111782-87-7Relevant articles and documents
CN128: A New Orally Active Hydroxypyridinone Iron Chelator
Chen, Wenteng,Yuan, Xin,Li, Zhi,Lu, Zidong,Kong, Sisi,Jiang, Huidi,Du, Houbing,Pan, Xiuhong,Nandi, Manasi,Kong, Xiaole,Brown, Kathryn,Liu, Zudong,Zhang, Guolin,Hider, Robert C.,Yu, Yongping
, p. 4215 - 4226 (2020/05/27)
Deferoxamine, deferiprone, and deferasirox are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy, and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation, leading to the formation of a nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the log P value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of β-thalassemia after regular blood transfusion.
Coumarin heterozygous pyridone compounds having iron chelation and monoamine oxidase B inhibitory activity as well as preparation and application of compounds
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Page/Page column 23-30, (2019/10/01)
The invention discloses coumarin/pyridone heterozygous derivatives represented by a formula (I) shown in the description or a pharmaceutically-acceptable salt of the derivatives. The preparation method of the coumarin/pyridone heterozygous derivatives comprises the following steps: one pyridone derivative represented by a formula 3 shown in the description is obtained by a series of synthesis by using one hydroxypyrone with different substituent groups represented by a formula 1 shown in the description as a raw material; and a compound represented by a formula 4 shown in the description is subjected to a condensation reaction to obtain a compound represented by a formula 5 shown in the description, one-step bromination is performed to obtain a compound represented by a formula 6 shown inthe description, the compound represented by the formula 6 and the pyridone derivative represented by the formula 3 are subjected to a one-step nucleophilic substitution reaction to obtain a compoundrepresented by a formula 7 shown in the description, and finally an alkyl protecting group in a pyridone structure is removed to obtain one target compound represented by the formula (I). The compounds provided by the invention are a novel series of single-molecular multi-target series drugs, and have iron chelation, targeted MAO-B inhibitory activity, antioxidant activity, unique advantages for an Alzheimer disease with complicated pathogenesis, a clear mechanism of action and excellent activity.
Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease
Zhang, Changjun,Yang, Ke,Yu, Sihang,Su, Jing,Yuan, Shengli,Han, Jiaxin,Chen, Yan,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
, p. 367 - 382 (2019/07/19)
A series of hybrids of hydroxypyridinone and coumarin were rationally designed, synthesized and biologically evaluated for their iron ion chelating and MAO-B inhibitory activities. Most of the compounds displayed excellent iron ion chelating effects and moderate to good anti-MAO-B activities. Compound 27a exhibited the most potent activity against MAO-B, with an IC50 value of 14.7 nM. Importantly, 27a showed good U251 cell protective effect and significantly ameliorated the cognitive dysfunction of scopolamine-induced AD mice. Moreover, molecular docking was performed to elucidate the probable ligand-receptor interaction, and the structure-activity relationships were also summarized.
Hydroxypyridinone and 5-Aminolaevulinic Acid Conjugates for Photodynamic Therapy
Battah, Sinan,Hider, Robert C.,MacRobert, Alexander J.,Dobbin, Paul S.,Zhou, Tao
, p. 3498 - 3510 (2017/05/05)
Photodynamic therapy (PDT) is a promising treatment strategy for malignant and nonmalignant lesions. 5-Aminolaevulinic acid (ALA) is used as a precursor of the photosensitizer, protoporphyrin IX (PpIX), in dermatology and urology. However, the effectiveness of ALA-PDT is limited by the relatively poor bioavailability of ALA and rapid conversion of PpIX to haem. The main goal of this study was to prepare and investigate a library of single conjugates designed to coadminister the bioactive agents ALA and hydroxypyridinone (HPO) iron chelators. A significant increase in intracellular PpIX levels was observed in all cell lines tested when compared to the administration of ALA alone. The higher PpIX levels observed using the conjugates correlated well with the observed phototoxicity following exposure of cells to light. Passive diffusion appears to be the main mechanism for the majority of ALA-HPOs investigated. This study demonstrates that ALA-HPOs significantly enhance phototherapeutic metabolite formation and phototoxicity.
