A theoretical antioxidant mechanism for cytoprotective effect of p-acetamidesalicylate derivatives against free radical initiator AAPH in human erythrocytes

Abstract

The molecular mechanism of cytoprotective effect on human erythrocytes of aminophenol and salicylates associated derivatives was related to their antioxidant capacity. The oxidative hemolysis induced by water-soluble free-radical initiator 2,2'-azobis-(2-amidine-propane)-dihydrochloride (AAPH) was inhibited by drug candidates named benzaminophen (BZL), salicytamide or 5-acetamide-salicylic acid (ASL), and salibenzamide or 5-benzamide-salicylic acid (BSL) when compared to their parents salicylic acid (SAC) and acetaminophen (ACP). Trolox (TLX) was the most powerful compound and used as positive control. BZL showed a potent effect followed by ACP > BSL > ASL. SAC did not show protective effect in any evaluated concentrations. These results are in accordance with the molecular mechanism by using theoretical calculation of single electron transfers (SET), hydrogen atom transfers (HAT), and sequential proton loss electron transfer (SPLET) by means of DFT/B3LYP/6-31++G(d,p) level of theory. [1,5] Hydrogen shift between carboxyl and phenol moieties and electronic properties related to pKa and other physical-chemical properties can be involved. The molecular association approach provides protective compounds more effective than SAC.