Hydroxycinnamic acids (HCAs) are important phytochemicals possessing significant biological properties.
Several investigators have studied in vitro antioxidant activity of HCAs in detail. In this review, we have gathered the
studies focused on the structure-activity relationships (SARs) of these compounds that have used medicinal chemistry to
generate more potent antioxidant molecules. Most of the reports indicated that the presence of an unsaturated bond on the
side chain of HCAs is vital to their activity. The structural features that were reported to be of importance to the antioxidant
activity were categorized as follows: modifications of the aromatic ring, which include alterations in the number and
position of hydroxy groups and insertion of electron donating or withdrawing moieties as well as modifications of the carboxylic
function that include esterification and amidation process. Furthermore, reports that have addressed the influence
of physicochemical properties including redox potential, lipid solubility and dissociation constant on the antioxidant activity
were also summarized. Finally, the pro-oxidant effect of HCAs in some test systems was addressed. Most of the investigations
concluded that the presence of ortho-dihydroxy phenyl group (catechol moiety) is of significant importance to
the antioxidant activity, while, the presence of three hydroxy groups does not necessarily improve the activity. Optimization
of the structure of molecular leads is an important task of modern medicinal chemistry and its accomplishment relies
on the careful assessment of SARs. SAR studies on HCAs can identify the most successful antioxidants that could be useful
for management of oxidative stress-related diseases.