Computational study of the mechanism and selectivity of [3 + 2] cycloaddition reactions between nitrone and carbodiimide leading to the formation of anticancer 1,2,4-oxadiazolidine compounds from a MEDT perspective.

This study explores the reactivity and pharmaceutical potential of a novel anticancer compound, 1,2,4-oxadiazolidine, synthesized through the [3 + 2] cycloaddition (32CA) reaction between nitrone (1a) and carbodiimide (2a). The mechanism, investigated using Density Functional Theory (DFT) with the B3LYP-D3 functional and the 6-311 + + G(2d,2p) basis set, reveals a polar, regioselective process involving two transition states (TS1 and TS2), with a thermodynamic preference for the ortho isomer, consistent with experimental findings. Molecular docking studies with the EGFR protein (PDB: 4HJO) indicate that compound P1 binds with a higher affinity (-8.8 kcal/mol) compared to the reference drug Erlotinib. Furthermore, molecular dynamics (MD) simulations over 100 ns demonstrate that the P1-EGFR complex exhibits greater stability and lower fluctuation, further supporting its promising interactions with the target protein. In silico ADMET analysis reveals excellent oral absorption, low toxicity, and a favorable pharmacokinetic profile. These findings comprehensively validate P1's reactivity, affinity, and stability, positioning it as a promising anticancer drug candidate.