Synthesis and in-vitro anti-EGFR screening of new 1,2,3-triazole-benzimidazole hybrids and insilico studies

Herein, the synthesis of benzimidazole- thiazolidine-2,4-dione -1,2,3-triazole conjugates (7a-7n) using copper (I) catalysed azide alkyne cycloaddition is reported. The synthesized compounds were screened for in vitro anticancer activity against MCF-7, MDA-MB-468 and MDA-MB-231 human breast cancer cells. Among all the compounds, four compounds namely 7d, 7i, 7k, and 7n displayed superior activity than 5-fluorouracil towards three breast cancer cell lines with IC50 values ranging from 1.8 mM to 9.7 mM. In vitro tyrosine kinase EGFR inhibition assay revealed that the compound 7d have 2.8 times more potency than that of erlotinib with IC50 value of 0.15mM and remaining three compounds (7i, 7k and 7n) also have more activity than erlotinib. Molecular docking studies on EGFR protein indicated that compound 7d exhibit greatest binding energy i.e. -11.04 kcal/mol compared to erlotinib. The molecule 7d was characterized by using density functional theory (DFT) with B3LYP/6–311++ G (d, p) basis set. The structural parameters were obtained from geometry optimization. Finally in silico pharmacokinetic profile also determined where 7d and 7i followed all the rules like Lipinski rule, Ghose rule, Veber rule, Egan rule and Muegge rule without any deviation.