Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects
We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated v...
| Autores: | , , , , , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | INCLIVA |
| Repositorio: | r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA |
| OAI Identifier: | oai:incliva.fundanetsuite.com:p18412 |
| Acceso en línea: | https://incliva.portalinvestigacion.com/publicaciones/18412 |
| Access Level: | acceso abierto |
| Palabra clave: | PPAR Metabolic syndrome MAFLD 2-Prenylated benzopyrans 2-Prenylated quinolines Anti-inflammatory agents |
| Sumario: | We have previously reported the total synthesis and structure-activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedla<spacing diaeresis>nder condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a gamma,8-unsaturated ester displayed a pan-PPAR agonism. They were full PPAR alpha agonists, but showed different preferences for PPAR gamma and PPARI3/8 activation. It was noteworthy that quinoline 4b displayed full hPPAR alpha activation (2-fold than WY-14,643), weak PPARI3/8 and partial PPAR gamma activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities. |
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