Structure-Guided Design of Benzothiazole and Benzimidazole-Based Urea Derivatives Curtailing Oncogenic Signaling via...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Receptor tyrosine kinases (RTKs) such as VEGFR-2, EGFR, and c-MET are crucial in cancer progression, invasion, and metastasis.
• Multitarget inhibitors offer a strategic approach to suppress tumor growth and angiogenesis while potentially reducing side effects.

Purpose of the Study:

• To design and synthesize novel benzothiazole- and benzimidazole-based urea derivatives as multitarget kinase inhibitors.
• To evaluate the in vitro antiproliferative, antiangiogenic, and cytotoxic activities of the synthesized compounds.

Main Methods:

• Rational design involving scaffold modification and linker optimization.
• In vitro antiproliferative assays against MCF7 and A549 cancer cell lines.
• Cytotoxicity assessment against normal HEK-293 cells.
• Chick embryo chorioallantoic membrane (CAM) assays for antiangiogenic efficacy.
• Molecular docking and molecular dynamics (MD) simulations to predict binding interactions and stability.

Main Results:

• Compounds 6a-c, 7a, 12a, 17, and 18 displayed multitarget inhibitory potential against VEGFR-2, EGFR, and c-MET.
• Compounds 11b, 12a, 17, and 18 exhibited significant antiproliferative activity.
• Compounds 6b, 7a, 17, and 18 showed negligible cytotoxicity against normal cells (IC50 > 100 μM).
• Compounds 11b, 12a, 17, and 18 demonstrated marked antiangiogenic effects in CAM assays.
• Molecular docking and MD simulations confirmed stable binding interactions with target kinases.

Conclusions:

• Benzothiazole, benzimidazole, and quinoline-based urea hybrids represent promising anticancer leads.
• These novel compounds exhibit enhanced multitarget kinase selectivity and reduced toxicity compared to existing inhibitors.
• The developed compounds hold significant therapeutic potential for treating angiogenesis-driven cancers.