1,2,4-Triazole-Acetamide Conjugates as hEGFR Inhibitors: Synthesis, Anticancer Evaluation, and In Silico Studies

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Molecular Biology

Background:

• Cancer remains a leading cause of mortality worldwide, necessitating the development of novel therapeutic agents.
• Targeting receptor tyrosine kinases like human epidermal growth factor receptor (hEGFR) is a validated strategy in cancer therapy.
• 1,2,4-triazole derivatives have shown promise as anticancer agents.

Purpose of the Study:

• To synthesize and evaluate novel 1,2,4-triazole-acetamide derivatives for their anticancer and hEGFR inhibitory potential.
• To identify lead compounds with high potency and selectivity against cancer cell lines and hEGFR.

Main Methods:

• Multistep synthesis of 1,2,4-triazole-acetamide derivatives.
• Characterization using spectroscopic methods.
• In vitro cytotoxicity assays against PC-3, MCF-7, A549, and K562 cancer cell lines.
• In vitro kinase assays for hEGFR inhibition.
• Molecular docking and molecular dynamics simulations.

Main Results:

• Compounds 18, 19, and 24 exhibited significant antiproliferative effects.
• Compound 24 displayed superior selectivity and potency compared to gefitinib, inducing apoptosis and inhibiting migration in A549 and PC-3 cells.
• Compound 20 emerged as the most potent hEGFR inhibitor, with an IC50 of 43.8 ± 1.3 nM.
• Molecular simulations confirmed stable binding of compound 20 to EGFR, interacting with Cys797.

Conclusions:

• The synthesized 1,2,4-triazole-acetamide derivatives hold significant promise as anticancer agents.
• Compounds 20 and 24 are identified as potential candidates for further development as EGFR-targeted therapies.
• This study provides a strong foundation for the rational design of novel EGFR inhibitors.