Synthesis, In‐Silico Evaluation, ADME Analysis, and Molecular Dynamics Simulation of Novel β‐Lactam Derivatives Based on Diclofenac and Sulindac With Anticancer and Antioxidant Activities

A new series of cis-β-lactam derivatives was synthesized from the anti-inflammatory drugs diclofenac and sulindac via a Staudinger [2 + 2] cycloaddition of ketenes with various imines, and the exclusively formed cycloadducts were fully characterized by spectroscopic methods. All synthesized compounds were screened for antiproliferative activity against MCF-7 breast cancer cells. Among them, compound 16 proved most potent (IC₅₀ = 21.74 µM; SI = 36.1) and was further evaluated against A375 melanoma cells (IC₅₀ = 168.0 µM; SI = 1.2). Furthermore, the total antioxidant capacity of compounds 12, 13, and 15-17 was assessed. Molecular docking studies of the mitotic kinase TTK showed strong binding for all compounds, with compounds 16 and 17 displaying especially strong interactions in the TTK-binding pocket, supporting experimental kinase inhibition findings. Computational analyses, including DFT calculations, revealed that compounds 16 and 17 possess favorable electronic properties, with lower HOMO-LUMO gaps suggesting enhanced reactivity. ADMET predictions revealed favorable pharmacokinetic properties for all compounds, with compounds 16 and 17 exhibiting good membrane permeability, minimal toxicity aside from immunotoxicity, and adequate bioavailability. In addition, molecular dynamics simulations confirmed the structural stability and sustained binding of the 16-TTK and 17-TTK complexes under physiological conditions.