Synthesis, Biological Evaluation, and Molecular Docking of Novel Pyrazole-Nitrone Derivatives as EGFR-targeted Anticancer Agents

Abstract

Objective: This study aimed to design, synthesise, and characterise some novel pyrazole-nitrone derivatives and evaluate their potential as anticancer agents targeting EGFR-expressing lung cancer cells. Biological evaluation included cytotoxicity assessment against A549 (lung cancer) and HdFn (normal fibroblast) cell lines, alongside in-silico docking and ADME profiling to predict drug-likeness and pharmacokinetic behaviour. We hypothesised that the presence of electron-donating groups (EDGs) at the para position of the aryl ring would enhance the cytotoxicity and selectivity of the nitrone derivatives by improving their interaction with EGFR and reducing off-target toxicity.

Methods: The synthesis started with the Vilsmeier-Haack reaction to prepare 4-formyl-3-(3-nitrophenyl)-1-phenyl-1H-pyrazole. N-substituted phenylhydroxylamines were obtained by reducing nitrobenzene derp tolylivatives, followed by condensation with the aldehyde to afford nitrones. The synthesised compounds were evaluated for anticancer activity against A549 lung cancer cells and HdFn normal dermal fibroblast cells using the MTT assay. Additionally, molecular docking studies were performed to investigate interactions with the EGFR tyrosine kinase.

Results: The IC₅₀ values indicated that compound 7a exhibited the most potent activity, with an IC₅₀ of 85.62 µg/mL against A549 cells and a high selectivity index (SI) of 5.5. Pre-ADME in silico analyses showed favourable oral bioavailability and no predicted CNS side effects for all tested compounds.

Conclusion: Spectroscopic data from FT-IR, ¹H-NMR, and ¹³C-NMR confirmed successful target compound syntheses. Biological evaluation revealed that compound 7a demonstrated promising anticancer activity with a favourable selectivity index (SI = 5.5) toward cancer cells over normal cells, indicating its potential as a promising EGFR-targeted therapeutic agent.