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

[Image: see text] Thirteen isopropyl chalcones (CA1–CA13) were synthesized and evaluated for their inhibitory activity against monoamine oxidase (MAO). All compounds inhibited MAO-B more effectively than MAO-A. Compound CA4 most potently inhibited MAO-B with an IC(50) value of 0.032 μM, similar to that of CA3 (IC(50) = 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 (CA4) or −F (CA3) group at the para position on the A ring provided higher MAO-B inhibition than that of the other substituents (−OH ≥ −F > −Cl > −Br > −OCH(2)CH(3) > −CF(3)). On the other hand, compound CA10 most potently inhibited MAO-A with an IC(50) value of 0.310 μM and effectively MAO-B (IC(50) = 0.074 μM). The Br-containing thiophene substituent (CA10) instead of the A ring showed the highest MAO-A inhibition. In a kinetic study, K(i) values of compounds CA3 and CA4 for MAO-B were 0.076 ± 0.001 and 0.027 ± 0.002 μM, respectively, and that of CA10 for MAO-A was 0.016 ± 0.005 μM. A reversibility study showed that CA3 and CA4 were reversible inhibitors of MAO-B and CA10 was a reversible inhibitor of MAO-A. In docking and molecular dynamics, the hydroxyl group of CA4 and two hydrogen bonds contributed to the stability of the protein–ligand complex. These results suggest that CA3 and CA4 are potent reversible selective MAO-B inhibitors and can be used for the treatment of Parkinson’s disease.