Triazole-(p-tolylthio)methyl hybrids via click chemistry: synthesis, molecular docking, and evaluation as promising anticancer candidates

Abstract

A series of novel (p-tolylthio)methyl-linked 1,2,3-triazole derivatives 10–17 was synthesized via Cu(I)-catalyzed click chemistry and structurally characterized. The prepared compounds were evaluated for cytotoxicity against HCT-116, HepG2, and MCF-7 cancer cell lines, with BJ-1 fibroblasts as a control. Several derivatives, notably compounds 13 and 17, showed strong activity against HepG2 and MCF-7 cells (IC₅₀ ≈ 1.4–1.6 µM), exceeding the activity reference drug doxorubicin, while maintaining low toxicity toward normal cells. Molecular docking studies proposed a potential interaction with the EGFR kinase active site, proposing a hypothetical mechanism that requires further experimental validation. Notably, derivatives 13 and 17 formed additional hydrogen bonds with key residues (Lys745, Leu799, Asp800), suggesting enhanced binding stability and inhibitory potential. These findings identify (p-tolylthio)methyl-triazole hybrids as promising anticancer candidates worthy of further development.