Dual action of novel 5-nitroguaiacol-based hydrazones: Targeting aldolase-a and inducing apoptosis in lung cancer

Building upon previous research on hydrazone-bearing aryloxyacetic acid derivatives, a novel series of 5-nitroguaiacol-based hydrazones (<b>3a–l</b>) was synthesized and characterized spectroscopically. Their <i>in vitro</i> cytotoxic effects were evaluated against human non-small cell lung cancer (A549) and normal bronchial epithelial cell lines (BEAS-2B) using the MTT assay. Compounds <b>3d</b> and <b>3k</b> exhibited selective and potent cytotoxicity (IC₅₀ = 10.24 µM and 4.99 µM, respectively) and strong aldolase A (ALDOA) inhibition at 10 µM (89.89% and 75.19%). Further mechanistic studies revealed that both compounds decreased HIF-1α expression and modulated apoptotic pathways by upregulating Bax and downregulating Bcl-2 protein levels. Molecular docking studies supported the experimental findings, demonstrating significant interactions of <b>3d</b> and <b>3k</b> with key residues in ALDOA, Bax, and Bcl-2, suggesting a dual mechanism involving glycolysis inhibition and apoptosis induction. These results indicate that <b>3d</b> and <b>3k</b> are promising lead compounds for targeted lung cancer therapy.