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Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation.

Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe3+ = 18.52) and selective hMAO-B inhibitory activity (IC50 = 67.02 ± 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood–brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation. [ABSTRACT FROM AUTHOR]

Hydroxypyridinones (HPs) are recognized as excellent chemical tools for engineering a diversity of metal chelating agents, with high affinity for hard metal ions, exhibiting a broad range of activities and applications, namely in medical, biological and environmental contexts. They are easily made and functionalizable towards the tuning of their pharmacokinetic properties or the improving of their metal complex thermodynamic stabilities. In this review, an analysis of the recently published works on hydroxypyridinone-based ligands, that have been mostly addressed for environmental applications, namely for remediation of hard metal ion ecotoxicity in living beings and other biological matrices is carried out. In particular, herein the most recent developments in the design of new chelating systems, from bidentate mono-HP to polydentate multi-HP derivatives, with a structural diversity of soluble or solid-supported backbones are outlined. Along with the ligand design, an analysis of the relationship between their structures and activities is presented and discussed, namely associated with the metal affinity and the thermodynamic stability of the corresponding metal complexes. [ABSTRACT FROM AUTHOR]

This study evaluates the potential of two chelators, 1,2-dimethyl-3-hydroxypyridine-4-one (Hdpp) and 1-n-butyl-2-methyl-3-hydroxypyridin-4-one (Hnbp), to modulate cerebral rates of free radical production. The fluorometric assay for 2',7'-dichlorofluorescein, which is formed by oxidation of a nonfluorescent precursor (2',7'-dichlorofluorescein diacetate), was used to assay reactive oxygen species (ROS) production. The chelator Hdpp alone and the aluminum complexes of each chelator, Al (dpp)3 and Al (nbp)3, all inhibited basal rates of generation of ROS within a rat cerebral synaptosomal fraction. In the presence of an iron salt (1 microM FeSO4), a major enhancement of synaptosomal ROS formation was apparent. However, with the addition of an equimolar concentration of Hdpp, Al(dpp)3, or Al(nbp)3, this stimulation was completely abolished. The N-substituted-3-hydroxy-4-pyridinones have been proposed to be of clinical utility for the removal of iron or aluminum from tissues. The clinical potential of this class of chelator may be enhanced by their ability to inhibit iron-related oxidative events.

The chelating agents for Al 3+ and Fe 3+ metal cations with therapeutic applications have been considered in the recent years. In designing of the hydroxypyridinones (HPOs) as the therapeutic chelating agents for iron and aluminium overload pathologies, quantum mechanical (QM) calculations are necessary for predicting the binding energies and thermodynamic parameters of the metal−HPO complexes. Three derivatives of the HPOs called 3-hydroxy-1,2-dimethylpyridin-4(1H)-one (DFP), 3-hydroxy-4(1H)-pyridinone (HOPO) and 5-hydroxy-2-(hydroxymethyl)pyridin-4(1H)-one (P1) were investigated for complexation with Fe 3+ and Al 3+ metal ions. Because of the maximum interaction between Fe 3+ and HPOs, all HPOs form stable complexes with Fe 3+ metal ion. Moreover, it was found that [Fe−P1] 2+ is a more stable complex than [Fe−DFP] 2+ and [Fe−3,4-HOPO] 2+ in the gas phase and water, confirming that P1 is the strongest selective iron chelator. The more stability of [Fe−P1] 2+ was attributed to an intramolecular hydrogen bond formation between the hydrogen atom of NH group and the oxygen atom of CH 2 OH chain. All complexes of the HPOs with Fe 3+ and Al 3+ were formed through the oxygen atoms of the C O and O H groups of the HPO. Natural bond orbital analysis showed that the interaction of the lone pair electrons of the oxygen atom of the chelator and antibonding orbitals of the Al 3+ and Fe 3+ are important in the complex formation. Topological parameters at the bond critical points confirmed the effective interaction between the Al 3+ and Fe 3+ metal ions and HPO as well as the nature of the metal−oxygen bonds. [ABSTRACT FROM AUTHOR]

Eight lipophilic 3-hydroxy-4-pyridinones have been prepared from a microwave-mediated reaction along with the corresponding copper(II) complexes. All complexes have been obtained elementally pure and X-ray diffraction studies on two of the copper complexes have confirmed the structure of these compounds. Some of these complexes showed a promising degree of anti-mycobacterial activity against Mycobacterium tuberculosis, where activity seemed to vary by substitution at the pyridinone nitrogen atom. [ABSTRACT FROM AUTHOR]

A study of a series of bifunctional 3-hydroxy-4-pyridinone derivatives, containing side-chains with various alkyl-aryl-amine-amides as extra-functional groups, was conducted to assess the relevance of those groups to the Al-chelating affinity, the lipo-hydrophilic balance of the compounds, and67Ga biodistribution in mice, in view of their potential use as Al-decorporating agents; the results were compared with those for the drug Deferriprone. Their acid-base properties and Al-chelating affinity in aqueous solution were studied by potentiometric techniques. These ligands form very stable tris-chelated Al complexes and the non-chelating extra-groups are only responsible for small differences in the complex stability (?pAl=1.2). At physiological pH the major ligand/complex species have different charges, because of the different extent of protonation of the ligands. The introduction of the different groups induces a well-balanced stepwise-like lipo-hydrophilic character (-0.2

The two polynitrogen heterocyclic based hydroxypyridinone chelators. • Synthesis of new 3-hydroxy-4-pyridinone based ligands. • Excellent iron chelation properties. • Promising ligands with potent antiproliferative activity through iron depletion in vitro. Iron depletion is an efficient strategy for the development of anticancer agents. In an effort to develop efficient chelators, two new 3-hydroxy-4-pyridinone based polyazamacrocycles 1e and 2e were designed and synthesized. A preliminary study of the ligands was carried out to investigate their iron chelating capability and anti-tumor activity. Chelating kinetics revealed that the ligands exhibited excellent iron depletion capacity in neutral and acidic NH 4 OAc buffer solutions. Moreover, MTT assay showed that the new ligands displayed potent inhibitory activity in the proliferation of HepG2 cells. The attachment of hydroxypyridione units on the polyazamacrocycles promoted iron chelating capability and improved the anti-tumor activity by offering additional chelating sites and lipophilicity. These results indicate that two novel compounds may possess the therapeutic potential in the treatment of cancer through depleting cellular iron. [ABSTRACT FROM AUTHOR]

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. [ABSTRACT FROM AUTHOR]