Novel benzothiazole-based dual VEGFR-2/EGFR inhibitors targeting breast and liver cancers: Synthesis, cytotoxic activity, QSAR and molecular docking studies

• Published in: Bioorganic & medicinal chemistry letters 2022-02, Vol.58, p.128529-128529, Article 128529
• Main Authors: Abd El-Meguid, Eman A., Naglah, Ahmed M., Moustafa, Gaber O., Awad, Hanem M., El Kerdawy, Ahmed M.
• Format: Article
• Language: English
• Subjects: Anticancer; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzothiazole; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - pharmacology; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; EGFR; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Humans; Liver Neoplasms - diagnostic imaging; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Molecular docking; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; QSAR; Quantitative Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR-2
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2022.128529

[Display omitted] •Novel derivatives bearing 2-aryl-benzothiazole core 2–23 were synthesized.•The novel compounds were evaluated as anticancer agents.•The novel compounds were evaluated as VEGFR-2 and EGFR inhibitors.•Molecular modeling studies were performed to elucidate the binding modes of all derivatives 2–23. A novel series of benzothiazole-based derivatives linked to various amino acids and their corresponding ethyl ester analogues were prepared and were initially evaluated for their anticancer activity againstMCF-7 and HepG-2 and were further assessed as VEGFR-2 inhibitors. All the newly synthesized benzothiazole derivatives showed promising cytotoxic activities against the tested cell lines. Derivatives exhibited potent cytotoxic and VEGFR-2 inhibitory activities were then evaluated further as anticancer agents against the resistant MDA-MB-231 and as EGFR inhibitors. The carboxylic acid derivatives 10–12 and their ester analogues 21–23 displayed the highest anticancer activities with IC50 of 0.73–0.89 µM, against MCF-7 and IC50 of 2.54–2.80 µM, against HepG-2; compared to doxorubicin (IC50 = 1.13 and 2.75 µM, respectively); also they showed safety towards the normal cell line, the ethyl ester derivatives 21–23 showed a potent activity against the resistant MDA-MB-231 cell line with IC50 of 5.45–7.28 µM, relative to doxorubicin (IC50 = 7.46 µM) surpassing their carboxylic acid analogues 10–12 (IC50 of 8.88–11.02 µM). Furthermore, the promising derivatives 10–12 and 21–23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15–0.19 µM) comparable to that of sorafenib (IC50 = 0.12 µM). Against EGFR, the ethyl ester derivatives 21–23 showed superior inhibitory activity relative to the used reference standard, erlotinib, with IC50 of 0.11–0.16 vs. 0.18 µM, respectively. The QSAR study revealed that the molecular bulkiness and molecular partial charge distribution govern the kinase inhibition potency in this series. Furthermore, the molecular docking study in VEGFR-2 active site showed that the novel synthesized benzothiazole derivatives adopted the common binding pattern of type II PK inhibitors.