Hypochlorous Acid Scavenger Activity of Heteroaryl‐Nitrones. A Combined Experimental and Theoretical Study

Abstract

AbstractThe HClO scavenging capacity of a group of heteroaryl‐nitrones (HA−N) that contain a substituted five‐membered ring (furan or thiophene) in their structure was studied using experimental and quantum computational methods. Experimentally, it was found that four HA−N showed scavenging activity with IC50 values ranging from 26.15 to 61.20 nM, while two HA−N were found to be inactive. To explain the HClO activity of the analyzed HA−N, we proposed and investigated a reaction mechanism based on a nucleophilic attack by the hypochlorous anion (pKa=7.46) on α‐carbon of each HA−N, taking into account the results obtained by calculating the electrostatic potential. For this purpose, we used the B3LYP functional of the density functional theory (DFT) and the basis set 6‐311+G(d,p) included in the Gaussian 09 program. We calculated the rate constants (k), the HOMO and LUMO energies, and several reactivity indices such as the electronic chemical potential (μ), chemical hardness (η), and global electrophilicity (ω) to establish a quantified relationship with the observed activities. The SAR analysis and the correlation between the rate constants and the global electrophilicity with the HClO scavenging activity allow us to explain the experimental activity presented by the six HA−N analyzed here.