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

Abstract

A series of cinnamic acid derivatives, amides (1-12) and esters (13-22), were synthesized, and structureactivity 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.Key words cinnamic acid amide; cinnamic acid ester; monoamine oxidase; cholinesterase; antioxidant; Alzheimer's disease Plant secondary metabolites are important sources of bioactive constituents that promote health. Natural products have long played a significant role in the development of new therapeutic leads. For example, phenolic compounds have been shown to prevent oxidative stress, a condition known to cause cell injury and death and to exacerbate the development of several age-related chronic pathologies like cancer, and neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.

Quantitative Structure–Cytotoxicity Relationship of Cinnamic Acid Phenetyl Esters

“…Culture plastic dishes and plates (96-well) were purchased from Becton Dickinson (Franklin Lakes, NJ, USA). [3], (2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid 2-(4-hydroxyphenyl)ethyl ester [4], (2E)-3-(4-hydroxyphenyl)-2-propenoic acid 2-(4-hydroxyphenyl)ethyl ester [5], (2E)-3-(3,4-dihydroxyphenyl)-2-propenoic acid 2-(4-hydroxyphenyl)ethyl ester [6], (2E)-3-phenyl-2-propenoic acid 2-(4hydroxyphenyl)ethyl ester [7], (2E)-3-(4-hydroxyphenyl)-2-propenoic acid 2-phenylethyl ester [8], (2E)-3-(3,4-dihydroxyphenyl)-2propenoic acid 2-phenylethyl ester [9], (2E)-3-phenyl-2-propenoic acid 2-phenylethyl ester [10] were synthesized by the condensations of cinnamic acid derivatives with selected phenethylalcohol derivatives, according to previous methods (4). All compounds were dissolved in DMSO at 40 mM and stored at -20˚C before use.…”

Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins

“…The first two HCA esters exhibited anti-atherosclerotic activity via inhibitory effects on acyl-CoA:cholesterol acyltransferase involved in cellular cholesterol storage and transport, and inhibition of LDL-oxidation and high-density lipoprotein particle size rearrangement [ 85 ]. The same coupling method (for the synthesis of amides) or alternative esterification utilizing diisopropyl azodicarboxylate and triphenylphosphine was used for preparation of a series of caffeic, ferulic and p -coumaric acids amides with biogenic amines (serotonin, dopamine, tyramine, vanillylamine) or esters with 3,4-dihydroxyphenethyl, 4-hydroxyphenethyl, and phenethyl alcohols [ 86 ]. Compounds containing catechol, o -methoxyphenol or 5-hydroxyindole moieties exhibited potent 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity (amides more potent than esters).…”

“…Compounds containing catechol, o -methoxyphenol or 5-hydroxyindole moieties exhibited potent 1,1-diphenyl-2-picrylhydrazyl free radical scavenging activity (amides more potent than esters). Some HCA derivatives also showed potent and selective MAO-B (phenethyl ( E )-3-(4-hydroxyphenyl)acrylate being the most potent one) or moderate BChE (e.g., 3,4-dihydroxyphenethyl ( E )-3-(4-hydroxyphenyl)acrylate) inhibitory activity [ 86 ]. The synthesis of phenethyl E -3-(4-hydroxy-3-methoxyphenyl)acrylate and E -3-(4-hydroxy-3-methoxyphenyl)- N -phenethylacrylamide from ferulic acid with phenethyl alcohol and phenethylamine, respectively, was performed via indirect reaction, including acetylation for hydroxyl group protection, acid chloride formation, esterification/amidation, and deacetylation as a deprotection reaction [ 87 ].…”

“…As previously described, esters and amides of coumaric, ferulic and caffeic acid possess numerous biological activities, e.g., antioxidant [ 82 , 83 , 86 , 89 , 94 , 95 , 96 ], anticancer [ 78 , 87 , 92 ], antibacterial [ 82 , 97 , 98 , 99 ], antifungal [ 100 , 101 , 102 ], antiviral [ 82 , 90 , 103 ], anti-inflammatory [ 104 , 105 , 106 ], and many other activities [ 84 , 107 , 108 ]. The most commonly described health beneficial properties of HCAs and their derivatives is antioxidant activity due to the phenolic hydroxyl group(s) on the main aromatic ring, which possess(es) the ability to react with free radicals and reactive oxygen species forming a resonance-stabilized phenoxyl radical.…”

Unexpected cytotoxicity of a triisopropylsilylated syringaldehyde derived cinnamic acid amide

“…During the last years, compounds holding a cinnamoyl scaffold attracted attention because of their biological activities combined with low toxicity [3][4][5][6][7][8] . However, several of these compounds have also shown cytotoxic [9][10][11][12][13][14] as well as antimicrobial [15][16][17][18][19][20] and anti-oxidant properties [21][22][23][24][25][26] . Also, cinnamic acid derivatives have been used as valuable starting materials for the synthesis of peroxisome proliferatoractivated receptors (PPAR).…”