- Bifunctional 3-hydroxy-4-pyridinones as effective aluminium chelators: synthesis, solution equilibrium studies and in vivo evaluation
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This paper reports the results on the study of a set of synthesized bifunctional 3-hydroxy-4-pyridinones chelators as potential aluminium sequestering agents. They were N-functionalized with alkyl-amino, -carboxylic and –(amino-carboxylic) groups, envisaging the improvement of the Al3+ sequestering capacity, in comparison with the marketed chelating drug deferiprone. The main focus of this work was given to the assessment of their binding ability towards Al3+, which was studied by potentiometric and UV–Vis spectrophotometric measurements carried out at T = 298.15 K. The speciation models were characterized by AlpLqHr (3p+r?qz) species with different stoichiometry. Depending on ligand side-chain structures and on their thermodynamic properties, different trends of stability was found. Furthermore, the sequestering ability of the ligands towards Al3+ was investigated by the calculation of pL0.5 values at different experimental conditions. These results clearly indicate that the presence of amino-carboxylic groups in the ligands increases the sequestering ability towards Al3+. The in silico evaluation of pharmacokinetic descriptors indicated no violation to the Lipinski's rule and drug-likeness properties. Furthermore, the in vivo bioassays on a model of metal-overload mice showed for three investigated ligands a higher metal-sequestering capacity than for the chelating drug deferiprone, thus suggesting their potential interest as Al-chelating drug candidates.
- Irto, Anna,Cardiano, Paola,Chand, Karam,Cigala, Rosalia Maria,Crea, Francesco,De Stefano, Concetta,Gano, Lurdes,Sammartano, Silvio,Santos, Maria Amélia
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- DIBI, a 3-hydroxypyridin-4-one chelator iron-binding polymer with enhanced antimicrobial activity
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Depriving microorganisms of bioavailable iron is a promising strategy for new anti-infective agents. The new, highly water-soluble, low molecular weight co-polymer DIBI was developed to selectively bind iron(iii) ions as a tris chelate and acts as a standalone anti-infective. Minimum inhibitory concentration (MIC) studies show DIBI is effective against representative reference strains for Gram-positive and Gram-negative bacteria S. aureus and A. baumannii, and the fungus C. albicans. Compared to the small molecule iron chelators, deferiprone and deferoxamine, DIBI outclassed these by factors of 100 to 1000 for inhibition of initial growth. DIBI and a series of related co-polymers (Mw of 2-9 kDa) were synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization of a chelating 3-hydroxypyridin-4-one (HPO) methacrylamide monomer and N-vinylpyrrolidone (NVP). Full incorporation of the HPO monomer into the co-polymers from the reaction solution was determined by 1H NMR spectroscopy and ranged from 4.6 to 25.6 mol%. UV-vis spectroscopy showed that all the HPO in DIBI binds readily to iron(iii) in a tris chelate mode to the maximum theoretical iron(iii) binding capacity of the co-polymer. Chemical characterization including single crystal X-ray diffraction analyses of the O-benzyl protected and the functional HPO monomer are discussed. By design, DIBI is highly water soluble; the highest mass fraction in water tested was 70% w/w, without the need of organic co-solvents.
- Ang, M. Trisha C.,Gumbau-Brisa, Roger,Allan, David S.,McDonald, Robert,Ferguson, Michael J.,Holbein, Bruce E.,Bierenstiel, Matthias
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- New polyazamacrocyclic 3-hydroxy-4-pyridinone based ligands for iron depletion antitumor activity
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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 liga
- Dong, Xiuxiu,He, Chuanchuan,Liu, Xiaoguang,Ma, Xiang,Xiang, Guangya,Zhang, Xiaojuan
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- In silico to in vitro screening of hydroxypyridinones as acetylcholinesterase inhibitors
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We have previously shown the improved acetylcholinesterase inhibitory activity of a model hydroxypyridinone compound transforming the hydroxyl group on the main ring into an N,N-dimethylcarbamate group; in the course of that study we developed a computational model to screen compounds for enzymatic activity. Herein we report development of second generation libraries. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Synthesis and characterization of chosen test compounds and their acetylcholinesterase inhibitory activity are presented.
- Telpoukhovskaia, Maria A.,Patrick, Brian O.,Rodríguez-Rodríguez, Cristina,Orvig, Chris
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- Phenylethylene glycol-derived LpxC inhibitors with diverse Zn2+-binding groups
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The Zn2+-dependent bacterial deacetylase LpxC is a promising target for the development of novel antibiotics. Most of the known LpxC inhibitors carry a hydroxamate moiety as Zn2+-binding group. However, hydroxamic acids generally exh
- Galster, Magdalena,L?ppenberg, Marius,Galla, Fabian,B?rgel, Frederik,Agoglitta, Oriana,Kirchmair, Johannes,Holl, Ralph
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- Preparation method of intermediate of antiviral drug
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The invention relates to a preparation method of an intermediate of an antiviral drug, belonging to the field of medicinal chemistry. According to the method provided by the invention, raw materials react with an alkene forming reagent under the condition that Lewis acid and acid anhydride are added to prepare an intermediate compound; and then the intermediate compound reacts under the action of sodium periodate, and then post-treatment is conducted under the conditions of alkali and an oxidizing agent to obtain the intermediate. According to the method disclosed by the invention, reagents with relatively high toxicity or relatively high price and conditions such as extremely low temperature which is difficult to reach or control are not needed, used reagents are cheap and easy to obtain, reaction conditions are easy to control and implement, and the method has relatively high industrial application value.
