MEDT insights into the mechanism and selectivity of the (3 + 2) cycloaddition of ()--methyl--(2-furyl)-nitrone with but-2-ynedioic acid and the bioactivity of the reaction products.

In this contribution, Molecular Electron Density Theory (MEDT) is employed to investigate the (3 + 2) cycloaddition reaction between ()--methyl--(2-furyl)-nitrone 1 and but-2-ynedioic acid 2. DFT calculations at the M06-2X-D3/6-311+G(d,p) level of theory under solvent-free conditions at room temperature show that this reaction proceeds CA3-Z diastereoselectivity, with the formation of the CA3-Z cycloadduct being both thermodynamically and kinetically more favoured than the CA4-Z one. Reactivity parameters obtained from CDFT calculations reveal that compound 1 predominantly behaves as a nucleophile with moderate electrophilic features, in contrast to compound 2, which demonstrates strong electrophilicity and limited nucleophilic ability. This disparity in electronic properties suggests a polar mechanism for the investigated 32CA reaction. Then, bonding evolution theory shows that this cycloaddition proceeds a one-step asynchronous process. On the other hand, both CA3-Z and CA4-Z cycloadducts demonstrate promising characteristics as lead compounds for drug development. Molecular docking studies indicate moderate affinity toward the 7BV2 protease, while their physicochemical properties and compliance with major drug-likeness rules support their potential as orally bioavailable agents. Furthermore, PASS predictions suggest a wide range of biological activities, notably in inflammation, neuroprotection, and anticancer applications. These findings, in line with experimental cytotoxicity data, highlight the therapeutic potential of these isoxazolidine derivatives and warrant further experimental validation.