Abstract
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 IC50 value of 0.032 mu M, similar to that of CA3 (IC50 = 0.035 mu M) 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 >-OCH2CH3 > -CF3). On the other hand, compound CA10 most potently inhibited MAO-A with an IC50 value of 0.310 mu M and effectively MAO-B (IC50 = 0.074 mu M). The Br-containing thiophene substituent (CA10) instead of the A ring showed the highest MAO-A inhibition. In a kinetic study, Ki values of compounds CA3 and CA4 for MAO-B were 0.076 +/- 0.001 and 0.027 +/- 0.002 mu M, respectively, and that of CA10 for MAO-A was 0.016 +/- 0.005 mu M. 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.