• Hypochlorous acid scavenger activity of nitrones: an experimental and theoretical study

FRIDA DIMARCO; ESTEBAN G. VEGA-HISSI; MATIAS ANDRADA,; SANDRA GOMEZ-MEJIBA; DARIO RAMIREZ; JUAN .C GARRO MARTINEZ

Conferencia; XLI Reunión Anual de la Sociedad de Biología de Cuyo; 2023

Hypochlorous acid (HOCl) is a hydrohalogenated reactive oxygen species (ROS) that is produced in living organisms, in the presence of hydrogen peroxide (H2O2). When HOCl is produced in excessive amounts, it can oxidize the body's own biomolecules such as proteins, lipids, and nucleic acids, leading to tissue damage and the appearance of certain cardiovascular and neurodegenerative diseases in addition to others such as atherosclerosis, arthritis, cancer. Groups of organic molecules called nitrones are of interest in this field. Nitrones are N-oxides of imines and have a molecular structure of the type R1R2C=N+-O- R3 (where R1, R2 and R3 = an alkyl group and R1 or R2=H). Nitrone functional group (C=N+-O-) is formed by three atoms that share four π electrons, this structure is responsible for the reactivity and turns them into organic compounds with highly reactive against different oxidizing species and free radicals. The objective of this research is to determine the HOCl scavenger activity of six of nitrones, which contain in their structure a substituted five-membered ring (furan or thiophene) and to explain the experimental activity by computational methods. Experimentally, four nitrones showed HOCl scavenging activity with IC50 values ranging from 26.15 to 61.20 nM, while two nitrones were inactive. To explain their activity, a reaction mechanism based on a nucleophilic attack of the hypochlorous anion (pKa=7.46) on the α-carbon of each Nitrone was proposed. In addition using DFT calculations, the rate constants (k), HOMO and LUMO energies, and various reactivity indices such as electronic chemical potential (μ), chemical hardness (η), and overall electrophilicity (ω) were calculated. We found the rate constants and the global electrophilicity showed a high correlation with the activity. In addition, we performed a SAR analysis to elucidate the influence of the substituents presented in the six nitrones.