- Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
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Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
- Yan, Yu-Hang,Li, Wenfang,Chen, Wei,Li, Chao,Zhu, Kai-Rong,Deng, Ji,Dai, Qing-Qing,Yang, Ling-Ling,Wang, Zhenling,Li, Guo-Bo
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- CYCLIC AMINE DERIVATIVE AS AGENT FOR PROMOTING ADVILLIN FUNCTION, AND NOVEL CYCLIC AMINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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An object of the present invention is to provide an agent for promoting advillin function that comprises a low molecular weight compound, and is useful for treatment of axonal injury. The present invention provides an agent for promoting advillin function, comprising a cyclic amine derivative typically represented by the following chemical formula, or a pharmacologically acceptable salt thereof as an active ingredient.
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Paragraph 0116-0119
(2022/03/22)
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- Photocatalytic acyl azolium-promoted alkoxycarbonylation of trifluoroborates
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Despite recent advancements in the selective generation and coupling of organic radical species, the alkoxycarbonyl radical remains underexplored relative to other carbon-containing radical species. Drawing inspiration from new strategies for generating acyl radical equivalents utilizing dual N-heterocyclic carbene catalysis and photocatalysis, we have prepared dimethylimidazolium esters that can function as an alkoxycarbonyl radical surrogate under photocatalytic conditions. We demonstrate the synthetic utility of these azolium-based partners through the preparation of esters arising from the coupling of this radical surrogate with an oxidatively generated alkyl radical.
- Scheidt, Karl A.,Zhu, Joshua L.
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- Application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors
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The invention relates to application of 1-substituted-1H-imidazole-2-carboxylic acid compounds in preparation of metal beta-lactamase inhibitors, and particularly discloses application of compounds shown in a formula I in preparation of metal beta-lactamase inhibitors or antibacterial combined medicines. Experiments prove that the compounds provided by the invention can be used for effectively inhibiting the activity of various MBL enzymes including VIM-2, NDM-1, IMP-1, VIM-1 and VIM-5; the compounds, especially the compounds 11, 13, 14, 29, 30, 34, 37 and 40, have an IC50 value of 2.13 [mu] Mor less on the VIM-2 type MBL enzymes, have a more significant inhibition effect than positive control drugs, and have very good potential in the preparation of MBL enzyme inhibitors. Meanwhile, thecompounds disclosed by the invention are combined with beta-lactam antibiotics, so that metal beta-lactamase generated by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotics is enhanced, and the compounds have a very good application prospect in preparation of antibacterial combined medicines.
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Paragraph 0070-0072
(2020/06/09)
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- 1 - Substituted - 111H-imidazol -2 - carboxylic acid compound (by machine translation)
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The invention relates to 1 - substituted - 111H-imidazol -2 - carboxylic acid compounds. Experiments prove that the compound provided by the invention can effectively inhibit the activity of various MBL enzymes including VIM-2, NDM-1, ?currcurrcurrcurry ?, VIM-IMP-1 1 and VIM IM IM, especially compounds 11 and 13, 14, 29, 30, 34, 37, 40, and IC of VIM-2 type MBL enzyme. 50 The value is below 2.13 μm, the inhibition effect is more remarkable than that of the positive control medicine, and the MBL enzyme inhibitor has great potential in preparing the MBL enzyme inhibitor. , The compound is combined with β - lactam antibiotics, metal β - lactamase produced by drug-resistant bacteria can be effectively inhibited, the antibacterial activity of the antibiotic is enhanced, and the compound has a very good application prospect in preparation of antibacterial and combined medicines. (by machine translation)
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Paragraph 0071-0073
(2020/07/02)
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- CRYSTALS OF CYCLIC AMINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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Crystals of a compound that exhibits an analgesic action against neuropathic pain and/or fibromyalgia syndrome are useful as pharmaceuticals. The crystals may be of (S)-1-(4-(dimethylamino)piperidin-1-yl)-3-hydroxy-3-(1-methyl-1H-imidazol-2-yl)propan-1-one or a pharmacologically acceptable salt thereof.