5-aminolevulinic acid/3-hydroxyl pyridone conjugate, preparation method therefor and use of 5-aminolevulinic acid/3-hydroxyl pyridone conjugate
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Paragraph 0046; 0047, (2017/08/28)
The invention discloses conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one. The conjugates are conjugates of 5-aminolevulinic acid and an iron chelating agent, i.e., 3-hydroxyl pyrid-4-one and are ALA-HPO conjugates 1 to 4 separately. The invention further simultaneously discloses a preparation method for the conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one and use of the conjugates of 5-aminolevulinic acid and 3-hydroxyl pyrid-4-one. The conjugates can be used for preparing photodynamic therapy drugs and can also be used for preparing drugs for treating skin cancer, lung cancer or verruca acuminata.
CHIRAL 3-HYDROXYPYRID-4-ONE DERIVATIVE, AND SYNTHESIS AND USE THEREOF
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Paragraph 0039; 0040, (2014/02/16)
Disclosed are a chiral 3-hydroxypyrid-4-one derivative and a salt thereof. The compound is acquired by reacting methyl maltol or ethyl maltol with benzyl chloride to acquire a 3-benzyl protected maltol, then by reacting compound VII with different chiral amino alcohols to acquire 3-benzyloxypyrid-4-one, and finally by performing a palladium on carbon-catalyzed hydride reduction deprotection on compound IX. The compound of the present invention is capable of having iron ion chelating bioactivity, and is applicable in preparing an anti-iron overload medicament. The structure of the compound of the present invention is represented as formula (I).
Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids
Andayi, Warren A.,Egan, Timothy J.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
supporting information, p. 642 - 646 (2013/07/26)
A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).
Synthesis, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives
Fassihi, Afshin,Abedi, Daryoush,Saghaie, Lotfollah,Sabet, Razieh,Fazeli, Hossein,Bostaki, Ghasem,Deilami, Omid,Sadinpour, Hekmatollah
body text, p. 2145 - 2157 (2009/09/30)
A series of Mannich bases of 2-alkyl-3-hydroxy-pyridine-4-ones, namely 2-alkyl-3-hydroxy-5-N-piperidylmethyl or N,N-dialkylaminomethyl pyridine-4-ones 9, 10 and 15-18, two derivatives of N-aryl-2-methyl-3-hydroxy-pyridine-4-ones 19, 20 and two N-alkyl derivatives of maltol, 21 and 22 were prepared. They were screened for their antibacterial and antifungal activities against a variety of microorganisms using micro plate Alamar Blue assay (MABA) method. Multiple linear regressions (MLR) analysis was performed for the synthesized compounds as well as a series of pyridinone and pyranone derivatives 23-43 which have been synthesized and evaluated for antimicrobial activity by other researchers previously. Studied compounds showed a better quantitative structure-activity relationship (QSAR) model for the antimicrobial activity against Candida albicans and Staphylococcus aureus in comparison with other tested microorganisms.
Basic 3-hydroxypyridin-4-ones: Potential antimalarial agents
Dehkordi, Lotfollah S.,Liu, Zu D.,Hider, Robert C.
, p. 1035 - 1047 (2008/09/20)
3-Hydroxypyridin-4-ones selectively bind iron under biological conditions and one such compound has found application in the treatment of thalassaemia-linked iron overload. Related molecules have also been demonstrated to possess an antimalarial effect at levels which are non-toxic to mammalian cells. In an attempt to improve the efficiency of such molecules we have investigated the effect of introducing basic nitrogen centres into 3-hydroxypyridin-4-ones in an attempt to achieve targeting to lysosomes and other intracellular acidic vacuoles. Several of the compounds reported in this communication possess enhanced antimalarial activity over that of the simple hydroxypyridinone class.
Design, synthesis, and evaluation of novel 2-substituted 3-hydroxypyridin-4-ones: Structure-activity investigation of metalloenzyme inhibition by iron chelators
Liu, Zu D.,Kayyali, Reem,Hider, Robert C.,Porter, John B.,Theobald, Anthony E.
, p. 631 - 639 (2007/10/03)
A range of novel 3-hydroxypyridin-4-ones with different R2 substitutents has been synthesized for the investigation of the structure-activity relationship between the chemical nature of the ligand and the inhibitory activity of the iron-contain
