Design, synthesis, and modelling study of new 1,2,3-triazole/chalcone hybrids with antiproliferative action as epidermal growth factor receptor inhibitors.

Abstract

A novel series of 1,2,3-triazole/chalcone hybrids 6a-n was designed and synthesized using a molecular hybridization approach to develop a new cytotoxic agent capable of targeting epidermal growth factor receptor (EGFR) and/or BRAF. The antiproliferative effect of the novel hybrids was investigated against four cancer cells using doxorubicin as a reference. Hybrids 6a, 6d, 6f-h, and 6n have the highest antiproliferative activity (IC50 values 0.95-1.80 μM) compared to doxorubicin (IC50 1.14 μM). The most potent antiproliferative derivative, compound 6d, was also the most potent EGFR inhibitor with an IC50 of 0.09 ± 0.05 μM, which is comparable to the reference Erlotinib (IC50 =0.05 ± 0.03 μM). 6d has modest BRAF inhibitory action with an IC50 of 0.90 ± 0.10μM. The findings were also related to molecular docking studies, which provided models of strong interactions with the EGFR-TK domain for the inhibitors. In cell cycle analysis, hybrid 6d caused a cell cycle arrest at the G1 transition phase.