Inhibition of horseradish peroxidase catalytic activity by new 3-phenylcoumarin derivatives: Synthesis and structure–activity relationships

• Published in: Bioorganic & medicinal chemistry 2007-02, Vol.15 (3), p.1516-1524
• Main Authors: Kabeya, Luciana M., de Marchi, Anderson A., Kanashiro, Alexandre, Lopes, Norberto P., da Silva, Carlos H.T.P., Pupo, Mônica T., Lucisano-Valim, Yara M.
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Catechol; Coumarin; Coumarins - chemical synthesis; Coumarins - chemistry; Coumarins - pharmacology; Docking; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes and enzyme inhibitors; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Fundamental and applied biological sciences. Psychology; General and cellular metabolism. Vitamins; Horseradish peroxidase; Horseradish Peroxidase - antagonists & inhibitors; Medical sciences; Models, Molecular; Molecular Structure; Oxidoreductases; Pharmacology. Drug treatments; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2006.10.068

Twenty hydroxylated and acetoxylated 3-phenylcoumarins were synthesized, and the structure–activity relationships were investigated by evaluating the ability of these compounds to modulate horseradish peroxidase (HRP) catalytic activity and comparing the results to four flavonoids (quercetin, myricetin, kaempferol and galangin), previously reported as HRP inhibitors. It was observed that 3-phenylcoumarins bearing a catechol group were as active as quercetin and myricetin, which also show this substituent in the B-ring. The presence of 6,2′-dihydroxy group or 6,7,3′,4′-tetraacetoxy group in the 3-phenylcoumarin structure also contributed to a significant inhibitory effect on the HRP activity. The catechol-containing 3-phenylcoumarin derivatives also showed free radical scavenger activity. Molecular modeling studies by docking suggested that interactions between the heme group in the HRP active site and the catechol group linked to the flavonoid B-ring or to the 3-phenyl coumarin ring are important to inhibit enzyme catalytic activity.