A series of new 1,3,4‐oxadiazole‐chalcone/benzimidazole hybrids 9a–o and 10a–k were designed and synthesized as potential antiproliferative agents. Hybrids 9a–o exhibited remarkable antiproliferative activities on different NCI‐60 cell lines in a single‐dose assay. The antiproliferative activities of the newly synthesized
compounds were evaluated against a panel of four human cancer cell lines
(A‐549, MCF‐7, Panc‐1, and HT‐29). Compounds 9g–i and their oxygen isosteres,
10f–h, exhibited promising antiproliferative activities with IC50 values ranging from
0.80 to 2.27 μM compared to doxorubicin (IC50 ranging from 0.90 to 1.41 μM).
Furthermore, the inhibitory potency of these compounds against the epidermal
growth factor receptor (EGFR) and BRAFV600E kinases was evaluated using erlotinib
as a reference drug. Molecular modeling studies were done to investigate the
binding mode of the most active hybrids in the ATP binding site of EGFR.