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Paragraph 0061-0064
(2021/06/22)
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- Polycyclic pyridine oxime-based compound as well as pharmaceutical composition and application thereof
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The invention discloses a polycyclic pyridine oxime-based compound and a pharmaceutical composition and application thereof, wherein the polycyclic pyridine oxime-based compound is shown as a formula (I). The compound shows strong inhibition of influenza
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Paragraph 0150-0153
(2021/11/26)
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- Design, synthesis and biological evaluation of potential anti-AD hybrids with monoamine oxidase B inhibitory and iron-chelating effects
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A series of active hybrids combining 3-hydroxypyridin-4(1H)-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (p
- Guo, Jianan,Mi, Zhisheng,Jiang, Xiaoying,Zhang, Changjun,Guo, Zili,Li, Linzi,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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- Design, synthesis and biological evaluation of a series of iron and copper chelating deferiprone derivatives as new agents active against Candida albicans
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Candida albicans, in specific conditions, is responsible of severe invasive systemic candidiasis that are related to its ability to produce biofilm on biological and artificial surfaces. Many studies reported the role of iron in fungal growth and virulence and the ability of metal chelating agents to interfere with C. albicans metabolism, virulence and biofilm formation. Here we report the activity of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone (deferiprone) derivatives against C. albicans planktonic cells and biofilm. Some of the studied compounds (2b and 3b) were able to chelate Fe(III) and Cu(II), and showed an interesting activity on planktonic cells (MIC50 of 32 μg/mL and 16 μg/mL respectively) and on biofilm formation (BMIC50 of 32 μg/mL and 16 μg/mL respectively) in cultured ATCC 10,231C. albicans; this activity was reduced, in a concentration dependent way, by the addition of Fe(III) and Cu(II) to the culture media. Furthermore, the most active compound 3b showed a low toxicity on Galleria mellonella larvae.
- Bortolami, Martina,Pandolfi, Fabiana,Messore, Antonella,Rocco, Daniele,Feroci, Marta,Di Santo, Roberto,De Vita, Daniela,Costi, Roberta,Cascarino, Paola,Simonetti, Giovanna,Scipione, Luigi
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- Design and synthesis of N-hydroxyalkyl substituted deferiprone: a kind of iron chelating agents for Parkinson's disease chelation therapy strategy
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The blood–brain barrier (BBB) permeability of molecules needs to meet stringent requirements of Lipinski’s rule, which pose a difficulty for the rational design of efficient chelating agents for Parkinson's disease chelation therapy. Therefore, the iron c
- Zhang, Qingchun,Feng, Shufan,Zhao, Yulian,Jin, Bo,Peng, Rufang
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p. 467 - 478
(2021/05/13)
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- N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer's disease
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AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N-propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe3+ = 17.09–22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase (hMAO-B IC50 = 0.083 ± 0.001 μM, hMAO-A IC50 = 6.11 ± 0.08 μM; SI = 73.5), prediction of blood–brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N-propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.
- Guo, Jianan,Zhang, Yujia,Zhang, Changjun,Yao, Chuansheng,Zhang, Jingqi,Jiang, Xiaoying,Zhong, Zhichao,Ge, Jiamin,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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- Spiro pyridone derivative and application
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The invention discloses a spiro pyridone derivative which has a structure shown in a general formula I in the specification. Researches show that the spiro pyridinone derivative has a relatively strong inhibition effect on the activity of influenza A virus RNA polymerase, and can be applied to the preparation of influenza A virus RNA polymerase activity inhibition and influenza A resistance medicines. The general formula I is shown in the specification.
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Paragraph 0049-0053
(2020/12/29)
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- CN128: A New Orally Active Hydroxypyridinone Iron Chelator
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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.
