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

  • Bioorg Med Chem Lett. 2024 Jul 1:106:129770. doi: 10.1016/j.bmcl.2024.129770.
Carlos Villarroel-Vicente  1 ,  Ainhoa García  1 ,  Khamis Zibar  2 ,  María Ayelén Schiel  3 ,  Jordi Ferri  4 ,  Nathalie Hennuyer  2 ,  Ricardo D Enriz  3 ,  Bart Staels  2 ,  Diego Cortes  5 ,  Nuria Cabedo  6
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. Univ Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France.
  • 3. Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis-IMIBIO-SL-CONICET, Chacabuco 915, San Luis, Argentina.
  • 4. Service of Endocrinology and Nutrition, University Clinic Hospital of Valencia, 46010 Valencia, Spain.
  • 5. 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: [email protected].
  • 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: [email protected].
PMID: 38677560 DOI: 10.1016/j.bmcl.2024.129770
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 Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ 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.

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