摘要 : 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 against MCF-7 and HepG-2 and we... 展开 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 against MCF-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 mu M, against MCF-7 and IC50 of 2.54-2.80 mu M, against HepG-2; compared to doxorubicin (IC50 = 1.13 and 2.75 mu M, 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 mu M, relative to doxorubicin (IC50 = 7.46 mu M) surpassing their carboxylic acid analogues 10-12 (IC50 of 8.88-11.02 mu M). Furthermore, the promising derivatives 10-12 and 21-23 displayed promising VEGFR-2 inhibitory activity (IC50 = 0.15-0.19 mu M) comparable to that of sorafenib (IC50 = 0.12 mu M). 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 mu M, 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 benzo-thiazole derivatives adopted the common binding pattern of type II PK inhibitors. 收起