A novel series of 1,2,3-triazole/chalcone hybrids 6a– n was designed and synthe-
sized 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 doxoru-
bicin (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 (IC 50 = 0.05 ± 0.03 μM). 6d has modest
BRAF inhibitory action with an IC50 of 0.90 ± 0.10 μM. The findings were also
related to molecular docking studies, which provided models of strong interac-
tions with the EGFR-TK domain for the inhibitors. In cell cycle analysis, hybrid
6d caused a cell cycle arrest at the G1 transition phase.