- Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products
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Natural product (NP) structures are a rich source of inspiration for the discovery of new biologically relevant chemical matter. In natural product inspired pseudo-NPs, NP-derived fragments are combined de novo in unprecedented arrangements. Described here is the design and synthesis of a 155-member pyrroquinoline pseudo-NP collection in which fragments characteristic of the tetrahydroquinoline and pyrrolidine NP classes are combined with eight different connectivities and regioisomeric arrangements. Cheminformatic analysis and biological evaluation of the compound collection by means of phenotyping in the morphological “cell painting” assay followed by principal component analysis revealed that the pseudo-NP classes are chemically diverse and that bioactivity patterns differ markedly, and are dependent on connectivity and regioisomeric arrangement of the fragments.
- Liu, Jie,Cremosnik, Gregor S.,Otte, Felix,Pahl, Axel,Sievers, Sonja,Strohmann, Carsten,Waldmann, Herbert
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p. 4648 - 4656
(2021/01/18)
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- Quinolinone compound and preparation method and application thereof
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The invention belongs to the field of medicine synthesis, and relates to a novel quinolinone compound and a preparation method and application thereof. Biological experiment results show that the quinolinone compound has a good inhibitory activity for hep
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Paragraph 0035; 0043; 0044; 0045
(2017/01/31)
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- Bicyclic 1-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-containing HIV-1 integrase inhibitors having high antiviral potency against cells harboring raltegravir-resistant integrase mutants
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Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG, and there is extensive cross-resistance to these two drugs. New "2nd- generation" INSTIs are needed that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK's Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamides, 1,4-dihydroxy-2-oxo-1, 2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8- naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K.
- Zhao, Xue Zhi,Smith, Steven J.,Métifiot, Mathieu,Johnson, Barry C.,Marchand, Christophe,Pommier, Yves,Hughes, Stephen H.,Burke Jr., Terrence R.
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p. 1573 - 1582
(2014/03/21)
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- Organocatalytic knoevenagel condensations by means of carbamic acid ammonium salts
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The Knoevenagel condensation between an active methylene compound and an aromatic aldehyde with a carbamic acid ammonium salt used as an organocatalyst gave the desired Knoevenagel products in up to 98% yield. The reaction occurred at rt and in a short reaction time under solvent-free conditions. In addition, no extraction, wash, or chromatography steps were needed to obtain a high-purity Knoevenagel product.
- Mase, Nobuyuki,Horibe, Takuya
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supporting information
p. 1854 - 1857
(2013/06/04)
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- Selection, synthesis, and anti-inflammatory evaluation of the arylidene malonate derivatives as TLR4 signaling inhibitors
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Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.
- Zhang, Shuting,Cheng, Kui,Wang, Xiaohui,Yin, Hang
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p. 6073 - 6079
(2012/11/07)
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- Asymmetric michael addition of ketones to alkylidene malonates and allylidene malonates via enamine - Metal lewis acid bifunctional catalysis
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Novel enamine-metal Lewis acid bifunctional catalysts were successfully applied to the asymmetric Michael addition of ketones to alkylidene malonates, offering excellent stereoselectivity (up to >99% ee and >99:1 dr). The asymmetric Michael addition of ketones to allylidene malonates was also achieved.
- Liu, Lu,Sarkisian, Ryan,Xu, Zhenghu,Wang, Hong
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supporting information
p. 7693 - 7699
(2012/11/07)
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- Amine compounds, their production and use
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The present invention provides a compound of the formula: wherein Ar represents an aromatic group which may be substituted; X represents methylene, S, SO, SO2or CO; Y represents a spacer having a main chain of 2 to 5 atoms; n represents an integer of 1 to 5; i) R1and R2each represents a hydrogen atom or a lower alkyl which may be substituted, ii) R1and R2form, taken together with the adjacent nitrogen atom, a nitrogen-containing heterocyclic ring which may be substituted, or iii) R1or R2together with —(CH2)n—N═ form, bonded to a component atom of Ring B, a spiro-ring which may be substituted; Ring A represents an aromatic ring which may be substituted; Ring B represents a 4- to 7-membered nitrogen-containing non-aromatic ring which may be further substituted by alkyl or acyl, with a proviso that X represents S, SO, SO2or CO when Ring A has as a substituent a group represented by the formula: —NHCOR11 where R11represents alkyl, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or a group represented by the formula: —NHR12 where R12represents alkyl, cycloalkyl, cycloalkylalkyl, aryl or arylalkyl, or a salt thereof; which has an excellent somatostatin receptor binding inhibition action.
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