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

• Published in: Journal of molecular structure 2021-09, Vol.1240, p.130595, Article 130595
• Main Authors: El-Meguid, Eman A. Abd, Moustafa, Gaber O., Awad, Hanem M., Zaki, Eman R., Nossier, Eman S.
• Format: Article
• Language: English
• Subjects: Anticancer; Bax; Bcl-2; Benzothiazole; Caspase-3; Cell cycle analysis; EGFR; Molecular docking; P53
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2021.130595

•New derivatives bearing benzo[d]thiazole core conjugated with different aliphatic, aromatic and / or heterocyclic rings were synthesized.•Utilizing cancer as a putative target, the new compounds were evaluated in vitro against human hepatocellular carcinoma (HepG-2) and breast cancer cells (MCF-7).•The promising compounds were examined as EGFR inhibitors.•As a representative example, compounds 5 and 6 were subjected to apoptosis induction and cell cycle analyses.•In addition, compounds 5 and 6 elevated the levels of the oncogenic parameters; Bax, p53 and caspase-3 with decreased level of Bcl-2.•Molecular modeling study was also performed to elucidate the binding modes of the active candidates with amino acid residues of EGFR and rationalize their pharmacological effects. 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 µM) and variable promising potency against HepG-2 (IC50 ranged from 2.53 ± 2.5 to 3.47 ± 3.4 µM) comparing with the standard (IC50 = 1.03 ± 0.8 µM and 2.85 ± 1.9 µM, 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 G1 and G2/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. New functionalized benzothiazole derivatives were designed, synthesized and evaluated for their in vitro anticancer activity. The most promising derivatives were evaluated in vitro as kinase inhibitor against