2. Academic Validation
  3. Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome

Development of 2- and 3-prenylated quinolines and tetrahydroquinolines with PPAR activity: From hit to lead and a novel pan-PPAR agonist as a potential candidate for metabolic syndrome

  • Bioorg Chem. 2025 Jun 15:160:108450. doi: 10.1016/j.bioorg.2025.108450.
Carlos Villarroel-Vicente 1,  María Martínez-Solsona 2,  Ainhoa García 1,  Laura Vila 3,  Khamis Zibar 4,  María Ayelén Schiel 5,  Nathalie Hennuyer 6,  Dorien Clarisse 7,  Ricardo D Enriz 5,  Bart Staels 4,  Karolien De Bosscher 7,  Herminia González-Navarro 2,  Diego Cortes 1,  Nuria Cabedo 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Valencia, 46100, 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; Department of Biochemistry and Molecular Biology, University of Valencia, 46010, Valencia, Spain.
  • 3 Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, 46010, Valencia, Spain.
  • 4 Univ Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France.
  • 5 Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis-IMIBIO-SL-CONICET, Chacabuco 915, San Luis, Argentina.
  • 6 Univ Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U-1011-EGID, F-59000 Lille, France. Electronic address: nathalie.hennuyer@pasteur-lille.fr.
  • 7 Translational Nuclear Receptor Research lab, VIB Center for Medical Biotechnology, VIB, Ghent, Belgium; Translational Nuclear Receptor Research lab, Faculty of Medicine and Health Sciences, Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
  • 8 Department of Pharmacology, University of Valencia, 46100, Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, 46010, Valencia, Spain. Electronic address: nuria.cabedo@uv.es.
PMID: 40215945 DOI: 10.1016/j.bioorg.2025.108450
Abstract

Peroxisome proliferator-activated receptors (PPARs) represent highly valuable therapeutic targets for the treatment of type 2 diabetes (T2D) and hypertriglyceridemia, both closely linked to the development of metabolic syndrome (MetS). Herein, we have synthesised two series of prenylated quinolines either at the 2- or 3-position, and their tetrahydroquinolines (THQs) using the Friedländer cyclodehydration, followed by the Grignard reaction and subsequent Johnson-Claisen rearrangement. All the synthesised compounds were evaluated in vitro for activity at each of the human PPAR, their cytotoxicity, their capacity to activate the PPAR target gene PDK4 and their anti-inflammatory effects. The compounds with a seven‑carbon prenylated side chain at the 2-position, such as THQ 5a and 6a (series a), displayed similar pan-PPAR agonism to the 2-prenylated benzopyran analogue BP-2. The compounds with a six‑carbon prenylated side chain at the 3-position, such as 5b and 6b (series b), had stronger selectivity for PPARα activation. The luciferase assays of the PPRE-driven gene PDK4 showed that THQ 5a, 5b, and quinoline 8a increased the transactivation of the PDK4-Luc + reporter, which confirmed their potential capacity to promote lipid metabolism. THQs 5a, 5b, and quinoline 8b repressed the transactivation of the TNFα-dependent NF-κB-Luc + reporter and efficiently down-regulated the transcription of several TNFα-induced pro-inflammatory genes. Furthermore, THQ 5a improves total Cholesterol, non-HDL-c, HOMA-IR index and lipid metabolism in ob/ob mice, without increasing liver Enzymes. Our results suggest that THQ 5a is a promising lead compound in the development of agents for treating metabolic disorders (T2D and dyslipidaemias), which may prevent further cardiovascular comorbidities associated with MetS.

Keywords

Friedländer reaction; Metabolic disorders; Molecular modelling; PPAR agonists; Quinoline synthesis; ob/ob mice.

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