Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions.

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound showed potent inhibitory activity against MAO-B, with an IC value of 0.010 µM, followed by , , , and (IC = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that and were reversible and competitive inhibitors of MAO-B with K values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both and were non-toxic to Vero cells with IC values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC values, both significantly reduced reactive oxygen species (ROS) levels. and showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between and and the active site of MAO-B. Conclusively, and are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.