Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates

The Journal of Pharmacy and Pharmacology
Mario D MartínezGerardo Burton

Abstract

Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a 'lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1-200 μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 μm) assays. Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. Lipophilic...Continue Reading

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Citations

Jan 5, 2017·Journal of Medicinal Chemistry·Yossi ZafraniSigal Saphier
Jun 5, 2020·Angewandte Chemie·Xiaojun ZengWei Liu
Feb 16, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mario David MartínezGerardo Burton
Sep 26, 2017·Chemistry : a European Journal·Maria V IvanovaThomas Poisson
Jun 3, 2021·Nature Communications·Aijie CaiWei Liu
May 14, 2020·Organic Letters·Zhichao LuGerald B Hammond
Nov 23, 2019·Journal of the American Chemical Society·Xiaojun ZengWei Liu
Nov 9, 2021·Chemical Communications : Chem Comm·Enzo NobileTatiana Besset

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