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<p>This study investigates the [3 + 2] cycloaddition (32CA) reaction between Glutaraldehyde-N-aryl nitrone (<b>GN-1</b>) and Cinnamaldehyde (<b>CA-2</b>) to elucidate its mechanistic pathway and biological relevance. Understanding this reaction is important because it leads to the synthesis of pharmacologically significant isoxazolidine derivatives, compounds with therapeutic potential. Using Density Functional Theory (DFT) within the framework of Molecular Electron Density Theory (MEDT), we explored the potential energy surface (PES) and identified four stereoisomeric routes. The <i>ortho</i>-<i>endo</i> pathway was found to be both thermodynamically (ΔG = − 8.92&#xa0;kcal.mol⁻¹) and kinetically the most favorable. Global Electron Density Transfer (GEDT) analysis indicated a forward electron density flux (FEDF) of 0.0594 e, confirming a polar mechanism. Electron Localization Function (ELF) and Bonding Evolution Theory (BET) analyses revealed asynchronous bond formation during the transition state. To explore biological potential, molecular docking against the EGFR L858R mutant (PDB ID: 2ITZ) showed that compound <b>IC-6</b> exhibited the strongest binding affinity (–10.19&#xa0;kcal.mol⁻¹). Molecular dynamics simulations (200 ns) confirmed the stability of the <b>IC-6</b>/EGFR complex, while absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated favorable pharmacokinetic and drug-likeness properties. Overall, this work provides quantitative mechanistic insight into the electron density reorganization governing the 32CA reaction and highlights the therapeutic potential of the resulting isoxazolidine derivatives. The novelty of this research lies in the integrated MEDT, ELF, molecular dynamics (MD) approach, which advances beyond previous studies by correlating electron density transfer with biological activity and drug behavior.</p>

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Mechanistic insights into (3 + 2) cycloaddition of glutaraldehyde-N-Aryl nitrone with cinnamaldehyde: Electron density, docking, and molecular dynamics analysis

  • 期刊论文

  • 发表日期：

    2026年1月16日

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  • Raad Nasrullah Salih,
  • Haydar Mohammad-Salim,
  • Muheb Algso

摘要

This study investigates the [3 + 2] cycloaddition (32CA) reaction between Glutaraldehyde-N-aryl nitrone (GN-1) and Cinnamaldehyde (CA-2) to elucidate its mechanistic pathway and biological relevance. Understanding this reaction is important because it leads to the synthesis of pharmacologically significant isoxazolidine derivatives, compounds with therapeutic potential. Using Density Functional Theory (DFT) within the framework of Molecular Electron Density Theory (MEDT), we explored the potential energy surface (PES) and identified four stereoisomeric routes. The ortho-endo pathway was found to be both thermodynamically (ΔG = − 8.92 kcal.mol⁻¹) and kinetically the most favorable. Global Electron Density Transfer (GEDT) analysis indicated a forward electron density flux (FEDF) of 0.0594 e, confirming a polar mechanism. Electron Localization Function (ELF) and Bonding Evolution Theory (BET) analyses revealed asynchronous bond formation during the transition state. To explore biological potential, molecular docking against the EGFR L858R mutant (PDB ID: 2ITZ) showed that compound IC-6 exhibited the strongest binding affinity (–10.19 kcal.mol⁻¹). Molecular dynamics simulations (200 ns) confirmed the stability of the IC-6/EGFR complex, while absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions indicated favorable pharmacokinetic and drug-likeness properties. Overall, this work provides quantitative mechanistic insight into the electron density reorganization governing the 32CA reaction and highlights the therapeutic potential of the resulting isoxazolidine derivatives. The novelty of this research lies in the integrated MEDT, ELF, molecular dynamics (MD) approach, which advances beyond previous studies by correlating electron density transfer with biological activity and drug behavior.