Hydrazonylthiazole Derivatives as Dual EGFR and ALR2 Inhibitors: Design, Synthesis, and Comprehensive In Vitro and In...

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Imbalances in epidermal growth factor receptor (EGFR) and aldose reductase (ALR2) signaling are implicated in solid tumors like non-small-cell lung cancer (NSCLC) and breast cancer.
• Targeting these signaling pathways offers a potential therapeutic strategy for cancer treatment.

Purpose of the Study:

• To synthesize and evaluate novel hydrazonylthiazole derivatives as potential dual modulators of EGFR and ALR2.
• To assess the anticancer activity and selectivity of these compounds against NSCLC, breast cancer, and leukemia cell lines.

Main Methods:

• Synthesis of thirteen hydrazonylthiazole derivatives (compounds 1-13).
• In vitro evaluation of cytotoxicity against A549 (NSCLC), MCF-7 (breast cancer), Jurkat cells, and peripheral blood mononuclear cells (PBMCs).
• Apoptosis assays, EGFR and ALR2 inhibition studies, molecular docking, molecular dynamics (MD) simulations, and pharmacokinetic profiling using SwissADME.

Main Results:

• Compound 13 demonstrated potent activity against A549 and MCF-7 cells (IC50 values ~1.3-1.7 µM) with high selectivity (SI=138.9) and induced apoptosis in A549 cells.
• Compound 13 significantly inhibited EGFR activity (74% at 10 µM).
• Compound 5 emerged as a potent ALR2 inhibitor (KI = 0.08 ± 0.01 µM). Both compounds exhibited favorable drug-likeness and oral absorption potential based on MD and SwissADME analyses.

Conclusions:

• Compound 13 acts as a selective EGFR-targeting agent, inducing apoptosis in NSCLC cells, suggesting its potential in EGFR-driven cancers.
• Compound 5 exhibits strong inhibitory activity against ALR2.
• These hydrazonylthiazole derivatives represent promising scaffolds for developing novel small-molecule therapeutics targeting EGFR and ALR2 pathways in cancer.