Discovery and optimization of 3-thiophenylcoumarins as novel agents against Parkinson's disease: Synthesis, in vitro and in vivo studies
| Autor: | Fernanda Rodríguez-Enríquez, José Angel Fontenla, Maria João Matos, Dolores Viña, Eugenio Uriarte |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Levodopa Parkinson's disease Monoamine Oxidase Inhibitors Pharmacology 01 natural sciences Biochemistry Neuroprotection Mice Structure-Activity Relationship In vivo Coumarins Drug Discovery medicine Animals Humans Molecular Biology Benserazide Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Selegiline Neurotoxicity Parkinson Disease medicine.disease 0104 chemical sciences 010404 medicinal & biomolecular chemistry Monoamine oxidase B medicine.drug |
| Zdroj: | Bioorganic chemistry. 101 |
| ISSN: | 1090-2120 |
| Popis: | Monoamine oxidase B (MAO-B) inhibitors are still receiving great attention as promising therapeutic agents for central nervous system disorders. This study explores, for the first time, the potential of 3-thiophenylcoumarins as in vitro and in vivo agents against Parkinsons disease. Twelve compounds were synthesized via Perkin-Oglialoro reaction, and in vitro evaluation of six hydroxylated molecules was performed. MAO-A and MAO-B inhibition, DPPH scavenging and inhibition of ROS formation, neurotoxicity on motor cortex neurons and neuroprotection against H2O2, were studied. In vivo effect on locomotor activity using the open field test was also evaluated for the best candidate [3-(4′-bromothiophen-2′-yl)-7-hydroxycoumarin, 5], a potent, selective and reversible MAO-B inhibitor (IC50 = 140 nM). This compound proved to have a slightly better in vivo profile than selegiline, one of the currently treatments for Parkinson's disease, in reserpinized mice pretreated with levodopa and benserazide. Results suggested that, comparing positions 7 and 8, substitution at position 7 of the coumarin scaffold is better for the enzymatic inhibition. However, the presence of a catechol at positions 7 and 8 exponentially increases the antioxidant potential and the neuroprotective properties. Finally, all the molecules present good theoretical physicochemical properties that make them excellent candidates for the optimization of a lead compound. |
| Databáze: | OpenAIRE |
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