Cancer is a complex and heterogenous disease characterized by uncontrolled cell proliferation, leading to the formation of abnormal tissue masses – tumors. While cytotoxic agents remain a cornerstone of cancer treatment, their therapeutic potential is restricted by limited selectivity and permeability. As a result, the search for novel, highly specific anticancer compounds is crucial to enhance treatment precision and minimize the adverse effects associated with conventional therapies. The current study focuses on designing molecules that exploit cancer cell vulnerabilities, including inhibiting key signaling pathways involved in tumor progression. Hydrazone derivatives have demonstrated promising anticancer activity by acting as protein kinase inhibitors [1].
This work’s objective was to synthesize variously substituted pyridine-1,2,4-triazole-3-thione-hydrazones and evaluate their binding affinity towards four protein kinase sites.
The reaction of 2-aminopyridine and 2-amino-5-chloropyridine with acrylic acid in toluene under reflux conditions resulted in the formation of the corresponding β-alanines in good yields [2]. The obtained compounds were melted with thioacetohydrazide at 200 \(^{\circ}\)C to provide 4-amino-1,2,4-triazole-3-thione and chloro-substituted 4-amino-1,2,4-triazole-3-thione in 74% and 76% yields, respectively. 4-Substituted-5-(2-(pyridine-2-yl-amino)ethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones and their chloro analogs were synthesized in 53-85% yield by reacting 4-amino-1,2,4-triazole-3-thiones with the corresponding aldehydes in methanol in the presence of a catalytic amount of hydrochloric acid under reflux conditions. The novel compounds’ structures were confirmed by \(^{1}\)H and \(^{13}\)C nuclear magnetic resonance (NMR), and mass spectrometry (MS).
Molecular docking studies of three newly synthesized compounds, which demonstrated significant cytotoxicity against MDA-MB-231 and U-87 cancer cell lines, were conducted to explore potential anticancer mechanisms. Kinase inhibitors have shown efficacy in treating breast cancer and glioblastoma [3], prompting the modeling of interactions between the 1,2,4-triazole-3-thione bearing pyridine-3-methylene moiety, its chloro analog, chloro-substituted 1,2,4-triazole-3-thione, bearing methylthio substituent and selected receptor protein kinases. The standard ligands dasatinib, sorafenib, and vemurafenib were used for comparison. All three compounds showed strong binding affinity to four kinase sites, with binding scores ranging from −9.103 to −10.122 kcal/mol, superior to the standard ligands.
Overall, the three selected compounds showed promising potential as anticancer agents. They have demonstrated strong binding affinity to the four protein kinase sites and likely exert their effects by targeting the MAPK pathway, inhibiting the BRAF and MEK serine-threonine protein kinases.