- 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
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p. 4215 - 4226
(2020/05/27)
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- Pyridone [1, 2-b] [1,5] triazepine derivatives as well as preparation and application thereof (by machine translation)
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The invention discloses a hydroxypyridone [1, a-b] [1,5] triazepine derivatives as well as preparation and application thereof. Experiments prove that the hydroxypyridinone [1, 2-b] [1,triazepine derivatives (general formula I) have a good inhibition effect on the RNA polymerase activity of influenza A virus RNA, and can be used as an influenza virus RNA polymerase inhibitor to treat influenza caused by influenza virus. General Formula I is as follows. (by machine translation)
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Paragraph 0062-0065
(2020/12/30)
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- Pd(ii)-Complexes of a novel pyridinone based tripeptide conjugate: Solution and solid state studies
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A novel peptide conjugate (H(L2)) incorporating N-donors of the peptide backbone and an (O,O) donor set of a hydroxypyridinone moiety is synthesized and characterized. This ambidentate chelating ligand is intended to develop Co(iii)/Pt(ii) heterobimetallic multitargeted complexes with anticancer potential. To explore its metal ion binding ability the interaction with Pd(ii) (as a Pt(ii) model but with faster ligand exchange reactions) was studied in aqueous solution by the combined use of pH-potentiometry, NMR and HR MS. In an equimolar solution H(L2) was found to bind Pd(ii) via the terminal amino group and increasing number of peptide nitrogens of the peptide backbone over a wide pH range. Around physiological pH an (N,N) and (O,O) chelated 2:2 minor species was also identified. At a 2:1 Pd(ii) to ligand ratio the formation of dinuclear species, [Pd2H-x(L2)] (x = 1-4), with high stability and with the involvement of the (O,O) chelating set of the ligand too, was demonstrated. Reaction of H3(L2)2+ with Pd(ii) in the presence of chloride ions at pH ~ 2.0 afforded [PdH(L2)Cl2]·2H2O (3) in a solid state whose molecular structure was assessed by single crystal X-ray diffraction. The structure of 3 revealed that Pd(ii) is coordinated by a (NH2, Namide) chelate of the ligand in a square planar fashion. It also indicates that under suitable conditions a 2N coordinated Pd(ii) complex can also be obtained even in the presence of four available nitrogen donors in the chelatable position in the ligand most likely due to its neutral charge and the decreased conditional stability of the amide-involved chelate(s) under acidic conditions. Reaction of H(L2) with [Co(tren)]3+ (tren = tris(2-aminoethyl)amine) revealed the exclusive coordination of (L2)-via its (O,O) chelate to the metal core while treatment of the Co-complex with Pd(ii) resulted in the formation of a Co/Pd heterobimetallic complex in solution with (NH2, Namide) chelated Pd(ii). Reaction of 3 with 9-methylguanine indicated the N7 coordination of this simple DNA model to Pd(ii) in a 1:1 ratio.
- Bényei, Attila Csaba,Buglyó, Péter,Diószegi, Róbert,Ozsváth, András
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p. 9254 - 9267
(2020/09/09)
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- Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity
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A series of (3-hydroxypyridin-4-one)-coumarin hybrids were developed and investigated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through the incorporation of iron-chelating and monoamine oxidase B (MAO-B) inhibition. This combination endowed the hybrids with good capacity to inhibit MAO-B as well as excellent iron-chelating effects. The pFe3+ values of the compounds were ranging from 16.91 to 20.16, comparable to more potent than the reference drug deferiprone (DFP). Among them, compound 18d exhibited the most promising activity against MAO-B, with an IC50 value of 87.9 nM. Moreover, compound 18d exerted favorable antioxidant activity, significantly reversed the amyloid-β1-42 (Aβ1-42) induced PC12 cell damage. More importantly, 18d remarkably ameliorated the cognitive dysfunction in a scopolamine-induced mice AD model. In brief, a series of hybrids with potential anti-AD effect were successfully obtained, indicating that the design of iron chelators with MAO-B inhibitory and antioxidant activities is an attractive strategy against AD progression.
- Bai, Renren,Gu, Jinping,Guo, Jianan,Jiang, Xiaoying,Lv, Yangjing,Mi, Zhisheng,Shi, Yuan,Xie, Yuanyuan,Yao, Chuansheng,Zhang, Changjun,Zhou, Tao
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- Coumarin hybrid pyridinone amide derivative with potential anti-AD activity and preparation method and application of derivative
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The invention discloses a coumarin hybrid pyridinone amide derivative and a preparation method and application thereof. The coumarin hybrid pyridinone amide derivative and pharmacologically acceptablesalt thereof are shown in the formula (I) and the formula (II), and the derivative can be used for preparing drugs for resisting the Alzheimer's disease, the Parkinson's disease or treating other diseases or symptoms by suppressing monoamine oxidase, chelating metallic iron ions, resisting A and resisting oxidation.
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Paragraph 0098-0100
(2020/02/27)
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- New deferiprone derivatives as multi-functional cholinesterase inhibitors: design, synthesis and in vitro evaluation
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In order to obtain multi-functional molecules for Alzheimer's disease, a series of deferiprone derivatives has been synthesized and evaluated in vitro with the hypothesis that they can restore the cholinergic tone and attenuate the dyshomeostasis of the metals mainly involved in the pathology. These compounds were designed as dual binding site AChE inhibitors: they possess an arylalkylamine moiety connected via an alkyl chain to a 3-hydroxy-4-pyridone fragment, to allow the simultaneous interaction with catalytic active site (CAS) and peripheral anionic site (PAS) of the enzyme. Deferiprone moiety and 2-aminopyridine, 2-aminopyrimidine or 2,4-diaminopyrimidine groups have been incorporated into these compounds, in order to obtain molecules potentially able to chelate bio-metals colocalized in Aβ plaques and involved in the generation of radical species. Synthesized compounds were tested by enzymatic inhibition studies towards EeAChE and eqBChE using Ellman's method. The most potent EeAChE inhibitor is compound 5a, with a Ki of 788 ± 51 nM, while the most potent eqBChE inhibitors are compounds 12 and 19, with Ki values of 182 ± 18 nM and 258 ± 25 nM respectively. Selected compounds, among the most potent cholinesterases inhibitors, were able to form complex with iron and in some cases with copper and zinc. Moreover, these compounds were characterized by low toxicity on U-87 MG Cell Line from human brain (glioblastoma astrocytoma).
