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.
Laddha et al. (Mon,) studied this question.