Myeloperoxidase Inhibitory and Antioxidant Activities of (E)-2-Hydroxy-α-aminocinnamic Acids Obtained through Microwave-Assisted Synthesis

Myeloperoxidase (MPO) is an enzyme present in human neutrophils, whose main role is to provide defenses against invading pathogens. However, highly reactive oxygen species (ROS), such as HOCl, are generated from MPO activity, leading to chronic diseases. Herein, we report the microwave-assisted synthesis of a new series of stable (E)-(2-hydroxy)-alpha-aminocinnamic acids, in good yields, which are structurally analogous to the natural products (Z)-2-hydroxycinnamic acids. The radical scavenging activity (RSA), MPO inhibitory activity and cytotoxicity of the reported compounds were evaluated. The hydroxy derivatives showed the most potent RSA, reducing the presence of DPPH and ABTS radicals by 77% at 0.32 mM and 100% at 0.04 mM, respectively. Their mechanism of action was modeled with BDEOH, IP and Delta EH-L theoretical calculations at the B3LYP/6 - 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC50 values comparable to indomethacin and 5-ASA, but cytotoxicities below 15% at 100-200 mu M. Docking calculations revealed that they reach the amino acid residues present in the distal cavity of the MPO active site, where both the amino and carboxylic acid groups of the alpha-aminopropenoic acid arm are structural requirements for anchoring. (E)-2-hydroxy-alpha-aminocinnamic acids have been synthesized for the first time with a reliable method and their antioxidant properties demonstrated.

Automated summary

A novel synthesis method for (E)-2-hydroxy-alpha-aminocinnamic acids was reported, demonstrating their antioxidant properties and ability to scavenge free radicals, inhibit MPO, with low cytotoxicity. The compounds show promising potential for further exploration as therapeutic agents for chronic diseases related to MPO activity.