- Alcaro, Stefano,Bagetta, Donatella,Bortolami, Martina,Carafa, Camilla,Chiarotto, Isabella,Colone, Marisa,Costi, Roberta,De Vita, Daniela,Di Santo, Roberto,Feroci, Marta,Messore, Antonella,Pandolfi, Fabiana,Scipione, Luigi,Stringaro, Annarita
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- PYRIDOPYRAZINE AND PYRIDOTRIAZINE INHIBITORS OF INFLUENZA VIRUS REPLICATION
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Provided herein are compounds that can inhibit the replication of influenza viruses, reduce the amount of influenza viruses, and/or treat influenza. (I)
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Paragraph 00267
(2020/05/06)
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- Intermediate and preparation method thereof
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The invention provides a compound as shown in a formula (III). R in the formula is hydrogen atom or hydroxyl protective group. The invention further provides a preparation method of the compound shownin the formula (III), and a preparation method of the compound shown in a formula (I). The compound shown in a formula (IV) is treated as a starting raw material and is reacted with DMF-DMA to obtainthe compound shown in the formula (III); the compound shown in the formula (III) is oxidized to obtain the compound shown in the formula (I). According to the preparation method, raw materials are low in price and easy to obtain; the conditions are mild and are easy to control; the yield is high; few three wastes are generated; massive industrial production can be carried out.
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Paragraph 0067-0070
(2019/07/04)
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- A new bis-(3-hydroxy-4-pyridinone)-DTPA-derivative: Synthesis, complexation of di-/tri-valent metal cations and in vivo M3+ sequestering ability
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A new polyaminocarboxylic bis-(3-hydroxy-4-pyridinone), derivative of DTPA, DTPA(PrHP)2, was synthesized starting from maltol by means of a coupling reaction of a protected 3-hydroxy-4-pyridinone and DTPA bis-anhydride. The DTPA(PrHP)2 acid-base behavior was investigated by UV–Vis spectrophotometry and spectrofluorimetry at I = 0.15 mol L?1 in NaCl(aq) at T = 298.15 K and T = 310.15 K. To confirm the speciation scheme, also 1H NMR measurements were performed at T = 298.15 K. The protonation constants obtained from the cited different analytical techniques showed good accordance and were also in agreement with data reported in the literature. The complexing ability of DTPA(PrHP)2 towards divalent (Ca2+, Cu2+, Zn2+) and trivalent (Al3+, Fe3+) cations was studied by potentiometric, UV–Vis spectrophotometric and 1H NMR titrations at T = 298.15 K and I = 0.15 mol L?1 in NaCl(aq). The fitting analysis of experimental data led to the determination of different speciation models consisting of MpLqHr (pn+r-5q) species with different stoichiometry and protonation stages, hydrolytic mixed and polynuclear complexes. The equilibrium model and complex formation constants, obtained from various analytical techniques, are in good agreement. The sequestering ability of the ligand towards the metal cations was assessed through the determination of the pL0.5 and pM parameters at different pH values and pH = 7.4, respectively, which showed to follow the trend Fe3+ > Al3+ > Cu2+ > Ca2+ > Zn2+. Finally, biodistribution studies were carried out in mice previously injected with the radiotracer 67Ga–citrate to evaluate the in vivo ability of DTPA(PrHP)2 as chelating agent towards trivalent metal cations.
- Irto, Anna,Cardiano, Paola,Chand, Karam,Cigala, Rosalia Maria,Crea, Francesco,De Stefano, Concetta,Gano, Lurdes,Gattuso, Giuseppe,Sammartano, Silvio,Santos, Maria Amélia
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p. 280 - 294
(2019/02/27)
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- Baloxavir intermediate as well as preparation method and application thereof
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The invention relates to the technical field of medicines, and in particular relates to a Baloxavir intermediate as well as a preparation method and application thereof. The invention provides a novelcompound (formula III) and a novel route for preparing a compound IV. The method comprises the following steps: by taking a cheap and easily-available formula I compound as a starting raw material, carrying out benzyl protection, condensation reaction and oxidation reaction to prepare the compound of the formula IV. The method has the advantages that the route is short and novel, the reaction conditions are mild, the yield is higher than that of the existing preparation method, the method is economical and effective, and the method is suitable for large-scale industrial production.
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Paragraph 0016
(2019/07/01)
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- 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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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.
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Page/Page column 12-19
(2019/10/01)
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- Practical and Scalable Synthetic Method for Preparation of Dolutegravir Sodium: Improvement of a Synthetic Route for Large-Scale Synthesis
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A practical and scalable synthetic method to obtain dolutegravir sodium (1) was established starting from the readily accessible material maltol (2). This synthetic method includes a scalable oxidation process of maltol and palladium-catalyzed amidation for introduction of an amide moiety, leading to a practical manufacturing method in short synthetic steps. The synthetic method demonstrated herein enables multikilogram scale manufacturing of 1 of high purity.
