Benmetir Sofiane, Chellegui Mohamed, Salih Raad Nasrullah, Benhamed Lakhdar, Salhi Ines, Mohammad-Salim Haydar A, de Julián-Ortiz Jesus Vicente
Department of Physical Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andrés Estellés s/n, 46100 Valencia, Spain.
Process and Environmental Engineering Laboratory (LIPE), Faculty of Chemistry, University of Science and Technology of Oran Mohamed BOUDIAF, P.O. Box 1503, El Mnaouer, 31000 Oran, Algeria.
Org Biomol Chem. 2025 Jul 16;23(28):6785-6800. doi: 10.1039/d5ob00658a.
In this investigation, molecular electron density theory (MEDT) is used to study the [3 + 2] cycloaddition (32CA) reaction between 1-(furan-2-yl)--phenylmethanimine oxide (1) and styrene (2). In fact, density functional theory (DFT) calculations at the M06-2X-D3/6-311G(d,p) level of theory in benzene at room temperature were performed to describe the regio- and stereoselectivity and the mechanism of the 32CA reaction studied. Using the CDFT approach, 1 is a moderate electrophile and a strong nucleophile, while 2 is classified as a moderate electrophile and a moderate nucleophile. As a consequence, the 32CA reaction under study is characterized by a non-polar characteristic. Analysis of thermodynamic data indicates that the meta-endo compound is both thermodynamically and kinetically more favored than the other compounds, which aligns perfectly with the experimental results. BET analysis shows that this reaction takes place a non-polar one-step cycloaddition with low asynchronous transition states. The QTAIM and ELF approaches further confirmed this asynchronous characteristic. Molecular docking analysis revealed that the meta-endo product exhibited notable binding affinity to the 1CIN protease, highlighting its potential as a therapeutic inhibitor. Although drug-likeness evaluations confirmed compliance with Lipinski's rule of five, suggesting favorable pharmacokinetic properties, the PASS analysis indicated a limited range of predicted biological activities for the compound.
在本研究中，运用分子电子密度理论（MEDT）研究了1-（呋喃-2-基）-亚苄基亚胺氧化物（1）与苯乙烯（2）之间的[3 + 2]环加成（32CA）反应。事实上，在室温下于苯中采用M06-2X-D3/6-311G(d,p)理论水平进行密度泛函理论（DFT）计算，以描述所研究的32CA反应的区域选择性和立体选择性以及反应机理。采用CDFT方法，1是中等亲电试剂和强亲核试剂，而2被归类为中等亲电试剂和中等亲核试剂。因此，所研究的32CA反应具有非极性特征。热力学数据分析表明，间位内型化合物在热力学和动力学上都比其他化合物更有利，这与实验结果完美吻合。BET分析表明，该反应以具有低非同步过渡态的非极性一步环加成方式进行。QTAIM和ELF方法进一步证实了这种非同步特征。分子对接分析表明，间位内型产物对1CIN蛋白酶表现出显著的结合亲和力，突出了其作为治疗抑制剂的潜力。尽管类药性质评估证实符合Lipinski的五规则，表明具有良好的药代动力学性质，但PASS分析表明该化合物的预测生物活性范围有限。
