Novel Triazole-Based Heterocycles Outperform Doxorubicin: Design, Synthesis, and Biological Evaluation as MMP13-Targeting Anticancer Agents

A series of novel triazole-fused heterocyclic compounds was prepared and evaluated for their anticancer potential. The target molecules (3, 5, 7, 9, 11, 13, 15, 17, 19, 21, and 23) were prepared through strategic cyclization reactions starting from the key intermediate 4-(bromoacetyl)-5-methyl-1-phenyltriazole (1). These triazole-containing scaffolds included imidazobenzimidazoles, imidazobenzothiazoles, imidazotriazoles, imidazothiadiazoles, triazolyl-imidazopyridines, triazolyl-quinoxalines, and triazolyl-benzothiazines. The chemical structures of the synthesized compounds were thoroughly characterized using spectroscopic methods. Evaluation of their in vitro anticancer activities against prostate (PC3) and breast (MDA-MB-231) cancer cell lines detected that 6,8-dichloro-2-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine (13) and 3-(5-methyl-1-phenyl-1H-1,2,3-triazol-4-yl)-4H-benzo[b][1,4]thiazine (17) exhibited the most potent cytotoxicity, outperforming the standard drug doxorubicin. Notably, triazolyl-imidazopyridine compound 13 displayed significantly lower IC₅₀ values of 5.86 and 23.07 μM against PC3 and MDA-MB-231 cells, respectively, compared to doxorubicin. In silico ADME property predictions were also performed to assess the drug-likeness of these triazole-based heterocycles. Target prediction identified MMP13 as a major target. Further mechanistic insights were gained through molecular docking investigations, which elucidated the binding interactions of the active triazole compounds 13 and 17 with the protein target MMP13. Molecular dynamics simulations over 100 ns provided evidence of the stability and flexibility of the docked complexes. The mechanism of the potent compound 13 was validated experimentally by wound healing inhibition and suppression of the expression of MMP13 in PC3 culture media.