- Aoyama, Yasunori,Hakogi, Toshikazu,Fukui, Yuki,Yamada, Daisuke,Ooyama, Takao,Nishino, Yutaka,Shinomoto, Shoji,Nagai, Masahiko,Miyake, Naoki,Taoda, Yoshiyuki,Yoshida, Hiroshi,Yasukata, Tatsuro
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p. 558 - 564
(2019/04/30)
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- Design, synthesis and biological evaluation of hydroxypyridinone-coumarin hybrids as multimodal monoamine oxidase B inhibitors and iron chelates against Alzheimer's disease
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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.
- Zhang, Changjun,Yang, Ke,Yu, Sihang,Su, Jing,Yuan, Shengli,Han, Jiaxin,Chen, Yan,Gu, Jinping,Zhou, Tao,Bai, Renren,Xie, Yuanyuan
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p. 367 - 382
(2019/07/19)
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- Synthesis, molecular modelling and biological studies of 3-hydroxy-pyrane-4-one and 3-hydroxy-pyridine-4-one derivatives as HIV-1 integrase inhibitors
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Background: Despite the progress in the discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is a growing need to increase the armamentarium against
- Sirous, Hajar,Fassihi, Afshin,Brogi, Simone,Campiani, Giuseppe,Christ, Frauke,Debyser, Zeger,Gemma, Sandra,Butini, Stefania,Chemi, Giulia,Grillo, Alessandro,Zabihollahi, Rezvan,Aghasadeghi, Mohammad R.,Saghaie, Lotfollah,Memarian, Hamid R.
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p. 755 - 770
(2019/11/02)
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- Improved method for synthesizing dolutegravir
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The invention relates to an improved method for synthesizing dolutegravir and belongs to the field of medicinal chemistry. The method takes maltol (compound 1) as a raw material, and a target is synthesized by the following route. The process raw material is cheap and easy to obtain, a reaction solvent can be recycled, the post-treatment operation is simple, the yield and the purity are high, especially the carbamoylation and debenzylation reaction are carried out in one step, the synthesis route is simplified, the cost is reduced, and the large-scale industrial production is facilitated.
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Paragraph 0032; 0033
(2019/03/30)
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- A new tripodal-3-hydroxy-4-pyridinone for iron and aluminium sequestration: Synthesis, complexation and: In vivo studies
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Elevated levels of iron and aluminium in the body can lead to tissue damage, organ failure and eventually death. To reduce complications of metal overload, specific chelating agents have been used. Following our recent developments in a series of hexadentate 3-hydroxy-4-pyridinones (3,4-HP) with high M3+ sequestering capacity, we herein present a novel tripodal homologue, whose design involves one methylene truncation on the linkers. This truncation aimed to reduce the ligand molecular weight and concomitant improvement in the membrane crossing ability and accessibility to cytoplasmic iron pools, but still retaining the capacity for the formation of a 1:1 (M3+:L) complex with high thermodynamic stability and kinetic inertness. Besides the synthesis of a new ligand, solution studies have been performed to evaluate the acid-base properties and complexation capacity towards Fe(iii) and Al(iii) using potentiometry and a panoply of spectrometric techniques. The pFe and pAl values show some decrease, as compared with the non-truncated homologues, but still represent an improvement of, respectively, 7- and 4-orders of magnitude, as compared to the marketed drug deferiprone. The ability of this new ligand to facilitate metal-mobilization from the body was investigated using a mice model injected with 67Ga. The new chelator possessing high pM3+ values shows promising ability to remove Fe and Al under in vivo conditions.
- Cappai, Rosita,Chand, Karam,Lachowicz, Joanna I.,Chaves, Sílvia,Gano, Lurdes,Crisponi, Guido,Nurchi, Valeria M.,Peana, Massimiliano,Zoroddu, Maria Antonietta,Santos, M. Amélia
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p. 8050 - 8061
(2018/05/24)
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- Chelating agent, synthesis method and application thereof as well as chelate containing the same
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The invention discloses a chelating agent, which has a structural general formula shown as the specification. The invention also discloses a chelate containing the chelating agent and metal ions, and a synthesis method of the chelating agent. The method includes: (1) synthesizing a precursor compound of the chelating agent by active ester method; (2) carrying out catalytic hydrogenation reaction to obtain the chelating agent. The chelating agent can be used as a radioactive imaging and therapy drug, a magnetic resonance imaging drug, selective chelation separate trivalent metal ions and the like. The chelating agent provided by the invention is a hexadentate ligand, has strong chelating ability with a lot of trivalent metal ions, and therefore has small dosage during chelate formation, and has reduced toxic and side effect when serving as a drugs, at the same time the chelating agent contains amino at the left end and can achieve connection with some biological target molecules, and can be used for preparation of various targeted drugs. The coordination reaction of the chelating agent and metal ions has mild conditions (usually at room temperature), and the drug preparation process is simplified. The preparation method of the chelating agent has the advantages of easily available raw materials and simple process, thus being easy for large-scale promotion.
