Mechanistic Study of N-t-Butyl Nitrone and Nitroethene (3 + 2) Cycloaddition: A Combined DFT, Docking, and ADMET Approach

IF 2 3区 化学 Q2 CHEMISTRY, ORGANIC
Raad Nasrullah Salih, Muheb Algso, Haydar Mohammad-Salim
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Abstract

In this study, the (3 + 2) cycloaddition 32CA reaction between N-t-butyl nitrone 1 and nitroethene 2 was comprehensively investigated using density functional theory (DFT), electron localization function (ELF), atoms-in-molecules (AIM) analysis, and ADMET profiling. The reaction paths were examined in terms of regio- and stereoisomeric outcomes, with four possible cycloadducts being characterized. DFT-based reactivity indices indicated a strong polar nature of the reaction, with the global electrophilicity index (ω) and nucleophilicity index (N) suggesting that nitroethene acts as a strong electrophile and the nitrone as a strong nucleophile. A significant global electron density transfer (GEDT) from the nitrone 1 to nitroethene 2 was observed at the transition states (0.19–0.23 e), confirming a polar character and forward electron density flux (FEDF). Topological analysis of ELF along the reaction coordinate revealed asynchronous one-step two-stage mechanisms, supported by the appearance of pseudoradical centers and disynaptic basin evolution. TSs were confirmed by intrinsic reaction coordinate (IRC) calculations. Molecular docking against the HPV-related 1MH1 protein and ADMET predictions demonstrated that compound 5 displayed the most favorable binding energy and drug-like properties. This integrated theoretical investigation offers new mechanistic insights and supports potential pharmacological applications of the synthesized nitroisoxazolidines.

Abstract Image

n -t-丁基硝基和亚硝基(3 + 2)环加成的机理研究:DFT、对接和ADMET联合方法
本研究采用密度泛函理论(DFT)、电子定位函数(ELF)、分子中原子(AIM)分析和ADMET分析等方法,对n- t-丁基硝基酮1与亚硝基乙烯2之间的(3 + 2)环加成32CA反应进行了全面研究。根据区域和立体异构体的结果对反应路径进行了检查,并对四种可能的环加合物进行了表征。基于dft的反应性指标表明,该反应具有很强的极性性质,总体亲电性指数(ω)和亲核性指数(N)表明,硝基乙烯是强亲电试剂,硝基酮是强亲核试剂。在过渡态(0.19-0.23 e)观察到从硝基酮1到硝基乙烯2的显著整体电子密度转移(GEDT),证实了极性特征和正向电子密度通量(FEDF)。沿反应坐标的拓扑分析揭示了非同步的一步两阶段机制,并得到了伪径向中心的出现和失配盆地演化的支持。用内在反应坐标(IRC)计算证实了TSs。与hpv相关的1MH1蛋白的分子对接和ADMET预测表明,化合物5显示出最有利的结合能和药物样特性。这一综合理论研究提供了新的机制见解,并支持了合成的硝基异恶唑烷的潜在药理应用。
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来源期刊
Journal of Heterocyclic Chemistry
Journal of Heterocyclic Chemistry 化学-有机化学
CiteScore
5.20
自引率
4.20%
发文量
177
审稿时长
3.9 months
期刊介绍: The Journal of Heterocyclic Chemistry is interested in publishing research on all aspects of heterocyclic chemistry, especially development and application of efficient synthetic methodologies and strategies for the synthesis of various heterocyclic compounds. In addition, Journal of Heterocyclic Chemistry promotes research in other areas that contribute to heterocyclic synthesis/application, such as synthesis design, reaction techniques, flow chemistry and continuous processing, multiphase catalysis, green chemistry, catalyst immobilization and recycling.
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