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Paragraph 0118-0121
(2020/06/29)
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- CYCLIC AMINE DERIVATIVE AND PHARMACEUTICAL USE THEREOF
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An object of the present invention is to provide a compound exerting an analgesic effect against pain, in particular, neuropathic pain and/or fibromyalgia syndrome. The present invention provides a cyclic amine derivative represented by the following general formula, or a pharmacologically acceptable salt thereof.
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Paragraph 0386; 0387
(2018/02/03)
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- METHOD FOR PRODUCING IMIDAZOLE-2-CARBOXYLATE DERIVATIVE OR SALT THEREOF
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PROBLEM TO BE SOLVED: To develop a method for stably obtaining an imidazole-2-carboxylate derivative or salt thereof at a high yield regardless of a scale of a reaction and an addition time of a reagent, and to efficiently produce an industrially useful imidazole-2-carboxylate derivative or salt thereof. SOLUTION: There is provided a method for producing an imidazole-2-carboxylate derivative or salt thereof including: an adding step of adding an imidazole derivative or salt thereof and triethylamine into a mixed liquid of a chloroformic ester derivative and acetonitrile under the condition of -45°C to 10°C; and a reacting step of reacting the imidazole derivative or salt thereof with the chloroformic ester to obtain the imidazole-2-carboxylate derivative or salt thereof. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Page/Page column 7; 8; 9; 10; 11
(2017/11/01)
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- Highly regioselective C-5 alkynylation of imidazoles by one-pot sequential bromination and Sonogashira cross coupling
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A variety of 2-substituted 5-alkynyl-1H-imidazoles were easily prepared by a one-pot sequential procedure involving a highly regioselective electrophilic C-5 bromination of 1,2-dimethyl-1H-imidazole, 2-chloro-1-methyl-1H-imidazole, and 2-aryl-1-methyl-1H-imidazoles, followed by an efficient palladium/copper co-catalyzed Sonogashira-type alkynylation.
- Bellina, Fabio,Lessi, Marco,Marianetti, Giulia,Panattoni, Alessandro
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supporting information
p. 3855 - 3857
(2015/06/08)
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- Toward encoding reactivity using double-stranded DNA. Sequence-dependent native chemical ligation of DNA binding polyamides
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The coupling reaction between distamycin-related polyamides equipped with cysteine and thioester groups can be accelerated in the presence of double-stranded (ds) oligonucleotides with selected sequences. While the coupling reaction of reactive partners containing three pyrrole units is accelerated by dsDNAs containing ATTTTA or ATGTTA sites, the heterodimeric coupling between a tripyrrole and a polyamide equipped with two pyrroles and one imidazole, is accelerated by the latter DNA, but not by the other containing the A/T rich tract. These differences can be exploited for selecting preferred coupling pairs from a mixture of reactive monomers; therefore the reaction outcome depends on the instructions provided by the dsDNA sequence.
- Jiménez-Balsa, Adrian,Dodero, Verónica I.,Mascare?as, José L.
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supporting information
p. 7847 - 7853
(2013/08/23)
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- Facile preparation of aromatic esters from aromatic bromides with ethyl formate or DMF and molecular iodine via aryllithium
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Various aromatic bromides were treated with n-BuLi and subsequently with ethyl formate, followed by the reaction with ethanol and molecular iodine in the presence of K2CO3 to provide the corresponding aromatic ethyl esters in good yields. Moreover, aromatic bromides could be transformed into the corresponding aromatic methyl esters in good yields by the treatment with n-BuLi and subsequently with DMF, followed by the reaction with methanol, molecular iodine, and K2CO3. Some aromatics could be also converted into the corresponding aromatic esters in good yields by the treatment with n-BuLi, and subsequently with ethyl formate or DMF, followed by the reaction with molecular iodine and K2CO3. The present reactions offer a novel route for the transition-metal-free, carbon-monoxide-free, and therefore environmentally benign one-pot conversion of aromatic bromides and aromatics into aromatic esters.
- Ushijima, Sousuke,Moriyama, Katsuhiko,Togo, Hideo
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experimental part
p. 4701 - 4709
(2012/07/28)
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- IMIDAZOPYRAZINE COMPOUNDS
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Novel imidazopyrazine compounds are disclosed that have a formula represented by the following: Formula (I). The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a viral infection, in particular a HCV, HRV, Sb and/or CVB in a patient in need thereof.
