Caffeic acid is a naturally occurring phenolic compound that is found in many fruits, vegetables, and herbs (e.g. sage), including coffee. Caffeic acid and its analogues have attracted much attention and have been studied in recent years because of their antiviral, anti-inflammatory, and neuroprotective properties, and their antioxidant effects. In particular, their antioxidative effects can be used for either the prevention of oxidative rancidity in foods or the treatment of diseases related to reactive oxygen species, such as stroke and Alzheimer’s diseases. However, since caffeic acid is not approved for direct use in food, due to it being a suspected human carcinogen based on testing in mice, there is still a need to develop an analogue that has similar biological properties. Bioisosterism is considered to be a powerful method for selecting molecular groups for drug design and lead-compound development. By the application of bioisosterism, we previously found that replacing the catechol moiety in dopamine with 1-hydroxy-2-pyridone analogues resulted in similar dopaminergic activity. Based on those results, we replaced the functional catechol moiety in caffeic acid with 1-hydroxy-2-pyridone systems whose isosteric and isoelectric character are considered to be equivalent. Therefore, they are interchangeable in terms of their contributions to biological activity. The antioxidant activities of the synthesized 1-hydroxy-2-pyridone analogues and caffeic acid were measured using the previously reported DPPH method, and the results are shown in Table 6. Although caffeic acid showed potent radical scavenging activity, the 1-hydroxy-2-pyridone analogues did not show any activity. These results clearly indicate that the antioxidant activity of caffeic acid is mainly attributed to the catechol moiety.
In conclusion, two 1-hydroxy-2-pyridone analogues of caffeic acid were successfully synthesized from the corresponding methoxynicotinaldehydes and it was found that the analogues revealed no antioxidant activities.
