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

TESIO A. Y.; BURTON G.; LUNA L.; DURAN F. J.; MARTINEZ M. D.; FERESIN G. E.

JOURNAL OF PHARMACY AND PHARMACOLOGY

PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN

Año: 2016 vol. 68 p. 233 - 244

0022-3573

AbstractObjectives Many natural antioxidants have poor pharmacokinetic propertiesthat impair their therapeutic use. For hydroxycinnamic acids (HCAs) and otherphenolic antioxidants, their major drawback is their low lipophilicity and a rapidmetabolism. The difluoromethyl group may be considered as a ?lipophilic hydroxyl?due to its hydrogen bond donor and acceptor properties; this prompted usto assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing thelipophilicity of HCAs.Methods Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c)related to caffeic acid were synthesized and their antioxidant activity evaluatedby chemical (FRAP, DPPH scavenging, inhibition of b-carotene bleaching, at1?200 lM), electrochemical (differential pulse voltammetry, cyclic voltammetry)and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and50 lM) assays.Key findings Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assaysand only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemicalactivity although with high redox potentials. Compounds 4a,b and 5a,bwere active in the inhibition of b-carotene bleaching assay and all analoguesinhibited lipid peroxidation in the human erythrocytes assay.Conclusions Lipophilic difluoromethyl-substituted cinnamic esters retain radicalscavenging capabilities that prove useful to confer antioxidant properties in anon-polar environment