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:	Bijo Mathew, Jong Min Oh, Ahmed Khames, Mohamed A. Abdelgawad, T. M. Rangarajan, Lekshmi R. Nath, Clement Agoni, Mahmoud E. S. Soliman, Githa Elizabeth Mathew, Hoon Kim
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chalcone MAO-B selectivity reversibility cytotoxicity ROS Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/dd6eb7ca415747acbb527b53f6944a97
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spelling	oai:doaj.org-article:dd6eb7ca415747acbb527b53f6944a972021-11-25T18:39:43ZReplacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions10.3390/ph141111481424-8247https://doaj.org/article/dd6eb7ca415747acbb527b53f6944a972021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1148https://doaj.org/toc/1424-8247To 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.Bijo MathewJong Min OhAhmed KhamesMohamed A. AbdelgawadT. M. RangarajanLekshmi R. NathClement AgoniMahmoud E. S. SolimanGitha Elizabeth MathewHoon KimMDPI AGarticlechalconeMAO-BselectivityreversibilitycytotoxicityROSMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1148, p 1148 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chalcone MAO-B selectivity reversibility cytotoxicity ROS Medicine R Pharmacy and materia medica RS1-441
spellingShingle	chalcone MAO-B selectivity reversibility cytotoxicity ROS Medicine R Pharmacy and materia medica RS1-441 Bijo Mathew Jong Min Oh Ahmed Khames Mohamed A. Abdelgawad T. M. Rangarajan Lekshmi R. Nath Clement Agoni Mahmoud E. S. Soliman Githa Elizabeth Mathew Hoon Kim Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
description	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.
format	article
author	Bijo Mathew Jong Min Oh Ahmed Khames Mohamed A. Abdelgawad T. M. Rangarajan Lekshmi R. Nath Clement Agoni Mahmoud E. S. Soliman Githa Elizabeth Mathew Hoon Kim
author_facet	Bijo Mathew Jong Min Oh Ahmed Khames Mohamed A. Abdelgawad T. M. Rangarajan Lekshmi R. Nath Clement Agoni Mahmoud E. S. Soliman Githa Elizabeth Mathew Hoon Kim
author_sort	Bijo Mathew
title	Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
title_short	Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
title_full	Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
title_fullStr	Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
title_full_unstemmed	Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions
title_sort	replacement of chalcone-ethers with chalcone-thioethers as potent and highly selective monoamine oxidase-b inhibitors and their protein-ligand interactions
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/dd6eb7ca415747acbb527b53f6944a97
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Replacement of Chalcone-Ethers with Chalcone-Thioethers as Potent and Highly Selective Monoamine Oxidase-B Inhibitors and Their Protein-Ligand Interactions

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