Indazol-Pyrimidine Hybrids: Design, Synthesis, and Antiproliferative Activity Against Human Cancer Cell Lines

The current study outlines a synthetic method for creating a new class of indazol-pyrimidine derivatives 4a-h and 5a-h. The new derivatives were evaluated as in vitro cytotoxic agents against three types of cancer cell lines (MCF-7, A549 and Caco-2), utilizing the MTT assay. Compounds 4a, 4c, 4d, 5a and 5f demonstrated potent cytotoxic activity against MCF-7 cell line, showing higher activity than the reference drug Staurosporine. Among the examined compounds, 5f showed a strong cytotoxic effect against all three tested cancer cells (MCF-7, A549 and Caco-2), with IC₅₀ values of 1.858, 3.628 and 1.056 µM, respectively. In comparison, the reference drug exhibited IC₅₀ values of 8.029, 7.354 and 4.202 µM respectively, indicating promising anti-proliferative potential of compound 5f. On the other hand, Compound 4b demonstrated the greatest potency against Caco-2 cell line, with an IC₅₀ of 0.827 µM, markedly outperforming reference compound's IC₅₀ of 4.202 µM. Furthermore, compound 5h revealed significant anti-proliferative activity against A549 cell line, with an IC₅₀ value of 1.378 µM, compared to the reference drug, with an IC₅₀ value of 7.354 µM. Additionally, the molecular docking study revealed a strong binding affinity of compound 5f within the binding site of the c-Kit tyrosine kinase protein, and the molecular dynamics study confirmed its stability.