2. Academic Validation
  3. Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages

Benzopyran hydrazones with dual PPARα/γ or PPARα/δ agonism and an anti-inflammatory effect on human THP-1 macrophages

  • Eur J Med Chem. 2024 Feb 5:265:116125. doi: 10.1016/j.ejmech.2024.116125.
Ainhoa García 1,  Laura Vila 2,  Isabelle Duplan 3,  María Ayelén Schiel 4,  Ricardo D Enriz 4,  Nathalie Hennuyer 5,  Bart Staels 3,  Nuria Cabedo 6,  Diego Cortes 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Valencia, 46100, Burjassot, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, 46010, Valencia, Spain.
  • 2 Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, 46010, Valencia, Spain.
  • 3 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000, Lille, France.
  • 4 Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis-IMIBIO-SL-CONICET, Chacabuco, 917-5700, San Luis, Argentina.
  • 5 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000, Lille, France. Electronic address: nathalie.hennuyer@pasteur-lille.fr.
  • 6 Department of Pharmacology, University of Valencia, 46100, Burjassot, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, 46010, Valencia, Spain. Electronic address: ncabedo@uv.es.
  • 7 Department of Pharmacology, University of Valencia, 46100, Burjassot, Valencia, Spain. Electronic address: dcortes@uv.es.
PMID: 38185055 DOI: 10.1016/j.ejmech.2024.116125
Abstract

Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ 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 hPPARα/γ agonism, while hydrazone 14 exerted dual hPPARα/δ agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-κB activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARα/γ or PPARα/δ 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.

Keywords

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

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