Development of Novel Quinoline Derivatives as Dual-Target Inhibitors: Synthesis, Characterization, and Anticancer Potential

In this study, a novel series of hybrid molecules was rationally designed and synthesized to function as dual inhibitors targeting both epidermal growth factor receptor (EGFR) and histone deacetylase (HDAC), two critical therapeutic targets in cancer. The synthetic approach yielded compounds in high purity (≥95%) and moderate to excellent yields (62–91%), confirmed through spectroscopic (¹H NMR, ¹³C NMR, HRMS) and analytical techniques. Structural novelty was validated through database searches. A comprehensive structure-activity relationship (SAR) analysis revealed that electron-withdrawing groups such as –NO₂ and –CF₃ significantly enhanced dual-target inhibitory activity, while bulky ortho-substituents negatively influenced potency. Lead compounds, particularly 1a and 1c, demonstrated superior bioactivity with sub-micromolar IC₅₀ values against both targets. Notably, compound 1c exhibited enhanced cytotoxicity in A549 and MCF-7 cancer cell lines, outperforming reference drugs Gefitinib and Vorinostat. Mechanistic studies confirmed that lead compounds induced apoptosis via mitochondrial pathways, evidenced by increased caspase-3 activation and Bcl-2 downregulation. Additionally, dual inhibition of PI3K/AKT and MAPK/ERK signaling pathways was observed, suggesting multi-pathway suppression as a mechanism of anticancer efficacy. The dual-selectivity profile and favorable in vitro potency position these compounds as promising candidates for further development in targeted cancer therapy.