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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  TM8  showed potent inhibitory activity against MAO-B, with an IC 50  value of 0.010 µM, followed by  TM1 ,  TM2 ,  TM7 , and  TM10  (IC 50  = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly,  TM8  had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that  TM8  and  TM1  were reversible and competitive inhibitors of MAO-B with K i  values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both  TM1  and  TM8  were non-toxic to Vero cells with IC 50  values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC 50  values, both significantly reduced reactive oxygen species (ROS) levels.  TM1  and  TM8  showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between  TM1  and  TM8  and the active site of MAO-B. Conclusively,  TM8  and  TM1  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.

pharmaceuticals

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