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Novel benzofuran-1,3,4-thiadiazole aryl urea hybrids as dual VEGFR-2/BRAF inhibitors: anticancer activity, apoptosis

Marwa I Serag¹, Mohamed R Elnagar², Wafaa A Ewes¹

¹Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

Bioorganic & Medicinal Chemistry

|August 6, 2026

Abstract:

The development of dual-directed anticancer agents has emerged as an effective strategy to simultaneously modulate tumor proliferation and angiogenesis while overcoming resistance associated with single-target therapies. In the present study, a novel series of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker were designed as dual VEGFR-2/BRAF^WT inhibitors using sorafenib as a pharmacophoric template. The in vitro cytotoxic activity of the synthesized compounds against cervix HeLa, prostate PC-3, colon HCT-116, and breast MCF-7 cancer cell lines was evaluated. Most derivatives showed variable activity, with 5-bromobenzofuran analogues displaying superior potency. Compound 7j emerged as the most active analogue, with IC₅₀ values of 7.83-13.27 μM and reduced toxicity toward normal lung fibroblast WI-38 cells. Enzymatic assays revealed potent dual inhibition of VEGFR-2 and BRAF^WT by 7j (IC₅₀ = 0.044 and 0.071 μM, respectively), outperforming sorafenib and vemurafenib. Mechanistic studies showed that 7j induced G2/M cell cycle arrest and promoted apoptosis in HeLa cells. This effect was associated with upregulation of BAX, p53, and caspase-9, downregulation of Bcl-2, and activation of the intrinsic apoptotic pathway. Additionally, in silico studies including molecular docking and molecular dynamics simulations demonstrated stable ligand-target interactions and favorable binding modes of 7j across both VEGFR-2 and BRAF, supporting the proposed hybrid design strategy. Overall, compound 7j represents a promising dual VEGFR-2/BRAF^WT inhibitor and highlights benzofuran-based scaffolds as valuable platforms for anticancer drug development.

Insights

Researchers developed novel dual inhibitors targeting VEGFR-2 and BRAF^WT for cancer therapy. Compound 7j, a benzofuran derivative, showed potent anticancer activity and induced apoptosis, offering a promising new drug development platform.

Area of Science:

Medicinal Chemistry
Molecular Biology
Drug Discovery

Background:

Dual-targeted anticancer agents offer advantages over single-target therapies by modulating proliferation and angiogenesis, and overcoming resistance.
Sorafenib serves as a pharmacophoric template for designing novel anticancer compounds.

Purpose of the Study:

To design and synthesize novel benzofuran-based aryl urea derivatives as dual VEGFR-2/BRAF^WT inhibitors.
To evaluate the in vitro cytotoxic activity and mechanistic effects of these compounds against various cancer cell lines.

Main Methods:

Synthesis of benzofuran-based aryl urea derivatives incorporating a 1,3,4-thiadiazole linker.
In vitro cytotoxicity assays against HeLa, PC-3, HCT-116, and MCF-7 cancer cell lines.
Enzymatic inhibition assays for VEGFR-2 and BRAF^WT, cell cycle analysis, apoptosis assays, and in silico studies (molecular docking, molecular dynamics).

Main Results:

Compound 7j, a 5-bromobenzofuran analogue, exhibited potent dual inhibition of VEGFR-2 (IC₅₀ = 0.044 μM) and BRAF^WT (IC₅₀ = 0.071 μM), outperforming sorafenib and vemurafenib.
Compound 7j demonstrated significant in vitro cytotoxicity against cancer cell lines (IC₅₀ = 7.83-13.27 μM) with reduced toxicity to normal cells.
Mechanistic studies revealed that 7j induces G2/M cell cycle arrest and apoptosis in HeLa cells via the intrinsic pathway, involving modulation of key proteins like BAX, p53, caspase-9, and Bcl-2.
In silico studies confirmed stable interactions and favorable binding modes of 7j with VEGFR-2 and BRAF.

Conclusions:

Compound 7j is a highly promising dual VEGFR-2/BRAF^WT inhibitor with significant anticancer potential.
Benzofuran-based scaffolds are valuable platforms for developing novel anticancer agents.
The hybrid design strategy combining VEGFR-2 and BRAF inhibition is effective for anticancer drug development.

Read full analysis

Keywords:

1,3,4-thiadiazole Anticancer agents Apoptosis BRAF inhibitors Benzofuran Dual kinase inhibition VEGFR-2 inhibitors

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