CN128: A New Orally Active Hydroxypyridinone Iron Chelator

Chen, Wenteng; Yuan, Xin; Li, Zhi; Lu, Zidong; Kong, Sijia; Jiang, Huidi; Du, Hou-bing; Pan, Xiuhong; Nandi, Manasi; Kong, Xiaole; Brown, Kathryn; Liu, Zudong; Zhang, Guolin; Hider, Robert C.; Yu, Yongping

doi:10.1021/acs.jmedchem.0c00137

Cited by 22 publications

(28 citation statements)

References 35 publications

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“…To further understand the drug-likeness, the molecular properties of these new hybrids were predicted and performed by molinspiration ( http://www.molinspiration.com ). It was found that miLog p -values of HPOs were closer to the experimentally measured values than those calculated by other programs 33 . All the compounds were in accordance with Lipinski’s rules and Veber’s rules.…”

Section: Resultssupporting

confidence: 48%

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Jiang

Guo

Zhang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds 18d , benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe 3+ values ranging from 18.13 to 19.39. Among all the compounds, 8g exhibited the most potent selective MAO-B inhibitor (IC 50 = 68.4 nM, SI = 213). Moreover, 8g showed favourable pharmacokinetic properties and had great potential to penetrate the BBB in silico and PAMPA-BBB assay. Molecular modelling showed that 8g could adopt an extended conformation and have more enhanced interactions with MAO-B than 18d . In vitro and in vivo assays demonstrated that 8g remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound 8g is a potential multifunctional candidate for anti-AD treatment.

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Section: Resultssupporting

confidence: 48%

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Jiang

Guo

Zhang

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…These would include iron mobilization, free-radical scavenging and the anti-proliferative effects of Fao cells when compared to DFP [ 27 , 28 ]. Currently, a novel synthetic bidentate amino alcohol-conjugated HPO chelator has been reported as being more lipophilic and efficient in terms of iron-binding affinity than the parent DFP (log P o / w values for free ligands = 0.56 versus −0.77; log P o / w values for [Fe-L 3 ] = 0.58 versus −2.6; iron-mobilizing efficacy in rats = 24.8 versus 11.8%, respectively); nevertheless, this chelator has never been assessed for anti-malarial activity, either in vitro or in vivo [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Identifying a Deferiprone–Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent

et al. 2021

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Malaria i a serious health problem caused by Plasmodium spp. that can be treated by an anti-folate pyrimethamine (PYR) drug. Deferiprone (DFP) is an oral iron chelator used for the treatment of iron overload and has been recognized for its potential anti-malarial activity. Deferiprone–resveratrol hybrids (DFP-RVT) have been synthesized to present therapeutic efficacy at a level which is superior to DFP. We have focused on determining the lipophilicity, toxicity and inhibitory effects on P. falciparum growth and the iron-chelating activity of labile iron pools (LIPs) by DFP-RVT. According to our findings, DFP-RVT was more lipophilic than DFP (p < 0.05) and nontoxic to blood mononuclear cells. Potency for the inhibition of P. falciparum was PYR > DFP-RVT > DFP in the 3D7 strain (IC50 = 0.05, 16.82 and 47.67 µM, respectively) and DFP-RVT > DFP > PYR in the K1 strain (IC50 = 13.38, 42.02 and 105.61 µM, respectively). The combined treatment of DFP-RVT with PYR additionally enhanced the PYR activity in both strains. DFP-RVT dose-dependently lowered LIP levels in PRBCs and was observed to be more effective than DFP at equal concentrations. Thus, the DFP-RVT hybrid should be considered a candidate as an adjuvant anti-malarial drug through the deprivation of cellular iron.

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“…A log P-guided investigation of 20 hydroxpyridinones resulted in the identification of CN128. A study by Chen et al [ 155 ] showed that the Fe(III) affinity and metal selectivity of CN128 are similar to those of DFP, the log p value is more lipophilic, and its iron scavenging ability is superior. It was concluded that CN128 was safe in a range of toxicity assessments and is currently used in clinical trials for the treatment of β -thalassemia after regular blood transfusion.…”

Section: Combined Therapy With More Than One Chelatormentioning

confidence: 99%

Iron Chelators in Treatment of Iron Overload

Entezari

Haghi

Norouzkhani

et al. 2022

Journal of Toxicology

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Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.

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CN128: A New Orally Active Hydroxypyridinone Iron Chelator

Cited by 22 publications

References 35 publications

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease

Identifying a Deferiprone–Resveratrol Hybrid as an Effective Lipophilic Anti-Plasmodial Agent

Iron Chelators in Treatment of Iron Overload

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