Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors.
Bioorg Chem
; 93: 103335, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31606547
ABSTRACT
The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC50 value of 0.0021⯵M, followed by compounds O10 and O17 (IC50â¯=â¯0.0030 and 0.0034⯵M, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC50 value of 0.029⯵M, followed by O3, O4, O9, and O2 (IC50â¯=â¯0.035, 0.053, 0.072, and 0.082⯵M, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC50 value for MAO-Bâ¯=â¯0.010⯵M) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective Ki values of 0.016⯱â¯0.0007 and 0.00050⯱â¯0.00003⯵M. Lead compound are also non-toxic at 200⯵g/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Oxigênio
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Desenho de Fármacos
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Chalconas
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Monoaminoxidase
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Inibidores da Monoaminoxidase
Limite:
Animals
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Arábia Saudita