Integrated experimental and computational exploration of 1,8-naphthyridine hydrazones as promising topoisomerase II-targeting anticancer agents

Abstract

DNA topoisomerase II (Topo II) is essential for maintaining DNA topology during replication, transcription, and chromosome segregation. Its increased expression is associated with tumor progression, which makes it an appealing target for anticancer therapy. However, clinically used Topo II inhibitors such as etoposide and doxorubicin are limited by toxicity and resistance, illustrating the importance of safer, more effective chemotherapeutic scaffolds. This study reports the rational design, synthesis, and biological evaluation of a novel series of hydrazone derivatives incorporating a 1,8-naphthyridine core as potential Topo II inhibitors. Hybrid molecules were generated by integrating hydrazone moieties with the naphthyridine scaffold and characterized using standard spectroscopic techniques. Their biological activities were assessed via in vitro cytotoxicity assays and Topo II inhibition tests. Complementary computational investigations, including density functional theory (DFT), molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free-energy analysis, and per-residue MM/GBSA free-energy decomposition analysis, were performed to explore electronic properties, ligand–target interactions, and binding determinants. Among the synthesized series, compound 3b displayed notable antiproliferative activity, particularly against the HL-60 (TB) leukemia cell line (GI₅₀ = 1.99–3.02 μM), and exhibited potent Topo II inhibition (IC₅₀ = 1.79 ± 0.73 μM), outperforming doxorubicin (IC₅₀ = 3.08 ± 0.59 μM) under the same conditions. Computational modelling supported these findings by indicating stable binding conformations and suggesting a potential DNA-intercalative binding mode within the Topo II catalytic environment. However, this interaction remains a computational prediction that requires experimental validation.