Introduction of benzyloxy pharmacophore into aryl/heteroaryl chalcone motifs as a new class of monoamine oxidase B inhibitors

The inhibitory action of fifteen benzyloxy ortho/para-substituted chalcones (B1-B15) was evaluated against human monoamine oxidases (hMAOs). All the molecules inhibited hMAO-B isoform more potently than hMAO-A. Furthermore, the majority of the molecules showed strong inhibitory actions against hMAO-B at 10 mu M level with residual activities of less than 50%. Compound B10 has an IC50 value of 0.067 mu M, making it the most potent inhibitor of hMAO-B, trailed by compound B15 (IC50=0.12 mu M). The thiophene substituent (B10) in the A-ring exhibited the strongest hMAO-B inhibition structurally, however, increased residue synthesis did not result in a rise in hMAO-B inhibition. In contrast, the benzyl group at the para position of the B-ring displayed more hMAO-B inhibition than the other positions. Compounds B10 and B15 had relatively high selectivity index (SI) values for hMAO-B (504.791 and 287.600, respectively). K-i values of B10 and B15 were 0.030 +/- 0.001 and 0.033 +/- 0.001 mu M, respectively. The reversibility study showed that B10 and B15 were reversible inhibitors of hMAO-B. PAMPA assay manifested that the benzyloxy chalcones (B10 and B15) had a significant permeability and CNS bioavailability with Pe value higher than 4.0x10(-6) cm/s. Both compounds were stabilized in protein-ligand complexes by the pi-pi stacking, which enabled them to bind to the hMAO-B enzyme's active site incredibly effectively. The hMAO-B was stabilized by B10- and B15-hMAO-B complexes, with binding energies of - 74.57 and - 87.72 kcal/mol, respectively. Using a genetic algorithm and multiple linear regression, the QSAR model was created. Based on the best 2D and 3D descriptor-based QSAR model, the following statistics were displayed: R-2 = 0.9125, Q(loo)(2) = 0.8347. These findings imply that B10 and B15 are effective, selective, and reversible hMAO-B inhibitors.

Automated summary

This study evaluated the inhibitory effects of fifteen benzyloxy ortho/para-substituted chalcones on human monoamine oxidases. The results showed that these compounds exhibited strong inhibitory activity against hMAO-B, making them potential candidates for drug development.