- 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 23-30
(2019/10/01)
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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, antimicrobial evaluation and QSAR study of some 3-hydroxypyridine-4-one and 3-hydroxypyran-4-one derivatives
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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.
- Fassihi, Afshin,Abedi, Daryoush,Saghaie, Lotfollah,Sabet, Razieh,Fazeli, Hossein,Bostaki, Ghasem,Deilami, Omid,Sadinpour, Hekmatollah
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body text
p. 2145 - 2157
(2009/09/30)
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- Novel synthetic approach to 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones
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Novel methods for the synthesis of high pFe3+ iron chelators, 2-(1′-hydroxyalkyl)- and 2-amido-3-hydroxypyridin-4-ones, have been developed. The products are obtained, via N-oxide intermediates, from either maltol or ethyl maltol.
- Piyamongkol, Sirivipa,Liu, Zu D,Hider, Robert C
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p. 3479 - 3486
(2007/10/03)
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- Synthesis, physicochemical properties, and biological evaluation of N- substituted 2-alkyl-3-hydroxy-4(1H)-pyridinones: Orally active iron chelators with clinical potential
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The synthesis of a range of novel bidentate ligands containing the chelating moiety 3-hydroxy-4(1H)-pyridinone is described. The pK(a) values of the ligands and the stability constants of their iron(III) complexes have been determined. The crystal structures of one of the ligands and one of the iron(III) complexes are presented. The distribution coefficients of the ligands are reported and are related to the ability of the ligands to remove iron from hepatocytes. The influence of 3-hydroxy-4(1H)-pyridinones on oxidative damage to cells is described. In contrast to the iron chelator in current therapeutic use, desferrioxamine-B, many of the bidentate ligands described in this study are orally active in iron-overloaded mice.
- Dobbin,Hider,Hall,Taylor,Sarpong,Porter,Xiao,Van der Helm
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p. 2448 - 2458
(2007/10/02)
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