4'-Aminochalcones as novel inhibitor of the chlorinating activity of myeloperoxidase

Excessive activation of neutrophils generates reactive oxygen species (ROS) and secretion of primary granular enzymes, such as myeloperoxidase (MPO), which is implicated in numerous inflammatory diseases. The purpose of this study has been evaluating the activity of chalcones as inhibitors of the chlorinating activity of MPO. Besides, cytotoxic properties, scavenger capacity and oxidation potential were measured. Neutrophils were isolated from the blood from healthy donors by Ficoll-Paque density gradient centrifugation. Several natural chalcones were tested and were inactive. However the synthetic 4'-aminochalcone (1); 4'-amino-4-fluorochalcone (2); 4'-amino-4-methylchalcone (3) were potent inhibitors of MPO activity, as potent as 5-fluorotryptamine, a compound considered an excellent inhibitor of the chlorinating activity of MPO: (1) IC₅₀=0.265±0.036µM; (2) IC₅₀=0.250±0.081µM; (3) IC₅₀=0.250±0.012 and 5-fluorotryptamine IC₅₀=0.192±0.012µM. These compounds were not toxic to neutrophils at concentrations lower than 100µM as evaluated by the trypan blue exclusion assay. The compounds 1–3 presented high oxidation potential (E _pa1≈0.80V) and low scavenger capacity against DPPH and HOCl. Hence, we propose that 4-aminochalcones, a derivative of non-toxic chalcones, could provide the basis designing novel and specific inhibitors of MPO, a target for the development of anti-inflammatory agents.

Acknowledgements: FAPESP and CNPq.