Synthesis of Fully Substituted 1,2,3-Triazoles via Organocatalytic [3+2] Cycloaddition: Incorporation of Pyrazole and Imidazole Scaffolds as Potent EGFR-Targeted Anticancer Agents

Objective: The present study aimed to synthesize novel imidazole- and pyrazole-containing 1,2,3-triazoles via organocatalytic [3+2] cycloaddition and to evaluate their anticancer activity against MCF-7, A-549, and HEK-293 cell lines. Methods: The synthesis began with S-alkylation of 1-methyl-1H-imidazole-2-thiol using 2-bromo-1-(4-chloro-1-methyl-1H-pyrazol-3-yl)ethan-1-one to yield 1-(4-chloro-1-methyl-1H-pyrazol-3-yl)-2-((1-methyl-1H-imidazol-2-yl)thio)ethan-1-one, followed by oxidation to form the key intermediate β-ketosulfone. Subsequent [3+2] cycloaddition between aryl azides and the α-ketosulfone led to the formation of fully substituted 1,2,3-triazoles. Anticancer activity of the synthesized compounds was assessed using the MTT assay. In silico molecular docking and ADMET analyses were also performed for the most active compounds. Results and Discussion: Structural confirmation of all synthesized compounds was achieved using ESI-MS, ¹H, and ¹³C NMR spectroscopy. Compound (Vi) exhibited the most potent cytotoxic activity against both MCF-7 and A-549 cancer cell lines, with IC₅₀ values of 4.18 ± 0.32 and 6.97 ± 0.41 μM, respectively. Compound (Vg) also demonstrated comparable activity, with IC₅₀ values of 4.42 ± 0.38 μM (MCF-7) and 7.53 ± 0.49 μM (A-549). These results were benchmarked against the standard drug Erlotinib. Further investigation of EGFR-inhibitory potential revealed that the most active compounds displayed strong binding affinity, with binding energies ranging from –7.98 to –9.63 kcal/mol, exceeding that of Erlotinib (–7.69 kcal/mol). Conclusions: A new series of fully substituted 1,2,3-triazoles was successfully synthesized and evaluated for their in vitro anticancer activity. Several compounds exhibited significant cytotoxicity against MCF-7 and A-549 cell lines while maintaining lower toxicity toward the non-cancerous HEK-293 cells. Compound (Vi), in particular, holds promise as a lead candidate for further development, given its potency and favorable in silico profile.