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

Abstract

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds—4f, 4i, 4a, 4g, and 4d—possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 μM, respectively, compared to the reference drug with an IC50 value of 8.029 μM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, 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.

Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host–Guest Complexes of β-Cyclodextrin

“…The predictive analysis and in silico studies of possible targets, ADME parameters (absorption, distribution, metabolism, and excretion), and compliance with the bioavailability criteria [ 11 , 22 ] were carried out for the studied compounds.…”

Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

“…By studying the structures of previously reported kinase inhibitors, we found that the vast majority of these inhibitors possess pyrimidine as either 2-anilinopyridine or 2-anilinopyrimide as a pharmacophore in their structure [21][22][23][24][25][26][27]. In this study, we aimed to synthesize pyrimidine derivatives, either 2-aminopyrimidine or 2-anilinopyrimidine, with a different hydrophobic system (phenyl, pyridinyl, or pyrimidinyl) at position 4 of the pyrimidine ring, attached to either electron-withdrawing or electron-donating groups, which could affect the activity of the target compounds.…”

“…In addition, position 5 of the pyrimidine ring was designed to be occupied either by a proton or cyano group that was reported to be in contact with the gatekeeper residues, allowing the study of the structureactivity relationship of these compounds as effective antitumor candidates with potential CDK inhibitory activities (Figure 2). By studying the structures of previously reported kinase inhibitors, we found that the vast majority of these inhibitors possess pyrimidine as either 2-anilinopyridine or 2anilinopyrimide as a pharmacophore in their structure [21][22][23][24][25][26][27]. In this study, we aimed to synthesize pyrimidine derivatives, either 2-aminopyrimidine or 2-anilinopyrimidine, with a different hydrophobic system (phenyl, pyridinyl, or pyrimidinyl) at position 4 of the pyrimidine ring, attached to either electron-withdrawing or electron-donating groups, which could affect the activity of the target compounds.…”