Advanced quantum and docking studies on the [3+2] cycloaddition of nitrile oxide with 1-Methyl-4-(Prop-1-en-2-yl)Cyclohex-1-ene: Exploring mechanisms and ADME properties

Abstract

This study employs Molecular Electron Density Theory (MEDT) to explore the [3+2] cycloaddition mechanisms involving 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene (2-R) and nitrile oxide (3-R). Density Functional Theory (DFT) calculations using the B3LYP/6-311(d,p) method were performed to determine reactivity indices, activation energies, and reaction energies. The conceptual DFT analysis indicates that 1-methyl-4-(prop-1-en-2-yl)cyclohex-1-ene 2-R acts as a nucleophile, while nitrile oxide 3-R functions as an electrophile. The reaction exhibits notable chemoselectivity and regioselectivity, supported by activation energies that align with experimental data. BET analysis suggests a one-step mechanism with asynchronous bond formation. Additionally, molecular docking studies of the reaction products against HIV-1 and COVID-19 reveal that the presence of oxygen and nitrogen atoms enhances the interaction energy with proteins, indicating potential therapeutic benefits.