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Journal Articles Bioorganic and Medicinal Chemistry Letters Year : 2019

Synthesis of benzopyran derivatives as PPARα and/ or PPARγ activators


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.
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hal-02347291 , version 1 (05-11-2019)



Almudena Bermejo, Isabel Barrachina, Noureddine El Aouad, Xavier Franck, Nadia Chahboune, et al.. Synthesis of benzopyran derivatives as PPARα and/ or PPARγ activators. Bioorganic and Medicinal Chemistry Letters, 2019, 27 (24), pp.115162. ⟨10.1016/j.bmc.2019.115162⟩. ⟨hal-02347291⟩
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