A Molecular Electron Density Theory Study for the Synthesis of Spirocyclic and Tricyclic Isoxazolines and Their Molecular Docking Evaluation for Antituberculosis Activity

The [3 + 2] cycloaddition (32CA) reactions of aryl and heteroaryl nitrile oxides with (S)-(−)-β-pinene and (R)-(+)-α-pinene have been theoretically studied from the Molecular Electron Density Theory (MEDT) perspective and a molecular docking evaluation for the antituberculosis activity of the isoxazoline products. The studied 32CA reactions show activation Gibbs free energies between 23.8 and 31.6 kcal·mol⁻¹, consistent with their zwitterionic character and exclusive regioselectivity, in complete agreement with the experiments. Two-stage one-step mechanism with a very low polar character is predicted. The molecular mechanism has been established from the Bonding Evolution Theory (BET) analysis along the reaction path, showing early transition state structures, with weak non-covalent interactions indicated from the quantum theory of atom-in-molecules (QTAIM) analysis. The isoxazoline products for the 32CA reactions of (S)-(−)-β-pinene show appreciable binding affinities towards Mycobacterium tuberculosis transcriptional repressor EthR2, revealing them as promising candidates with antituberculosis potential.