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 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.

Anticancer; Benzothiazole; EGFR; Molecular docking; QSAR; VEGFR-2.