Novel quinoline-3-carboxamides (Part 2): Design, optimization and synthesis of quinoline based scaffold as EGFR...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Oncology

Background:

• Epidermal Growth Factor Receptor (EGFR) is crucial for cell growth and implicated in epithelial cancers.
• Quinazoline and quinoline derivatives are established intracellular inhibitors of EGFR kinase.
• Optimization of these inhibitors is vital for developing targeted anticancer therapies.

Purpose of the Study:

• To optimize a previously reported quinoline-3-carboxamide (compound III) as a potent EGFR inhibitor.
• To synthesize and evaluate novel derivatives for enhanced anticancer activity.
• To identify lead compounds for further development of targeted cancer therapies.

Main Methods:

• Molecular modeling techniques were employed for compound optimization.
• Synthesized quinoline-3-carboxamide derivatives were subjected to EGFR binding assays.
• Anticancer activity was assessed against the MCF-7 cell line.

Main Results:

• Several optimized quinoline-3-carboxamides demonstrated improved EGFR inhibition.
• The furan derivative 5o, thiophene derivative 6b, and benzyloxy derivative 10 showed potent EGFR inhibition with IC50 values of 2.61, 0.49, and 1.73 μM, respectively.
• Compounds 5o, 5p, 6b, 8a, 8b, and 10 exhibited significant anticancer activity against MCF-7 cells, with IC50 values as low as 0.839 μM for compound 8b.

Conclusions:

• Compound 6b emerged as a highly potent EGFR inhibitor and anticancer agent.
• The study successfully identified optimized quinoline-3-carboxamides with potential as targeted cancer therapeutics.
• Compound 6b was selected as a lead structure for further optimization to develop more potent EGFR inhibitors.