Discovery of potent anticancer tricarboxamide analogs linked to 1,2,3-triazole, promoting EGFR and VEGFR downregulation

Abstract

This study presents the design, synthesis, and biological evaluation of a novel series of 1,2,3-triazole-based tricarboxamide and tricarboxylate analogs as potential anticancer agents targeting EGFR and VEGFR-2. A total of sixteen tris-triazole derivatives were synthesized via Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC) and structurally confirmed through comprehensive spectroscopic analyses. The compounds were evaluated for cytotoxic activity against MCF-7, HCT-116, and A549 cancer cell lines, with several compounds, notably 8i, 8h, and 8g, exhibiting potent sub-micromolar IC₅₀ values (0.09–0.7 μM) and high selectivity toward tumor cells. Mechanistic studies confirmed their inhibitory effects on EGFR (epidermal growth factor receptor), VEGFR-2 (vascular endothelial growth factor receptor-2), and MAPK-p38, along with induction of apoptosis, as evidenced by BAX upregulation and BCL-2/HSP-70 downregulation. Compound 8i emerged as the most promising candidate, exhibiting potent dual EGFR and VGFR inhibition and strong pro-apoptotic activity, with IC₅₀ values of 4.051 ± 0.72 μM (EGFR/MCF-7), 5.492 ± 1.47 μM (EGFR/HCT-116), 1.791 ± 0.05 μM (VGFR/MCF-7), and 1.474 ± 0.09 μM (VGFR/HCT-116), respectively. Molecular docking supported the binding interactions within EGFR, while ADME profiling and metabolic analysis suggested that the compounds may function as prodrugs, activated by esterase- or amidase-mediated hydrolysis. These findings highlight the potential of tris-triazole hybrids as multi-targeted anticancer agents.