Design, synthesis, biological evaluation, QSAR analysis and molecular modelling of new thiazol-benzimidazoles as EGFR inhibitors

Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for Cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1H-benzo[d]imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n, 4h, 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67-152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j, 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast Cancer cell line (MCF-7) (IC50; 5.96-11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast Cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; Caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 Enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR.

Apoptosis; Bax/Bcl-2; Benzimidazole; Breast cancer; Caspase-3; EGFR inhibitors; Molecular docking; QSAR; Thiazole; p53.