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Synthesis and biological activity of fibrate-based acyl- and alkyl-phenoxyacetic methyl esters and 1,2-dihydroquinolines

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Abstract

A series of highly potent antihyperlipidemic agents constituted by a fibrate-based structure was recently reported by our group, whose synthesis started from isovanillin derivatives. In the interest of evaluating the bioisosteric effect of the vanillin-based isomers on their antihyperlipidemic activity, the present study focuses on the synthesis of 5-acyl-1-phenoxyacetic methyl esters 5ac and their saturated side-chain 5-alkyl-1-phenoxyacetates 6ac. Their strong in vivo effect was associated with the inhibition of HMG-CoA reductase. Since 1,2-dihydroquinolines inhibit this enzyme, a series of such heterocycles (9ad) was prepared by our efficient regioselective, one-step, solvent-free method. Apart from showing hypolipidemic activity in vivo, some of the compounds displayed antifungal, antioxidant and cytotoxic activity in vitro. The binding mode of four compounds at the active site of HMGRh was examined with docking simulations, observing an interaction with most of the amino acids targeted by simvastatin.

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Acknowledgements

We thank Dr Alberto Feliciano and Rsuini U. Gutiérrez for experimental support and Bruce Allan Larsen for proofreading the manuscript. AM, LG-S, MCC-L, FJ, OG-G, LV-T, ER-G, GC-C, FD, and JT gratefully acknowledge the financial support provided by SIP-IPN (grants 20160791, 20170902, 20180198, 20181332, 20181433, 20195228, 20195287, and 20195606) and CONACYT (grants 178319, 282033, CB-283225, A1-S-17131, and 300520). AF-B and CG-R are thankful to the UAEM for funding. MAV gratefully recognized the spectroscopy services provided by the National Laboratory of the Universidad de Guanajuato (UGUAA-CONACYT grant 260373). AP, AM, DAM, RIH-B, LR, CR-E, AR-V, JL, BR-A, and AS-J appreciate the graduate scholarship awarded by CONACYT, as well as the scholarship complements furnished by the SIP-IPN (BEIFI) and the Ludwig K. Hellweg Foundation. LG-S, MCC-L, FJ; LV-T, ER-G, GC-C, FD and JT are fellows of the EDI-IPN and COFAA-IPN programs.

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Correspondence to Germán Chamorro-Cevallos or Joaquín Tamariz.

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Pucheta, A., Mendieta, A., Madrigal, D.A. et al. Synthesis and biological activity of fibrate-based acyl- and alkyl-phenoxyacetic methyl esters and 1,2-dihydroquinolines. Med Chem Res 29, 459–478 (2020). https://doi.org/10.1007/s00044-019-02496-1

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Keywords

  • Antihyperlipidemic activity
  • 2-Acyl-1-hydroxyphenoxyacetic esters
  • 2-Alkyl-1-hydroxyphenoxyacetic esters
  • 1,2-Dihydroquinolines
  • HMG-CoA reductase
  • Antioxidant activity