Design, Synthesis, and Molecular Docking of Triazole-Coumarin Hybrids as Potent Breast Cancer Inhibitors Targeting...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Oncology

Background:

• Breast cancer remains a major global health challenge, necessitating new chemotherapeutics with enhanced efficacy and safety.
• Existing treatments often suffer from limited selectivity and significant side effects.
• Combining coumarin and triazole pharmacophores offers a rational approach to discovering novel anticancer agents.

Purpose of the Study:

• To design and synthesize novel amide-bridged triazole-coumarin hybrids.
• To evaluate the in vitro anticancer activity and cytotoxicity of these compounds against breast cancer cell lines.
• To elucidate the mechanism of action of the most potent derivative.

Main Methods:

• Rational drug design and chemical synthesis of six triazole-coumarin hybrids (5a-f).
• Cytotoxicity assays using MCF-7, MDA-MB-231 (breast cancer), and MCF-10A (non-tumorigenic) cell lines.
• Apoptosis induction analysis (Bax, Bcl-2), cell cycle arrest studies (CDK2, Cyclin E), and molecular docking simulations.

Main Results:

• Compound 5f exhibited significant cytotoxicity against both tested breast cancer cell lines.
• Derivative 5f demonstrated minimal toxicity towards non-tumorigenic MCF-10A cells, indicating selectivity.
• Mechanistic studies showed 5f induces apoptosis and S-phase cell cycle arrest, with high binding affinity to CDK2 and Bcl-2.

Conclusions:

• Compound 5f is a potent and selective anticancer agent with a dual-targeting mechanism.
• This novel triazole-coumarin hybrid represents a promising lead structure for developing novel breast cancer therapeutics.
• Further investigation into compound 5f is warranted for its potential clinical application.