Novel nano-sized N-Thiazolylpyridylamines targeting CDK2: Design, divergent synthesis, conformational studies, and multifaceted In silico analysis

This study involves the design, divergent synthesis, conformational and structural analysis, target prediction, and molecular docking simulations of novel nano N-thiazolylpyridylamines 2-7 and 10 as potential cyclin-dependent kinase 2 (CDK2) inhibitors. Using a divergent synthesis approach, the compounds were designed with structural variation and optimization in mind. The conformational and structural properties were explored through various spectroscopic techniques, confirming the structure, stability, and preferred conformations. Additionally, nanocrystalline characterization, including X-ray diffraction analysis, revealed the nanoscale structural features of the synthesized molecules. Most compounds exhibited a crystalline nature with crystallite sizes ranging from 10.75 to 57.77 nm, which is crucial for improving cellular uptake and anticancer efficacy. Biological testing was performed to evaluate the cytotoxicity of compounds 2-7 and 10 against cancer cell lines, including HepG2, MCF-7, and HCT-116. Compound 5 exhibited significant cytotoxicity with IC₅₀ values of 10.9 ± 0.5 μM, 6.98 ± 0.3 μM, and 6.3 ± 0.2 μM against MCF-7, HePG2, and HCT116, respectively. Other compounds demonstrated varied activities, with compounds 4, 6, and 10 showing moderate activity against the MCF-7 cell line. Computational techniques suggested a strong probability of these compounds targeting CDK2, with molecular docking and dynamics used to predict their binding mechanisms. These findings suggest that N-thiazolylpyridylamines may serve as new anticancer agents for further lead optimization.