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Paragraph 0095; 0112-0114; 0137-0139; 0178; 0198
(2018/01/04)
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- Multifunctional diamine AGE/ALE inhibitors with potential therapeutical properties against Alzheimer's disease
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An important part of pathogenesis of Alzheimer's disease (AD) is attributed to the contribution of AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid peroxidation Endproducts). In order to attenuate the progression of AD, we designed a new type of molecules that consist of two trapping parts for reactive carbonyl species (RCS) and reactive oxygen species (ROS), precursors of AGE and ALE, respectively. These molecules also chelate transition metals, the promoters of ROS formation. In this paper, synthesis of the new AGE/ALE inhibitors and evaluation of their physicochemical and biological properties (carbonyl trapping capacity, antioxidant activity, Cu2+-chelating capacity, cytotoxicity and protective effect against in?vitro MGO-induced apoptosis in the model AD cell-line PC12) are described. It is found that compounds 40b and 51e possess promising therapeutic potentials for treating AD.
- Lohou, Elodie,Sasaki, N. André,Boullier, Agnès,Sonnet, Pascal
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p. 702 - 722
(2016/07/26)
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- Design and synthesis of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates for photodynamic therapy: Enhancement of protoporphyrin IX production and photo-toxicity in tumor cells
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5-Aminolaevulinic acid (ALA) and its derivatives have been widely used in photodynamic therapy (PDT) as precursors of the photosensitizer, protoporphyrin IX (PpIX) in dermatology and urology. However, ALA-PDT is limited by the low bioavailability of ALA due to the fact that ALA is poorly absorbed by cells by virtue of its zwitterionic nature at physiological pH. In order to improve the therapeutic effect and induce higher levels of PpIX, a series of ALA prodrugs were synthesized by the conjugation of ALA to 3-hydroxypyridin-4-one (HPO) iron chelator using an amino acid linkage via amide bonds. Pharmacokinetic studies indicated that one ALA-HPO conjugate significantly enhanced PpIX production in a range of tumor cell lines over ALA alone or the co-administration of ALA and CP94 (1,2-diethyl-3-hydroxypyridin-4-one). The intracellular porphyrin fluorescence levels showed good correlation with cellular photo-toxicity following light exposure, suggesting the potential application of the ALA-HPO conjugates in photodynamic therapy.
- Zhou, Tao,Shao, Le-Le,Battah, Sinan,Zhu, Chun-Feng,Hider, Robert C.,Reeder, Brandon J.,Jabeen, Asma,MacRobert, Alexander J.,Ren, Gerui,Liang, Xinle
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supporting information
p. 1190 - 1196
(2016/07/06)
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- METAL CHELATING COMPOSITIONS AND METHODS FOR CONTROLLING THE GROWTH OR ACTIVITIES OF A LIVING CELL OR ORGANISM
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The present invention provides for metal chelating compositions which are soluble in aqueous media. The present invention also provides chelating compositions that possess acceptable iron sequestering strengths and are able to present a physical form that potentially inhibits (e.g. does not permit easy) access of iron sequestered by the compositions to the cells being targeted. Compositions comprising chelating aspects affixed to or incorporated into suitable carrier materials such that the resulting metal chelating composition is soluble in aqueous media are also provided. Disclosed herein are chelating compositions, for chelating one or more essential metals. The chelating compositions being soluble in an aqueous medium and comprising one or more metal binding chemical groups affixed to or incorporated into the structure of a carrier material, such that the resulting chelating composition is able to bind one or more metals, and remains substantially soluble in the aqueous medium with its bound metal or metals.
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Paragraph 0227; 0228
(2016/03/05)
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- Synthesis of new bis(3-hydroxy-4-pyridinone) ligands as chelating agents for uranyl complexation
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Five new bis(3-hydroxy-4-pyridinone) tetradentate chelators were synthesized in this study. The structures of these tetradentate chelators were characterized by 1H-NMR, 13C-NMR, FT-IR, UV-vis, and mass spectral analyses. The binding
- Jin, Bo,Zheng, Rongzong,Peng, Rufang,Chu, Shijin,Dehaen, Wim
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- Macromolecular iron-chelators via RAFT-polymerization for the inhibition of methicillin-resistant Staphylococcus aureus growth
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A series of linear poly (glycidyl methacrylate) (PGMA) polymers were synthesized via RAFT polymerization and conjugated with amine-containing 3-hydroxypyridin-4-ones (HPOs) to generate a panel of HPO-containing materials with controlled structures and spe
- Li, Junpei,Olaleye, Eniola D.,Kong, Xiaole,Zhou, Tao,Ma, Yongmin,Jurach, Jagoda,Al Rugaie, Osamah,Hider, Robert C.,Zhang, Guoqing,Alsam, Selwa,Abbate, Vincenzo
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supporting information
p. 64 - 72
(2016/02/19)
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- Intermediate of these pyridonecarboxylic carbamoylalkanoic and HIV integrase inhibitor
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A synthesis approach providing an early ring attachment via a bromination to compound I-I yielding compound II-II: whereby a final product such as AA: can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.
