Study of 1,3-Dipolar Cycloaddition Between 4-Acyl-1H-pyrrole-2,3-diones Fused at the [e]-Side with a Heterocyclic Moiety and Diphenylnitrone: A Comprehensive MEDT, Docking Approach and MD Simulation

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 <b>1b</b> and diphenylnitrone <b>2</b>, 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 "<i>one-step two-stage</i>" 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.