Synthesis of benzopyran derivatives as PPARα and/or PPARγ activators

• Published in: Bioorganic & medicinal chemistry 2019-12, Vol.27 (24), p.115162-115162, Article 115162
• Main Authors: Bermejo, Almudena, Barrachina, Isabel, El Aouad, Noureddine, Franck, Xavier, Chahboune, Nadia, Andreu, Inmaculada, Figadère, Bruno, Vila, Laura, Hennuyer, Nathalie, Staels, Bart, Dacquet, Catherine, Caignard, Daniel H., Sanz, María-Jesús, Cortes, Diego, Cabedo, Nuria
• Format: Article
• Language: English
• Subjects: Benzopyrans; Chemical Sciences; Polycerasoidol; PPARα agonism; PPARγ agonism
• ISSN: 0968-0896; 0960-894X; 1464-3391
• DOI: 10.1016/j.bmc.2019.115162

[Display omitted] •Benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol derivatives were synthetized.•Four benzopyran-4-ones and three dihydrobenzopyrans activated hPPARα.•A chlorinated benzopyran-4-one with C-5 alkyl side chain activated hPPARγ.•Benzopyran nucleus and the length of side chain play a key role in PPAR activation. We describe the synthesis of 26 compounds, small polycerasoidol analogs, that are Lipinski’s rule-of-five compliant. In order to confirm key structural features to activate PPARα and/or PPARγ, we have adopted structural modifications in the following parts: (i) the benzopyran core (hydrophobic nucleus) by benzopyran-4-one, dihydrobenzopyran or benzopyran-4-ol; (ii) the side chain at 2-position by shortening to C3, C4 and C5-carbons versus C-9-carbons of polycerasoidol; (iii) the carboxylic group (polar head) by oxygenated groups (hydroxyl, acetoxy, epoxide, ester, aldehyde) or non-oxygenated motifs (allyl and alkyl). Benzopyran-4-ones 6, 12, 13 and 17 as well as dihydrobenzopyrans 22, 24 and 25 were able to activate hPPARα, whereas benzopyran-4-one (7) with C5-carbons in the side chain exhibited hPPARγ agonism. According to our previous docking studies, SAR confirm that the hydrophobic nucleus (benzopyran-4-one or dihydrobenzopyran) is essential to activate PPARα and/or PPARγ, and the flexible linker (side alkyl chain) should containg at least C5-carbon atoms to activate PPARγ. By contrast, the polar head (“carboxylic group”) tolerated several oxygenated groups but also non-oxygenated motifs. Taking into account these key structural features, small polycerasoidol analogs might provide potential active molecules useful in the treatment of dyslipidemia and/or type 2 diabetes.