# Structure-Guided Design of Benzothiazole and Benzimidazole-Based Urea Derivatives Curtailing Oncogenic Signaling via Concurrent Inhibition of VEGFR-2, EGFR, and c‑Met

## TL;DR

This paper introduces new drug candidates that target multiple cancer-related proteins to reduce tumor growth and spread while minimizing side effects.

## Contribution

The study presents novel benzothiazole and benzimidazole-based urea derivatives with multitarget inhibition of VEGFR-2, EGFR, and c-Met.

## Key findings

- Compounds 6a–c, 7a, 12a, 17, and 18 showed multitarget inhibitory potential in vitro.
- Compounds 11b, 12a, 17, and 18 exhibited strong antiproliferative effects against cancer cells with low toxicity to normal cells.
- Molecular docking and MD simulations confirmed stable and flexible binding of key compounds to target kinases.

## Abstract

Receptor tyrosine
kinases (RTKs), including VEGFR-2, EGFR, and
c-MET, have been recognized as promising oncogenic targets in tumor
progression, invasion, and metastasis. Developing multitarget inhibitors
that block these kinases simultaneously offers a powerful strategy
to suppress angiogenesis and oncogenic signaling, while potentially
minimizing adverse effects. A new series of benzothiazole- and benzimidazole-based
urea derivatives was designed rationally through scaffold modification
and linker optimization to enhance multikinase inhibition. Moreover, in vitro evaluation of the newly synthesized series revealed
that compounds 6a–c, 7a, 12a, 17, and 18 exhibited
multitarget inhibitory potential. Additionally, 11b, 12a, 17, and 18 showed the best
antiproliferative potential against MCF7 and A549 cells, as indicated
by the antiproliferative assay. While compounds 6b, 7a, 17, and 18 demonstrated negligible
cytotoxicity against normal HEK-293 cells, with IC50 values
exceeding 100 μM (>100 μM). Furthermore, the antiangiogenic
efficacy of 11b, 12a, 17, and 18 was validated through CAM assays, which markedly suppressed
neovascularization. Molecular docking revealed efficient occupation
of 6b, 7a, 12a, 17, and 18 with key binding pockets across VEGFR-2, EGFR,
and c-Met. The 200 ns molecular dynamics (MD) simulations confirmed
the stability of the 4ASD–6b complex with enhanced
flexibility compared to sorafenib. Collectively, these findings establish
benzothiazole, benzimidazole, and quinoline-based urea hybrids as
promising leads with enhanced multikinase selectivity and reduced
toxicity compared to existing inhibitors, offering strong therapeutic
potential in angiogenesis-driven cancers.