Design, synthesis and evaluation of 2-(indolylmethylidene)-2,3-dihydro-1-benzofuran-3-one and 2-(indolyl)-4H-chromen-4-one derivatives as novel monoamine oxidases inhibitors
| Autor: | Shiori U, Yoshiaki Sugita, Koichi Takao, Hitoshi Kamauchi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Monoamine Oxidase Inhibitors
Monoamine oxidase Stereochemistry Positive control Inhibitory postsynaptic potential 01 natural sciences Biochemistry Structure-Activity Relationship 1-benzofuran Drug Discovery medicine Humans Benzopyrans Monoamine Oxidase Molecular Biology IC50 Benzofurans Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Pargyline Recombinant Proteins 0104 chemical sciences Molecular Docking Simulation 010404 medicinal & biomolecular chemistry Monoamine neurotransmitter Design synthesis Drug Design medicine.drug |
| Zdroj: | Bioorganic Chemistry. 87:594-600 |
| ISSN: | 0045-2068 |
| Popis: | A series of 2-(indolylmethylidene)-2,3-dihydro-1-benzofuran-3-ones (aurone-indole hybrids) and 2-(indolyl)-4H-chromen-4-ones (flavone-indole hybrids) were designed, synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 5b and 11b showed potent inhibitory activities against MAO-A, comparable to that of pargyline used as a positive control, and most of the compounds, except for 2a and 10b, showed potent inhibitory activities against MAO-B. Compound 9a was the most potent and highly selective inhibitor of MAO-B (IC50 value for MAO-B: 0.0026 μM, and MAO-A: >100 μM). Comparison of the inhibitory activities of 1a vs. 9a vs. 13a and 1b vs. 7b vs. 11b suggested that methoxy substitution at R1 on the A-rings of flavonoids increases MAO-A inhibition whereas methoxy substitution at R2 increased MAO-B inhibition. Comparison of 4a vs. 10a, 6a vs. 11a, 3b vs. 8b and 4b vs. 9b showed incremental increases in MAO-B inhibitory activity by R2 substitution on the A ring. Comparison of the MAO-B inhibitory effects of the flavone-indole hybrids and aurone-indole hybrids showed that most of the aurone-indole hybrids were stronger inhibitors than the corresponding flavone-indole hybrids. Molecular docking analysis of compounds 1a and 9a with MAO-B further supported the above structural effects of these compounds on MAO-B inhibitory activity. This is the first report identifying aurone-indole hybrids as potent MAO-B inhibitors. The results reported here suggest that 2-(1H-indol-1-ylmethylene)-6-methoxy-3(2H)-benzofuranone (9a) might be a useful lead for the design and development of novel MAO-B inhibitors |
| Databáze: | OpenAIRE |
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