Novel benzothiazole-based dual VEGFR-2/EGFR inhibitors targeting breast and liver cancers: Synthesis, cytotoxic activity, QSAR and molecular docking studies. (15th February 2022)

• Record Type: Journal Article
• Authors: Abd El-Meguid, Eman A.; Naglah, Ahmed M.; Moustafa, Gaber O.; Awad, Hanem M.; El Kerdawy, Ahmed M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 58(2022)
• Publication Date: 2022-02-15
• Subjects: MCF-7 Human breast cancer cell line -- HepG-2 Human liver carcinoma -- MDA-MB-231 Resistant triple-negative breast cancer (TNBC) cell line -- PKs Protein kinases -- VEGFR-2 Vascular endothelial growth factor receptor 2 -- RTK Receptor tyrosine kinase -- EGFR Epidermal growth factor -- WI-38 Human normal fibroblast cells -- IC50 Compound concentration required to inhibit the cell viability by 50% -- SD Standard deviation mean, each value is the mean of three values -- QSAR Quantitative structure-activity relationship study -- MLR Multiple Linear Regression -- RMSE Root mean square error -- L10%OCV Leave-10%-out cross-validation -- RMSECV Root mean square error of a leave-10%-out cross-validation -- FS Forward selection -- NSCLC Non-small cell lung cancer; Benzothiazole -- Anticancer -- VEGFR-2 -- EGFR -- QSAR -- Molecular docking; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2022.128529
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: 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 . Abstract: 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.