Alzheimer’s disease (AD) is driven by the accumulation of amyloid-β (Aβ) peptides into neurotoxic aggregates, a process amplified by aberrant metal ion homeostasis. Copper (Cu), zinc (Zn), iron (Fe), and aluminum (Al) ions are known to bind Aβ with high affinity, promoting fibril formation and catalyzing oxidative stress through Fenton-like reactions. Targeting these metal-Aβ interactions via chelation therapy presents a rational strategy for disease intervention. This study employs density functional theory (DFT) to conduct a comprehensive analysis of the structural and energetic properties of metal-chelator complexes involving 8-hydroxyquinoline-2-carboxaldehyde isonicotinoyl hydrazone (INNHQ), 8-hydroxyquinoline-2-carboxaldehyde 2-furoyl hydrazone (HQFUH), quercetin, and graphene oxide (GO).
The optimized geometries of each metal-chelator complex reveal distinct coordination patterns. HQFUH forms stable five-membered chelate rings with Cu²⁺, Zn²⁺, Fe³⁺, and Al³⁺, primarily through nitrogen atoms from the hydrazone and quinoline moieties. The calculated binding energies—749.8, 738.5, 775.8, and 850.5 kcal mol⁻¹ for Cu, Zn, Fe, and Al, respectively—are all significantly higher than those of their corresponding metal-Aβ complexes (35.6, 15.7, 15.1, and 49.6 kcal mol⁻¹). This energy advantage confirms that HQFUH can effectively displace metals from Aβ, thereby inhibiting aggregation and reducing ROS generation.
In contrast, INNHQ exhibits negative binding energies ranging from −106.5 to −20.3 kcal mol⁻¹, indicating thermodynamically unstable complexes. Despite its structural resemblance to HQFUH, the presence of an isonicotinoyl group appears to disrupt optimal coordination geometry, resulting in weaker metal binding. Quercetin shows moderate interaction strength, particularly for Al (18.8 kcal mol⁻¹), due to coordination through phenolic oxygen atoms.151-18-8 References However, its binding energy remains below that of Al–Aβ, limiting its potential as a standalone chelator.525-66-6 InChIKey
Graphene oxide (GO) was analyzed at three oxygen concentrations: 3.125%, 9.375%, and 12.5%. Only the 12.5% oxygen configuration—characterized by four epoxy groups on a single hexagonal ring—demonstrated effective chelation. The Al–GO complex achieved a binding energy of 55.3 kcal mol⁻¹, exceeding the Al–Aβ value (49.6 kcal mol⁻¹), confirming its capacity to sequester aluminum. The high surface area and polar functional groups of GO facilitate strong electrostatic and covalent interactions with metal ions.
Charge transfer calculations show substantial electron donation from ligands to metal centers, especially in HQFUH and GO systems.PMID:28613794 Isosurface plots illustrate clear electron depletion at the metal and enrichment at donor sites, consistent with the formation of stable coordination bonds. This redistribution supports the redox-inert nature of the resulting complexes, minimizing pro-oxidant activity.
These results highlight HQFUH as a highly effective, multi-metal chelator capable of disrupting pathogenic metal-Aβ interactions. Graphene oxide, when properly functionalized, emerges as a promising nanomaterial platform for aluminum removal. Together, these findings provide critical insights for designing next-generation therapeutics aimed at restoring metal homeostasis in Alzheimer’s disease. Future work should focus on experimental validation, blood-brain barrier permeability, and long-term safety profiles of these agents.MedChemExpress (MCE) offers a wide range of high-quality research chemicals and biochemicals (novel life-science reagents, reference compounds and natural compounds) for scientific use. We have professionally experienced and friendly staff to meet your needs. We are a competent and trustworthy partner for your research and scientific projects.Related websites: https://www.medchemexpress.com