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Page/Page column 72-73
(2009/04/25)
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- Asymmetric reduction of ketimines with trichlorosilane employing an imidazole derived organocatalyst
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Organocatalysts for the asymmetric reduction of ketimines are presented that function well at low catalyst loadings providing chiral amines in good yield and enantioselectivity, the latter appearing to be independent of the ketimine substrate geometry.
- Gautier, Franois-Moana,Jones, Simon,Martin, Stephen J.
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supporting information; experimental part
p. 229 - 231
(2009/03/11)
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- SEQUENCE SELECTIVE PYRROLE AND IMIDAZOLE POLYAMIDE METALLOCOMPLEXES
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The present invention relates to sequence selective compounds for targeting therapeutic or diagnostic groups to polynucleotides. More particularly, the present invention relates to sequence selective targeting of metallocomplexes, such as metallodrugs and metallodiagnostics, to polynucleotides.
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Page/Page column 53
(2010/02/11)
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- 4(SPIROPIPERIDINYL)METHYL SUBSTITUTED PYRROLIDINES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
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3-Substituted pyrrolidines having a spiropiperidinylmethyl substituent on the 4-position of the ring are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-3 and/or CCR-5.
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- Method for the synthesis of pyrrole and imidazole carboxamides on a solid support
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The present invention describes a novel method for the solid phase synthesis of polyamides containing imidazole and pyrrole carboxamides. The polyamides are prepared on a solid support from aromatic carboxylic acids and aromatic amines with high stepwise coupling yields (>99%), providing milligram quantities of highly pure polyamides. The present invention also describes the synthesis of analogs of the natural products Netropsin and Distamycin A, two antiviral antibiotics. The present invention also describes a novel method for the solid phase synthesis of imidazole and pyrrole carboxamide polyamide-oligonucleotide conjugates. This methodology will greatly increase both the complexity and quantity of minor-groove binding polyamides and minor-groove binding polyamide-oligonucleotide conjugates which can be synthesized and tested.
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- Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids
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The solid phase synthesis of sequence specific DNA binding polyamides containing N-methylimidazole (Im) and N-methylpyrrole (Py) amino acids is described. Two monomer building blocks, Boc-Py-OBt ester and Boc-Im acid, are prepared on a 50 g scale without column chromatography. Using commercially available Boc-β-alanine-Pam resin, cycling protocols were optimized to afford high stepwise coupling yields (>99%). Deprotection by aminolysis affords up to 100 mg quantities of polyamide. Solid phase methodology increases both the number and complexity of minor groove binding polyamides which can be synthesized and analyzed with regard to DNA binding affinity and sequence specificity. The solid phase synthesis of a representative eight-residue polyamide is reported.
- Baird, Eldon E.,Dervan, Peter B.
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p. 6141 - 6146
(2007/10/03)
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- Transfer of Alkoxycarbonyl from Alkyl Imidazolium-2-carboxylates to Benzyl Alcohol, a Cyclohexanone Enamine and Diethylamine
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Alkylimidazole-2-carboxylates may be alkylated with methyl triflate to give the corresponding N-methylimidazolium salts.These salts react with benzyl alcohol in the presence of 1,4-diazabicyclooctane, with 1-(pyrrolidin-1-yl)cyclohexene and with diethylamine to give benzyl alkyl carbonates, an enamino ester and a urethane respectively; in one case a tetrahedral intermediate is observed.The corresponding phenyl ester was consumed without attack by benzyl alcohol at the carbonyl group.A 2-cyanoimidazolium salt underwent similar ill-defined consumption whereas a 2-dimethylaminocarbonyl derivative remained unchanged. 2-Methylsulfonylimidazolium salts suffered attack by benzyl alcohol at the ring C-2.
- Bakhtiar, Cuross,Smith, Edward H.
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p. 239 - 244
(2007/10/02)
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- Synthesis of Novel Imidazole-Containing DNA Minor Groove Binding Oligopeptides Related to the Antiviral Antibiotic Netropsin
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Analysis of the structural and stereochemical requirements for the strict DNA base sequence recognition of (AT)4 and (AT)5 respectively for the oligopeptide minor groove binding agents netropsin and distamycin leads to proposals for the rational structure
- Krowicki, Krzysztof,Lown, J. William
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p. 3493 - 3501
(2007/10/02)
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