Synthesis and Screening of 1-Methylisatin-linked 1,2,3-Triazoles as VEGFR-2 Inhibitors and Their Molecular Docking Studies
摘要
Objective: The pharmacophore hybridization strategy is an effective method to reduce side effects and overcome drug resistance by utilizing multiple mechanisms of action. In this context, we have applied this approach to synthesize isatin-1,2,3-triazole hybrids (Va–Vn) as potential in vitro VEGFR-2 inhibitors. Methods: Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) was employed for the synthesis of isatin-1,2,3-triazole hybrids (Va–Vn). The compounds were screened for in vitro anticancer activity against MCF-7 and HepG2 cell lines using the MTT assay, with sunitinib as the reference drug. Additionally, in vitro tyrosine kinase VEGFR-2 inhibition assays and molecular docking studies were conducted for four potent compounds. Results and Discussion: Among all the compounds, Vb, Vc, Vj, and Vl exhibited greater activity than sunitinib, with IC50 values ranging from 0.9 to 3.6 μM. Moreover, compounds Vl and Vj showed 2.8- and 1.5-fold higher in vitro VEGFR-2 inhibition compared to sunitinib, respectively. Molecular docking studies of these compounds with VEGFR-2 protein (PDB ID: 3VHE) revealed favorable binding interactions with the target protein. Conclusions: Compounds Vb, Vc, Vj, and Vl may serve as promising anticancer drug candidates targeting VEGFR-2.