Novel quinazolin-2-yl 1,2,3-triazole hybrids as promising multi-target anticancer agents: Design, synthesis, and molecular docking study

In our study, a series of quinazoline-1,2,3-triazole hybrids ( 14a-r ) have been designed and synthesized as multitarget EGFR, VEGFR-2, and Topo II inhibitors. All synthesized hybrids were assessed for their anticancer capacity. MTT assay revealed that compounds 14a , 14d , and 14k were the most potent hybrids against four cancer cell lines, HeLa, HePG-2, MCF-7, and HCT-116 at low micromolar range while exhibiting good selectivity against normal cell line WI-38. Sequentially, the three compounds were evaluated for EGFR, VEGFR-2, and Topo II inhibition. Compound 14d was moderate EGFR inhibitor (IC 50 0.103 mu M) compared to Erlotinib (IC 50 0.049 mu M), good VEGFR-2 inhibitor (IC 50 0.069 mu M) compared to Sorafenib (IC 50 0.031 mu M), and stronger Topo II inhibitor (IC 50 19.74 mu M) compared to Etoposide (IC 50 34.19 mu M) by about 1.7 folds. Compounds 14k and 14a represented strong inhibitory activity against Topo II with (IC 50 31.02 mu M and 56.3 mu M) respectively, compared to Etoposide. Additionally, cell cycle analysis and apoptotic induction were performed. Compound 14d arrested the cell cycle on HeLa at G2/M phase by 17.53 % and enhanced apoptosis by 44.08 %. A molecular Docking study was implemented on the three hybrids and showed proper binding interaction with EGFR, VEGFR-2, and Topo II active sites.