New Indazol-Pyrimidine-Based Derivatives as Selective Anticancer Agents: Design, Synthesis, and In Silico Studies.

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds-, , , , and -possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC value of 8.029 μM, thus demonstrating promising suppression power. Compounds , , , , and showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds and exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, and , werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.