Identification of novel ureido benzothiophenes as dual VEGFR-2/EGFR anticancer agents

Abstract

Presently, dual-targeting by a single small molecule stands out as a fruitful cancer-fighting strategy. Joining the global effort to fight cancer, a leading cause of death worldwide, we report in this study a novel set for benzothiophene-based aryl urea derivatives as potential anti-proliferative candidates endowed with dual VEGFR-2/EGFR inhibitory activities. The prepared ureido benzothiophenes 6a-r have been evaluated for their anticancer action on a panel of tumor cell lines, namely PanC-1, MCF-7, and HepG2 cells. Most newly synthesized benzo[b]thiophene ureas disclosed effective cytotoxic activities against the examined cancer cell lines. In particular, compound 6q, with an appended 4-trifluoromethoxy group on the terminal phenyl ring, exhibited the most significant cytotoxic activity in MCF-7 with IC₅₀ 3.86 ± 0.72 ug/mL; IC₅₀ of 3.65 ± 0.18 ug/ml in PanC-1 cell line and an IC₅₀ of 4.78 ± 0.06 ug/ml in HepG2. After that, derivatives that exhibited the most potent cytotoxic activities (6g, 6j, 6q, and 6r) were further evaluated as VEGFR-2 and EGFR inhibitors. Fortunately, they displayed low nanomolar IC₅₀ values against both enzymes, where compound 6q emerged to possess superior inhibitory effects towards both EGFR and VEGFR-2 with IC₅₀ 46.6 nM and 11.3 nM simultaneously compared to the reference medications Erlotinib and Sorafenib, respectively. The docked structure of 6q within the catalytic region of VEGFR-2 and EGFR kinases was acquired and studied so that we could investigate potential binding mechanisms for the target ureido benzothiophenes. Hence, the benzothiophene-based aryl urea scaffold has great potential for advancing the development of highly effective dual inhibitors targeting both EGFR and VEGFR-2, which can serve as effective candidates for anticancer therapy.

Keywords: Anticancer; Docking; Drug design; Synthesis; VEGR-2 and EGFR.