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 investiga...
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| Autores principales: | , , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/dd6eb7ca415747acbb527b53f6944a97 |
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| Sumario: | 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 <b>TM8</b> showed potent inhibitory activity against MAO-B, with an IC<sub>50</sub> value of 0.010 µM, followed by <b>TM1</b>, <b>TM2</b>, <b>TM7</b>, and <b>TM10</b> (IC<sub>50</sub> = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, <b>TM8</b> had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that <b>TM8</b> and <b>TM1</b> were reversible and competitive inhibitors of MAO-B with K<sub>i</sub> values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both <b>TM1</b> and <b>TM8</b> were non-toxic to Vero cells with IC<sub>50</sub> values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC<sub>50</sub> values, both significantly reduced reactive oxygen species (ROS) levels. <b>TM1</b> and <b>TM8</b> showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between <b>TM1</b> and <b>TM8</b> and the active site of MAO-B. Conclusively, <b>TM8</b> and <b>TM1</b> 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. |
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