Abdellah Zeroual

In this article, the 1,3-dipolar cycloaddition (1,3-DC) reactions between 4-acyl-1H-pyrrole-2,3-diones fused at the [e]-side with a heterocyclic moiety (FPDs) and diphenylnitrone are studied using Molecular Electron Density Theory (MEDT) at different computational levels. An analysis of the global reactivity descriptors has determined the role of the reagents. FPDs will act as electrophiles, while diphenylnitrone will be a nucleophile. It was found that the reactions proceed according to a one-step but asynchronous mechanism. Additionally, based on the Bonding Evolution Theory (BET) analysis of the model 1,3-DC reaction between FPDs 1b and diphenylnitrone 2, we can distinguish eight different phases. The formation of the first C1-O5 single bond takes place in phase VII through the disappearance of the V(C1) monosynaptic basin and the depopulation of the V″(O5) monosynaptic basin, while the formation of the second C2-C3 single bond begins at the last phase of the reaction through the connection of two V(C2) and V(C3) monosynaptic basins. Based on this, we can classify this reaction as a “one-step two-stage” process. Furthermore, molecular dynamics (MD) simulation analysis up to 100 ns demonstrated the stability of both the 2P3B–Ligand1 and 2P3B–Zidovudine complexes. An enhancer of shape compression was generated for ligand1, whereas Zidovudine generated a more packed and stable hydrogen bond network that would allow a better occupancy of the active site.

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.

The theoretical study of the reaction between cinnamaldehyde and nitrile-imine, conducted using the MEDT/B3LYP/6-311G(d,p) method, clarified the nucleophilic and electrophilic roles of the two components, demonstrating that the dipole acts as a nucleophile, while the dipolarophile acts as an electrophile. Parr functions indicate that the double bond of the dipolarophile is identified as the most reactive site, providing a clear explanation for the chemoselectivity observed in the experiment. Furthermore, the study of interactions reveals that the formation of the first bond involves the most electrophilic carbon. The analysis of the products and transition states reveals that one of the products is thermodynamically favored, while a certain transition state represents the dominant kinetic pathway.