Benzopyran hydrazones with dual PPARa/? or PPARa/d agonism and an anti-inflammatory effect on human THP-1 macrophages

Autores de INCLIVA

• Ainhoa Natividad García Martín

  Autor

• 

  Laura Vila Dasí

  Autor

• 

  Nuria Cabedo Escrig

  Autor

• Diego Cortes Martinez

  Autor

Participantes ajenos a INCLIVA

• Duplan, I
• Schiel, MA
• Enriz, RD
• Hennuyer, N
• Staels, B

Grupos y Plataformas de I+D+i

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

  

  Established Researcher

  Nuria Cabedo Escrig

• Unidad de Cromatografía Líquida Analítica

  

  Established Researcher

  Nuria Cabedo Escrig

Abstract

Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPAR gamma partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry. In an attempt to discover novel and safety PPAR activators, we efficiently prepared benzopyran hydrazone/hydrazine derivatives containing benzothiazole (series 1) or 5-chloro-3-(trifluoromethyl)-2-pyridine moiety (series 2) with a 3-or 7 -carbon side chain at the 2-position of the benzopyran nucleus. Benzopyran hydrazones 4 and 5 showed dual hPPAR alpha/gamma agonism, while hydrazone 14 exerted dual hPPAR alpha/delta agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-kappa B activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPAR alpha/gamma or PPAR alpha/delta partial agonism, depending on the length of the side chain. Benzopyran hydrazones emerge as potential lead compounds which could be useful for treating metabolic diseases.

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Keywords

• Benzopryan hydrazones; Synthesis; Molecular modelling; PPAR agonists; Anti-inflammatory activity; Cytotoxicity