Synthesis and Anticancer Evaluation of Pyridine, Triazole, and Thiazole Compounds

Abstract

Heterocyclic scaffolds are ubiquitous in modern anticancer drug discovery, with pyridine, triazole, and thiazole rings featuring prominently in many potent agents. In this study, we designed and synthesized a new series of compounds incorporating pyridine, 1,2,4-triazole, and thiazole moieties, hypothesizing that these heterocycles would impart significant cytotoxic activity against cancer cells. The synthetic routes yielded two main classes of compounds: 2-pyridone derivatives (dihydropyridine-dicarbonitriles) and thiazolidinone derivatives, with additional analogues for comparison. All compounds were fully characterized by elemental analysis and spectroscopic methods (FT-IR, NMR, MS), confirming their structures. In vitro anticancer activity was evaluated against human lung carcinoma (A549) and breast adenocarcinoma (MCF-7) cell lines using the MTT assay. Several compounds showed remarkable cytotoxic potency, with sub-micromolar to nanomolar IC₅₀ values. Notably, two pyridone–based analogues exhibited IC₅₀ ≈ 8–15 nM in both cell lines, outperforming the reference drug cisplatin (IC₅₀ ≈ 50 µM) and even matching or exceeding doxorubicin’s potency. Thiazole-based derivatives also displayed strong activity in the ~50–120 nM range. The compounds were relatively selective for cancer cells over normal cells, showing high safety indices (e.g. >28-fold). A preliminary structure–activity relationship (SAR) analysis suggests that electron-withdrawing substituents on the phenyl ring (e.g. nitro) enhanced cytotoxicity, whereas electron-donating groups reduced it. Overall, these findings demonstrate the potential of pyridine-, triazole-, and thiazole-containing hybrids as promising anticancer agents. Four lead compounds are identified for further development, and possible mechanisms of action (including EGFR kinase inhibition and pro-apoptotic effects) are proposed based on initial enzyme assays and literature precedents.