A Theoretical Antioxidant Mechanism for Cytoprotective Effect of p-AcetamideSalicylate Derivatives against Free Radical Initiator AAPH in Human Erythrocytes

Valéria Barros,Rosivaldo Borges,Fernanda Melo,Anderson Lima,Glaécia Pereira,Ana Carolina De Jesus,Albérico Da Silva,Sirlene Ota

doi:10.21577/0103-5053.20210033

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 physicalchemical properties can be involved. The molecular association approach provides protective compounds more effective than SAC.

Highlights

Recent studies[1] suggest that aggregation of platelets from patients with coronary artery and cerebrum-vascular disease may be resistant to low-dose aspirin treatment, which may promote plaque-associated thrombus formation
The structure-capacity relationship of p-aminophenol and salicylate association derivatives using five phenolic derivatives: ACP, salicylic acid (SAC), BZL, ASL, and benzamide-salicylic acid (BSL) showed that these compounds, that here are assessed for their antioxidant capacity in human erythrocytes, differ mainly in the carbonyl or acylamide substituent group at the ortho and para positions, respectively
Benzaminophen showed a potential scavenger capacity or small hemolysis percentage when compared to acetaminophen

Summary

Introduction

Recent studies[1] suggest that aggregation of platelets from patients with coronary artery and cerebrum-vascular disease may be resistant to low-dose aspirin treatment, which may promote plaque-associated thrombus formation. The pre-incubation with ACP or TLX inhibits AAPH-induced RBC hemolysis as a function of the drug concentration and SAC has no apparent effect. Phenolic compounds have been found to be effective antioxidants in biological systems and their effectiveness depends on the stability of phenoxyl radical formed in the reaction, but of their electron or hydrogen donating capacities.[17,25,26] ACP and SAC, closely related to the molecular structure exert very different activities as free-radical scavengers.

Results

Conclusion