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

Grupos y Plataformas de I+D+i

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

  

  Leading Researcher

  Nuria Cabedo Escrig

• Unidad de Cromatografía Líquida Analítica

  

  Leading 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? 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 hPPARa/? agonism, while hydrazone 14 exerted dual hPPARa/d agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-?B activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARa/? or PPARa/d 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

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