Synthesis of Amide and Ester Derivatives of Cinnamic Acid and Its Analogs : Evaluation of Their Free Radical Scavenging and Monoamine Oxidase and Cholinesterase Inhibitory Activities

• Published in: Chemical and Pharmaceutical Bulletin Vol. 65; no. 11; pp. 1020 - 1027
• Main Authors: Koichi Takao, Kazuhiro Toda, Takayuki Saito, Yoshiaki Sugita
• Format: Journal Article
• Language: Japanese
• Published: Pharmaceutical Society of Japan 01.11.2017
• ISSN: 0009-2363

A series of cinnamic acid derivatives, amides (1 - 12) and esters (13 - 22), were synthesized, and structure-activity relationships for antioxidant activity, and monoamine oxidases (MAO) A and B, acetylcholinesterase, and butyrylcholinesterase (BChE) inhibitory activities were analyzed. Among the synthesized compounds, compounds 1 - 10, 12 - 18, and rosmarinic acid (23), which contained catechol, o-methoxyphenol or 5-hydroxyindole moieties, showed potent 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity. Compounds 9 - 11, 15, 17 - 22 showed potent and selective MAO-B inhibitory activity. Compound 20 was the most potent inhibitor of MAO-B. Compounds 18 and 21 showed moderate BChE inhibitory activity. In addition, compound 18 showed potent antioxidant activity and MAO-B inhibitory activity. In a comparison of the cinnamic acid amides and esters, the amides exhibited more potent DPPH free radical scavenging activity, while the esters showed stronger inhibitory activities against MAO-B and BChE. These results suggested that cinnamic acid derivatives such as compound 18, p-coumaric acid 3,4-dihydroxyphenethyl ester, and compound 20, p-coumaric acid phenethyl ester, may serve as lead compounds for the development of novel MAO-B inhibitors and candidate lead compounds for the prevention or treatment of Alzheimer's disease.