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.