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

[Display omitted] •Synthesis and PPAR activity of 2-prenylated benzopyrans and quinolines.•γ,δ-Unsaturated ester of benzopyran 5a and quinoline 4b showed pan-PPAR agonism.•2-Prenylated quinoline 4b as a first-in-class promising lead for metabolic syndrome. We have previously reported the total synth...

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Published in:Bioorganic & medicinal chemistry letters 2024-07, Vol.106, p.129770-129770, Article 129770
Main Authors: Villarroel-Vicente, Carlos, García, Ainhoa, Zibar, Khamis, Schiel, María Ayelén, Ferri, Jordi, Hennuyer, Nathalie, Enriz, Ricardo D., Staels, Bart, Cortes, Diego, Cabedo, Nuria
Format: Article
Language:English
Subjects:
2-Prenylated benzopyrans
2-Prenylated quinolines
Anti-inflammatory agents
MAFLD
Metabolic syndrome
PPAR
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Summary:[Display omitted] •Synthesis and PPAR activity of 2-prenylated benzopyrans and quinolines.•γ,δ-Unsaturated ester of benzopyran 5a and quinoline 4b showed pan-PPAR agonism.•2-Prenylated quinoline 4b as a first-in-class promising lead for metabolic syndrome. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2024.129770