Novel benzothiazole hybrids targeting EGFR: Design, synthesis, biological evaluation and molecular docking studies

Novel benzo[d] thiazole-based analogues were synthesized with the aim of screening their in vitro anticancer activity. All the new derivatives 4-21 were evaluated against human hepatocellular carcinoma (HepG-2) and breast cancer cells (MCF-7) using doxorubicin as a reference drug. All compounds exhibited excellent potency against MCF-7 (IC50 values ranging from 0.71 +/- 0.4 to 1.04 +/- 0.7 mu M) and variable promising potency against HepG-2 (IC50 ranged from 2.53 +/- 2.5 to 3.47 +/- 3.4 mu M) comparing with the standard (IC50 = 1.03 +/- 0.8 mu M and 2.85 +/- 1.9 mu M, respectively) in addition to their safety towards the normal cell line. Compounds 5, 6, 7, 13 and 16 having the highest cytotoxic activity, were further evaluated for their EGFR inhibitory activity using Erlotinib as a reference drug. Molecular docking studies were performed for the promising compounds 5, 6 and 7 to interpret their detected enzymatic activities based upon their binding interactions with the receptor. Moreover, cell cycle analysis and detection of apoptosis induction illustrated that compounds 5 and 6 exhibited a significant pre G(1) and G(2)/M cell cycle arrest, in comparison with the untreated MCF-7 cells. In addition, compounds 5 and 6 elevated the levels of the oncogenic parameters; Bax, p53 and caspase-3 with decreased level of Bcl-2. These previous encouraging results of biological evaluation of the newly synthesized benzothiazoles could recommend an excellent framework toward the detection of new potent antitumor leads. (C) 2021 Elsevier B.V. All rights reserved.

Automated summary

The novel benzo[d] thiazole-based analogues showed excellent potency against MCF-7 cancer cells and promising potency against HepG-2 cells, suggesting their potential as new antitumor leads. Molecular docking studies and cell cycle analysis further supported the cytotoxic and EGFR inhibitory activities of compounds 5, 6, and 7.