Hybrid amine-derived compounds as cytotoxic anticancer leads: design, synthesis, and biological evaluation

Aurora kinases are key regulators of cell division and promising therapeutic targets in cancer treatment, particularly Aurora-A kinase, which is overexpressed in many tumors and associated with malignant progression. In this study, a series of novel amine-based hybrid molecules were designed and synthesized via amine reduction to explore their potential as inhibitors of Aurora-A kinase. The synthesized compounds (4a-l, 8a-c) were structurally confirmed by NMR and HRMS and evaluated for in vitro kinase inhibition and cytotoxicity. Among them, compound 8a demonstrated the most potent Aurora-A inhibition (IC₅₀ = 5.6 µM) and significant cytotoxic activity against A549 lung cancer cells (IC₅₀ = 8.32 µM) and HT-29 colorectal cancer cells (IC₅₀ = 7.94 µM). Molecular docking studies suggested that compound 8a may form multiple hydrogen bonds and hydrophobic interactions within the ATP-binding pocket of Aurora-A kinase, consistent with its experimental activity. Its physicochemical properties (log P = 4.05, TPSA = 60.99) indicate promising characteristics similar to leading compounds, making it suitable for further refinement. Overall, these results highlight compound 8a as a promising construct for developing next-generation Aurora-A kinase inhibitors, which may be used in targeted cancer therapy.