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Paragraph 0030; 0036
(2016/10/07)
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- Design, synthesis and biological evaluation of 5-aminolaevulinic acid/3-hydroxypyridinone conjugates as potential photodynamic therapeutical agents
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5-Aminolaevulinic acid (ALA) prodrugs have been widely used in photodynamic therapy (PDT) as precursors to the natural photosensitizer, protoporphyrin IX (PpIX). The main disadvantage of this therapy is that ALA is poorly absorbed by cells due to its high hydrophilicity. In order to improve the therapeutical effect and induce higher yields of PpIX, a range of prodrugs of ALA conjugated to 3-hydroxypyridin-4-ones (HPO) were synthesized. Pharmacokinetic studies indicated that some of the ALA-HPO conjugates are more efficient than ALA for PpIX production in the human breast adenocarcinoma cell line (MDA-MB-468). The intracellular porphyrin fluorescence levels showed good correlation with cellular phototoxicity following light exposure, suggesting the potential application of the ALA-HPO conjugates in photodynamic therapy.
- Zhu, Chun-Feng,Battah, Sinan,Kong, Xiaole,Reeder, Brandon J.,Hider, Robert C.,Zhou, Tao
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p. 558 - 561
(2015/03/05)
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- Novel 3-hydroxypyridin-4-one hexadentate ligand-based polymeric iron chelator: Synthesis, characterization and antimicrobial evaluation
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A novel 3-hydroxypyridin-4-one (HPO) hexadentate monomeric chelator 14 has been synthesized and incorporated into polymers by copolymerization with 2-hydroxyethyl acrylate (HEA), using azobisisobutyronitrile (AIBN) as an initiator. The monomeric chelator was found to possess very high affinity for iron(III), with the log stability constant of the iron complex (log K1) = 33.61 and pFe3+ = 30.37. The iron binding capacity and monomer recovery of the copolymers were determined using spectrophotometry. The in vitro antimicrobial activity of monomeric chelator 14 and polymeric chelator 16-4 against both Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Salmonella spp., and Pseudomonas aeruginosa) was evaluated by inhibition zone and minimum inhibitory concentration (MIC) assays, which demonstrated that both monomeric and polymeric chelators possess inhibitory activity. The polymeric chelators possess potential application for the treatment of wound infection.
- Zhou, Ying-Jun,Kong, Xiao-Le,Li, Jun-Pei,Ma, Yong-Min,Hider, Robert C.,Zhou, Tao
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supporting information
p. 1620 - 1625
(2015/09/21)
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- PROCESS FOR THE PREPARATION OF INTERMEDIATE OF DOLUTEGRAVIR
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The present invention provides a novel processes for preparation of methyl 3- (benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyiridine-2- carboxylate using novel intermediates.
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Page/Page column 20
(2015/01/16)
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- TETRACYCLIC HETEROCYCLE COMPOUNDS USEFUL AS HIV INTEGRASE INHIBITORS
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The present invention relates to Tetracyclic Heterocycle Compounds of Formula (I) and pharmaceutically acceptable salts or prodrug thereof, wherein n, X, Y, Z, R1, R2, and R3 are as defined herein. The present invention also relates to compositions comprising at least one Tetracyclic Heterocycle Compound, and methods of using the Tetracyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.
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Page/Page column 24
(2015/04/15)
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- (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenymethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10
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The compounds are intermediates in the preparation of therapeutic agents useful in the treatment of viral infections, particularly HIV infection. The compounds are (3S,11aR)-6-[(phenylmethyl)oxy]-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-9 and/or (3S,11aR)-6-[(phenylmethyl)oxy]-8-bromo-3-methyl-2,3,11,11a-tetrahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-5,7-dione of the formula P-10.
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Page/Page column 15; 18
(2016/01/20)
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- CHIRAL 3-HYDROXYPYRID-4-ONE DERIVATIVE, AND SYNTHESIS AND USE THEREOF
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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).
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-
Paragraph 0037; 0038
(2014/02/16)
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- Design, synthesis, and antimicrobial evaluation of hexadentate hydroxypyridinones with high iron(iii) affinity
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A range of hexadentate 3-hydroxypyridin-4-ones (HPOs) with high affinity for iron(III) has been synthesized. The log stability constants of two HPO-iron complexes (logK1) were determined to be over 34, and pFe values of the two HPOs were determined to be over 31. Antimicrobial assay indicated that they are able to markedly inhibit the growth of both Gram-positive and Gram-negative bacteria. Compounds 14a and 14e were found to exhibit the strongest inhibitory activity against Staphyloccocus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, with MIC values of 8, 8, 16, and 8 lg/mL, respectively. These results indicate that hexadentate 3-hydroxypyridin-4-ones have potential application as antimicrobial agents, especially in the treatment of wound infection.
- Zhang, Ming-Xia,Zhu, Chun-Feng,Zhou, Ying-Jun,Kong, Xiao-Le,Hider, Robert C.,Zhou, Tao
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p. 659 - 668
(2015/02/19)
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- Multicellular aggregation of maltol-modified cells triggered by Fe 3+ ions
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The synthesis of a maltol-derived hydrazide is described which, once attached to a cell surface, induces rapid multicellular aggregation selectively in the presence of Fe3+ ions. Heterocellular aggregates are also reported. The Royal Society of Chemistry 2013.
