhibitors

Abstract

Five dimethylamino-based chalcone derivatives (AC) were synthesized and evaluated for their inhibition degree against monoamine oxidase (MAO) enzymes. All AC compounds showed better inhibitory activity against MAO-B than that against MAO-A. AC4 showed the highest inhibitory ability with an IC₅₀ value of 0.020 µM, similar to that of a reference drug safinamide (IC₅₀ = 0.019 µM) against MAO-B, followed by AC1 (IC₅₀ = 0.068 µM) and AC3 (IC₅₀ = 0.083 µM). Substituent -F in ring A (AC4) increased the MAO-B inhibition, followed by -H (AC1), -Br (AC3), and -Cl (AC2). The selectivity index (SI) value of AC4 was high (SI = 82.00) as well as other compounds (44.41 to 98.15). AC4 was found to be a reversible inhibitor as confirmed through analysis using the dialysis method. Interestingly, AC4 was observed to be a noncompetitive MAO-B inhibitor with a rare case and with K_i values of 0.011 ± 0.0036 µM. These experiments confirmed that AC4 is a reversible and potent selective inhibitor of MAO-B. Molecular docking experiments revealed that AC4 showed the highest inhibitory activity with a docking score (-9.510 kcal/mol). A study using molecular dynamics modeling revealed that the protein–ligand complex was more stable. It was observed that AC4 was non-cytotoxic in the study using L929 cell line. In conclusion, compound AC4 shows promise as a MAO-B inhibitor.