Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects

Autores de INCLIVA

• Ainhoa Natividad García Martín

  Autor

• Diego Cortes Martinez

  Autor

• 

  Nuria Cabedo Escrig

  Autor

Participantes ajenos a INCLIVA

• Villarroel-Vicente, C
• Zibar, K
• Schiel, MA
• Ferri, J
• Hennuyer, N
• Enriz, RD
• Staels, B

Grupos y Plataformas de I+D+i

• Grupo de investigación en Química Médica para el Desarrollo de Fármacos

  

  Responsable de Plataforma

  Nuria Cabedo Escrig

• Unidad de Cromatografía Líquida Analítica

  

  Responsable de Plataforma

  Nuria Cabedo Escrig

Abstract

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.

Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Keywords

• PPAR; Metabolic syndrome; MAFLD; 2-Prenylated benzopyrans; 2-Prenylated quinolines; Anti-inflammatory agents