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

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.

Automated summary

A series of benzothiazole-based derivatives were synthesized and showed promising cytotoxic activities, as well as inhibitory activities against VEGFR-2 and EGFR. Some derivatives exhibited potent activity against resistant cell lines. QSAR study revealed the impact of molecular bulkiness and molecular partial charge distribution on the kinase inhibition potency in this series. Molecular docking study showed that the synthesized derivatives adopted the common binding pattern of type II PK inhibitors in VEGFR-2.