Docking Survey, ADME, Toxicological Insights, and Mechanistic Exploration of the Diels–Alder Reaction Between Hexachlorocyclopentadiene and Dichloroethylene

Abstract

The Diels–Alder (DA) reaction between hexachlorocyclopentadiene and 1,2-dichloroethylene has been studied using the Molecular Electron Density Theory (MEDT) through Density Functional Theory (DFT) calculations at the B3LYP/6−31G(d) level. The electronic structure of the reagents has been characterized through the electron localization function (ELF) and the conceptual DFT (CDFT). The DA reaction of hexachlorocyclopentadiene with 1,2-dichloroethylene proceeds via a synchronous or low asynchronous one-step mechanism. Based on the conducted research, a two-step mechanism with a biradical intermediate was completely ruled out. Bonding Evolution Theory (BET) study of the DA reaction shows that this reaction is topologically characterized by nine different phases. The reaction begins with the rupture of the double bonds in substrate molecules. Formation of the first CC single bond takes place in phase VII, while the second CC single bond takes place in phase IX. Formation of these two single bonds takes place by sharing the nonbonding electron densities of the two pairs of pseudoradical centers. In addition, this study evaluates some ligands as potential HIV-1 inhibitors. Docking results identified 5 and 5-F as the most promising candidates, surpassing AZT in theoretical affinity. ADME analysis revealed limitations in solubility and absorption for compounds 3, 4, and 5, while 5-F showed better solubility but low absorption. Toxicity concerns around 5-F suggest the need for risk management, while the other compounds require further safety assessment.