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<p>The Molecular Electron Density Theory (MEDT) has been used to study the [3 + 2] cycloaddition (32CA) reaction of an <i>N</i>-<i>t</i>-butyl nitrone with a cyanoacetylene at the B3LYP/6–311 + + G(d,p) computational level. However, the DFT-based reactivity indices show that <i>N</i>-<i>t</i>-butyl nitrone is a strong nucleophile, while cyanoacetylene exhibits strong electrophile properties. The reaction takes place in two paths (a and b). In addition, in the Potential Energy Surface (PES) analysis, energy profiles show that path a is more favorable and more spontaneous, with both products forming through exothermic reactions. Moreover, Bonding Evolution Theory (BET) analysis revealed that these 32CA reactions proceed via the coupling of pseudoradical centers, with the formation of new C–C and C–O covalent bonds occurring only after the transition states (TS). It is interesting to note that, with the electronic flux from the <i>N</i>-<i>t</i>-butyl nitrone to the cyanoacetylene, a low polarity of the forward electron density transfer (FEDF) type is predicted by the global electron density transfer (GEDT) between 0.1169 and 0.14862 e. In particular, in this one-step zw-type 32CA reaction, the atom-in-molecules (AIM) topological characterization of the electron density at the TSs structures and the electron localization function (ELF) are not considered. Certainly, the major cervical intraepithelial neoplasia or (1CIN) protein underwent a docking survey for cycloadducts 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-4-carbonitrile and 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-5-carbonitrile. The analysis shows that cycloadducts 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-4-carbonitrile have higher binding energy, while cycloadducts 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-5-carbonitrile have lower binding energy than the co-crystal ligand. Finally, the drug-likeness assessment and ADMET predictions were demonstrated for products 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-4-carbonitrile and 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-5-carbonitrile. The ADMET analysis of molecule 2-(<i>tert</i>-butyl)-2,3-dihydroisoxazole-4-carbonitrile is the most promising drug-like molecule.</p> Graphical abstract <p></p>

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Mechanistic study of N-t-butyl nitrone and cyanoacetylene [3 + 2] cycloaddition: a combined DFT, docking, and ADMET approach

  • 期刊论文

  • 发表日期：

    2025年3月1日

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

摘要

The Molecular Electron Density Theory (MEDT) has been used to study the [3 + 2] cycloaddition (32CA) reaction of an N-t-butyl nitrone with a cyanoacetylene at the B3LYP/6–311 + + G(d,p) computational level. However, the DFT-based reactivity indices show that N-t-butyl nitrone is a strong nucleophile, while cyanoacetylene exhibits strong electrophile properties. The reaction takes place in two paths (a and b). In addition, in the Potential Energy Surface (PES) analysis, energy profiles show that path a is more favorable and more spontaneous, with both products forming through exothermic reactions. Moreover, Bonding Evolution Theory (BET) analysis revealed that these 32CA reactions proceed via the coupling of pseudoradical centers, with the formation of new C–C and C–O covalent bonds occurring only after the transition states (TS). It is interesting to note that, with the electronic flux from the N-t-butyl nitrone to the cyanoacetylene, a low polarity of the forward electron density transfer (FEDF) type is predicted by the global electron density transfer (GEDT) between 0.1169 and 0.14862 e. In particular, in this one-step zw-type 32CA reaction, the atom-in-molecules (AIM) topological characterization of the electron density at the TSs structures and the electron localization function (ELF) are not considered. Certainly, the major cervical intraepithelial neoplasia or (1CIN) protein underwent a docking survey for cycloadducts 2-(tert-butyl)-2,3-dihydroisoxazole-4-carbonitrile and 2-(tert-butyl)-2,3-dihydroisoxazole-5-carbonitrile. The analysis shows that cycloadducts 2-(tert-butyl)-2,3-dihydroisoxazole-4-carbonitrile have higher binding energy, while cycloadducts 2-(tert-butyl)-2,3-dihydroisoxazole-5-carbonitrile have lower binding energy than the co-crystal ligand. Finally, the drug-likeness assessment and ADMET predictions were demonstrated for products 2-(tert-butyl)-2,3-dihydroisoxazole-4-carbonitrile and 2-(tert-butyl)-2,3-dihydroisoxazole-5-carbonitrile. The ADMET analysis of molecule 2-(tert-butyl)-2,3-dihydroisoxazole-4-carbonitrile is the most promising drug-like molecule.

Graphical abstract