- Ciupa, Alexander,De Bank, Paul A.,Caggiano, Lorenzo
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supporting information
p. 10148 - 10150
(2013/10/22)
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- Synthesis, physico-chemical properties, and antimicrobial evaluation of a new series of iron(III) hexadentate chelators
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A series of related 3-hydroxypyridin-4-one hexadentate ligands have been synthesized. These chelators were found to possess a high affinity for iron(III), with a pFe value of about 30. As iron is a critical element to the survival of bacteria, these chelators were predicted to inhibit the growth of bacteria by disrupting bacterial iron absorption. Indeed, they were demonstrated to possess appreciable inhibitory activity against both Gram-positive and Gram-negative bacteria, and therefore, they have potential as antimicrobial agents. 1c and 1g were found to be particularly effective against Gram-negative species. Graphical Abstract: A series of related 3-hydroxypyridin-4-one hexadentate ligands have been synthesized. These chelators were found to possess a high affinity for iron(III), and exhibit appreciable inhibitory activity against both Gram-positive and Gram-negative bacteria, and therefore, they have potential as antimicrobial agents. [Figure not available: see fulltext.]
- Xie, Yuan-Yuan,Liu, Mu-Song,Hu, Pan-Pan,Kong, Xiao-Le,Qiu, Di-Hong,Xu, Ji-Lin,Hider, Robert C.,Zhou, Tao
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p. 2351 - 2359
(2013/07/26)
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- COMPOUND
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In one aspect, there is provided a fluorescent iron-binding compound bound to a solid phase. Also provided is a method for detecting non-transferrin bound iron in a sample, comprising contacting the sample with a fluorescent iron-binding compound bound to a solid phase and detecting a fluorescent signal derived from the fluorescent iron-binding compound bound to the solid phase, wherein the fluorescent signal is indicative of non-transferrin bound iron levels in the sample. Further provided is use of a fluorescent iron-binding compound bound to a solid phase to detect non-transferrin bound iron in a sample.
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Paragraph 0101
(2013/06/28)
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- In vitro studies of lanthanide complexes for the treatment of osteoporosis
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Lanthanide ions, Ln(iii), are of interest in the treatment of bone density disorders because they are found to accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation, and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of the bone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1- (3-hydroxypropyl)-4-pyridinone, H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4- pyridinone, H4 = 3-hydroxy-2-methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-pyridinone, H7 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H8 = 1-carboxyethyl-3-hydroxy- 2-methyl-4-pyridinone) were coordinated to Ln3+ (Ln = La, Eu, Gd, Lu) forming stable tris-ligand complexes (LnL3, L = 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-). The dissociation (pKan) and metal ligand stability constants (log βn) of the 3-hydroxy-4- pyridinones with La3+ and Gd3+ were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-EDTA derivative (H5XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was also synthesized and coordinated to Ln3+ (Ln = La, Eu, Lu), forming the potassium salt of [Ln(XT)]2-. Cytotoxicity assays were carried out in MG-63 cells; all the ligands and metal complexes tested were observed to be non-toxic to this cell line. Studies to investigate the toxicity, cellular uptake and apparent permeability (Papp) of the lanthanide ions were conducted in Caco-2 cells where it was observed that [La(XT)] 2- had the greatest cell uptake. Binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral hydroxyapatite (HAP) are high, as well as moderate to strong for the free ligand with the bone mineral depending on the functional group.
- Mawani, Yasmin,Cawthray, Jacqueline F.,Chang, Stanley,Sachs-Barrable, Kristina,Weekes, David M.,Wasan, Kishor M.,Orvig, Chris
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supporting information
p. 5999 - 6011
(2013/06/27)
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- Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids
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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).
- Andayi, Warren A.,Egan, Timothy J.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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supporting information
p. 642 - 646
(2013/07/26)
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- Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles
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This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of
- Kawasuji, Takashi,Johns, Brian A.,Yoshida, Hiroshi,Weatherhead, Jason G.,Akiyama, Toshiyuki,Taishi, Teruhiko,Taoda, Yoshiyuki,Mikamiyama-Iwata, Minako,Murai, Hitoshi,Kiyama, Ryuichi,Fuji, Masahiro,Tanimoto, Norihiko,Yoshinaga, Tomokazu,Seki, Takahiro,Kobayashi, Masanori,Sato, Akihiko,Garvey, Edward P.,Fujiwara, Tamio
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supporting information
p. 1124 - 1135
(2013/03/28)
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- Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators
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Iron is an essential growth component in all living organisms and plays a central role in numerous biochemical processes due to its redox potential and high affinity for oxygen. The use of iron chelators has been suggested as a novel therapeutic approach
- Gehrke, Sebastian S.,Pinto, Erika G.,Steverding, Dietmar,Pleban, Karin,Tempone, Andre G.,Hider, Robert C.,Wagner, Gerd K.
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p. 805 - 813
(2013/02/25)
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- TRICYCLIC COMPOUNDS AS mPGES-1 INHIBITORS
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The present disclosure is directed to compounds of formula (I), and pharmaceutically acceptable salts thereof, as m PGES-1 inhibitors. These compounds are inhibitors of the microsomal prostaglandin E synthase-1 (m PGES-1) enzyme and are therefore useful in the treatment of pain and/or inflammation from a variety of diseases or conditions, such as asthma, osteoarthritis, rheumatoid arthritis, acute or chronic pain and neurodegenerative diseases.
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Page/Page column 68-69
(2013/11/05)
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