Design,synthesis, and biological evaluation of pyrimidine derivatives as potential inhibitors of human calcium/calmodulin‐dependent protein kinase IV

Calcium/calmodulin‐dependent protein kinase IV (CAMKIV ) is a multifunctional Ser/Thr kinase, associated with cerebral hypoxia, cancer, and neurodegenerative diseases. Here, we report design, synthesis, and biological evaluation of seven pyrimidine‐substituted novel inhibitors of CAMKIV . We successfully synthesized and extensively characterized (ESI ‐MS , ¹H NMR , and ¹³C NMR studies) seven compounds that are showing appreciable binding affinity to the CAMKIV . Molecular docking and fluorescence binding studies revealed that compound 1 is showing very high binding free energy (ΔG  = ?11.52 kcal/mol) and binding affinity (K  =  9.2 × 10¹⁰ m ^?1) to the CAMKIV . We further performed MTT assay to check the cytotoxicity and anticancer activity of these compounds. An appreciable IC ₅₀ (39 μm ) value of compound 1 was observed on human hepatoma cell line and nontoxic till the 400 μm on human embryonic kidney cells. To ensure anticancer activity of all these compounds, we further performed propidium iodide assay to evaluate cell viability and DNA content during the cell cycle. We found that compound 1 is again showing a better anticancer activity on both human hepatoma and human embryonic kidney cell lines.