{"title":"Mechanistic study of nitrone and maleimide [3 + 2] cycloaddition: a combined DFT, BET study, docking, and ADMET approach from the MEDT perspective","authors":"Raghad Mowafak Al-Mokhtar, Haydar Mohammad-Salim, Muheb Algso","doi":"10.1007/s11224-025-02455-0","DOIUrl":null,"url":null,"abstract":"<div><p>A [3 + 2] cycloaddition (32CA) reaction between maleimide (<b>MD1, MD2</b>) and nitrones (<b>NT1, NT2, NT3</b>) was investigated at the MPWB95/6-311G(d,p) level of theory utilizing Molecular Electron Density Theory (MEDT). Conceptual density functional theory (CDFT) indices substantiated the roles of maleimide (<b>MD1, MD2</b>) and nitrones (<b>NT1, NT2, NT3</b>) as electrophiles and nucleophiles, respectively. The reaction proceeds via two possible pathways: <b><i>exo</i></b> and <b><i>endo</i></b>. Investigation of the Potential Energy Surface (PES) revealed that the <b><i>exo</i></b> and <b><i>endo</i></b> pathways exhibit Gibbs free energy values of (− 13.84, − 13.82, − 12.31, − 14.18 kcal·mol<sup>-1</sup>) and (− 8.78, − 7.87, − 7.88, − 8.54 kcal·mol<sup>-1</sup>), respectively, indicating kinetically controlled, highly exothermic, and spontaneous reactions, as evidenced by negative ΔG values. The global electron density transfer (GEDT) values ranging from 0.08 to 0.19e suggest a low-polarity electron density transfer of the forward electron density flux (FEDF) type from nitrones (<b>NT1, NT2, NT3</b>) to maleimide (<b>MD1, MD2</b>), while local indices, particularly Parr functions, elucidate the electronic spin distribution. Analyses employing electron localization function (ELF) in conjunction with quantum theory of atoms in molecules (QTAIM) identified the nitrone species as participating in a one-step <i>zw-type</i> 32CA reaction. However, topological analysis of the electron density at the transition state demonstrated that these reactions proceed via a non-concerted mechanism. Bonding Evolution Theory (BET) analysis further elucidated the reaction mechanism, revealing six Structural Stability Domains (SSDs) and pseudoradical centers at the C4–C3 and C5–O1 bonds in the transition states. Molecular docking studies demonstrated that the cycloadducts (<b>IZ1, IZ2, IZ3</b>, and <b>IZ4</b>) exhibited binding energies (− 10.88, − 10.61, − 10.40, and − 11.68 kcal mol<sup>-1</sup>) with the Michigan Cancer Foundation-7 (MCF-7) protein (3ERT) that were lower than the co-crystal ligand (− 13.10 kcal mol<sup>-1</sup>). The in silico ADMET and drug-likeness predictions suggest promising potential for further investigation.</p></div>","PeriodicalId":780,"journal":{"name":"Structural Chemistry","volume":"36 5","pages":"1707 - 1727"},"PeriodicalIF":2.2000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Structural Chemistry","FirstCategoryId":"92","ListUrlMain":"https://link.springer.com/article/10.1007/s11224-025-02455-0","RegionNum":4,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
A [3 + 2] cycloaddition (32CA) reaction between maleimide (MD1, MD2) and nitrones (NT1, NT2, NT3) was investigated at the MPWB95/6-311G(d,p) level of theory utilizing Molecular Electron Density Theory (MEDT). Conceptual density functional theory (CDFT) indices substantiated the roles of maleimide (MD1, MD2) and nitrones (NT1, NT2, NT3) as electrophiles and nucleophiles, respectively. The reaction proceeds via two possible pathways: exo and endo. Investigation of the Potential Energy Surface (PES) revealed that the exo and endo pathways exhibit Gibbs free energy values of (− 13.84, − 13.82, − 12.31, − 14.18 kcal·mol-1) and (− 8.78, − 7.87, − 7.88, − 8.54 kcal·mol-1), respectively, indicating kinetically controlled, highly exothermic, and spontaneous reactions, as evidenced by negative ΔG values. The global electron density transfer (GEDT) values ranging from 0.08 to 0.19e suggest a low-polarity electron density transfer of the forward electron density flux (FEDF) type from nitrones (NT1, NT2, NT3) to maleimide (MD1, MD2), while local indices, particularly Parr functions, elucidate the electronic spin distribution. Analyses employing electron localization function (ELF) in conjunction with quantum theory of atoms in molecules (QTAIM) identified the nitrone species as participating in a one-step zw-type 32CA reaction. However, topological analysis of the electron density at the transition state demonstrated that these reactions proceed via a non-concerted mechanism. Bonding Evolution Theory (BET) analysis further elucidated the reaction mechanism, revealing six Structural Stability Domains (SSDs) and pseudoradical centers at the C4–C3 and C5–O1 bonds in the transition states. Molecular docking studies demonstrated that the cycloadducts (IZ1, IZ2, IZ3, and IZ4) exhibited binding energies (− 10.88, − 10.61, − 10.40, and − 11.68 kcal mol-1) with the Michigan Cancer Foundation-7 (MCF-7) protein (3ERT) that were lower than the co-crystal ligand (− 13.10 kcal mol-1). The in silico ADMET and drug-likeness predictions suggest promising potential for further investigation.
期刊介绍:
Structural Chemistry is an international forum for the publication of peer-reviewed original research papers that cover the condensed and gaseous states of matter and involve numerous techniques for the determination of structure and energetics, their results, and the conclusions derived from these studies. The journal overcomes the unnatural separation in the current literature among the areas of structure determination, energetics, and applications, as well as builds a bridge to other chemical disciplines. Ist comprehensive coverage encompasses broad discussion of results, observation of relationships among various properties, and the description and application of structure and energy information in all domains of chemistry.
We welcome the broadest range of accounts of research in structural chemistry involving the discussion of methodologies and structures,experimental, theoretical, and computational, and their combinations. We encourage discussions of structural information collected for their chemicaland biological significance.