Development of Isopropyl-Tailed Chalcones as a New Class of Selective MAO-B Inhibitors for the Treatment of Parkinson's Disorder.

Thirteen isopropyl chalcones () were synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO). All compounds inhibited MAO-B more effectively than MAO-A. Compound most potently inhibited MAO-B with an IC value of 0.032 μM, similar to that of (IC = 0.035 μM) and with high selectivity index (SI) values for MAO-B over MAO-A (SI = 49.75 and 353.23, respectively). The -OH () or -F () group at the para position on the A ring provided higher MAO-B inhibition than that of the other substituents (-OH ≥ -F > -Cl > -Br > -OCHCH > -CF). On the other hand, compound most potently inhibited MAO-A with an IC value of 0.310 μM and effectively MAO-B (IC = 0.074 μM). The Br-containing thiophene substituent () instead of the A ring showed the highest MAO-A inhibition. In a kinetic study, values of compounds and for MAO-B were 0.076 ± 0.001 and 0.027 ± 0.002 μM, respectively, and that of for MAO-A was 0.016 ± 0.005 μM. A reversibility study showed that and were reversible inhibitors of MAO-B and was a reversible inhibitor of MAO-A. In docking and molecular dynamics, the hydroxyl group of and two hydrogen bonds contributed to the stability of the protein-ligand complex. These results suggest that and are potent reversible selective MAO-B inhibitors and can be used for the treatment of Parkinson's disease.