- 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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- A 2 - chloro - 3 - pyridine formaldehyde synthetic method (by machine translation)
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The invention discloses a 2 - chloro - 3 - pyridyl aldehyde synthesis method, the method to 2 - chloro - 3 - methyl pyridine as raw materials, passes through chlorine chlorinated, ester hydrolysis, oxidation three-step to obtain 2 - chloro - 3 - pyridine formaldehyde product. The method of the invention mild reaction conditions, high yield, low cost, product purity up to 98% or more, and has a good industrial application prospect. (by machine translation)
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Paragraph 0029; 0030; 0038; 0039; 0040
(2018/01/12)
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- DIFLUOROMETHYLENE COMPOUND
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The present invention relates to a compound having an URAT1 inhibitory activity, and to an URAT1 inhibitor, a blood uric acid level-reducing agent and a pharmaceutical composition containing the compound. More specifically, the present invention relates to a compound represented by the formula (I): wherein R1 is -Q1-A1 or the like; R2 is a hydrogen atom, a halogen atom, a lower alkyl group or the like; W1, W2, W3 and W4 are each independently a nitrogen atom or a methine group optionally having substituents, or the like; X and Y are each a single bond, an oxygen atom or the like; Z is a hydroxyl group or COOR3 or the like.
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Paragraph 0797-0799
(2015/06/16)
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- Discovery of N-substituted 7-azaindoline derivatives as potent, orally available M1 and M4 muscarinic acetylcholine receptors selective agonists
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We designed and synthesized novel N-substituted 7-azaindoline derivatives as selective M1 and M4 muscarinic acetylcholine receptors (mAChRs) agonists. Hybridization of compound 2 with the HTS hit compound 5 followed by optimization of the N-substituents of 7-azaindoline led to identification of compound 1, which showed highly selective M1 and M4 mAChRs agonistic activity, weak human ether-a-go-go related gene inhibition, and good bioavailability in multiple animal species.
- Takai, Kentaro,Inoue, Yasunao,Konishi, Yasuko,Suwa, Atsushi,Uruno, Yoshiharu,Matsuda, Harumi,Nakako, Tomokazu,Sakai, Mutsuko,Nishikawa, Hiroyuki,Hashimoto, Gakuji,Enomoto, Takeshi,Kitamura, Atsushi,Uematsu, Yasuaki,Kiyoshi, Akihiko,Sumiyoshi, Takaaki
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p. 3189 - 3193
(2014/06/24)
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- Fatty acid amide hydrolase inhibitors. 3: Tetra-substituted azetidine ureas with in vivo activity
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We describe here our attempts to optimise the human fatty acid amide hydrolase (FAAH) inhibition and physicochemical properties of our previously reported tetrasubstituted azetidine urea FAAH inhibitor, VER-156084. We describe the SAR of a series of analogues and conclude with the demonstration of in vivo dose-dependant FAAH inhibition in an anandamide-loading study in rats.
- Roughley, Stephen D.,Browne, Helen,MacIas, Alba T.,Benwell, Karen,Brooks, Teresa,D'Alessandro, Jalanie,Daniels, Zoe,Dugdale, Sarah,Francis, Geraint,Gibbons, Ben,Hart, Terance,Haymes, Timothy,Kennett, Guy,Lightowler, Sean,Matassova, Natalia,Mansell, Howard,Merrett, Angela,Misra, Anil,Padfield, Anthony,Parsons, Rachel,Pratt, Robert,Robertson, Alan,Simmonite, Heather,Tan, Kiri,Walls, Steven B.,Wong, Melanie
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p. 901 - 906
(2012/03/11)
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- A spirocyclic oxindole analogue: Synthesis and antitumor activities
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A new synthesis of spirocyclic oxindole analogue spiro[piperidine-4, 3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one 1 is described. The key steps involve dialkylation of arylacetonitrile and cyclization of the azaoxindole ring by an intramolecular Buchwald-Hartwig amidation of carboxylic amide and aryl chloride. A small library was obtained by reductive amination of 1 with various aldehydes and was screened against human lung cancer cell A549, human liver cancer cell BEL7402, and human colon cancer cell HCT-8. The results show that most of the library compounds 2 have some inhibitory activities. 2-(Trifluoromethoxy) benzylic substituted spirocyclic azaoxindole 2e was identified as a nanomolar inhibitor against human lung cancer cell A-549 (IC50 = 50 nmol/L).
- Hong, Hui,Huang, Long Jiang,Teng, Da Wei
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p. 1009 - 1012
(2012/06/29)
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- Intramolecular N-arylation in heterocyclization: synthesis of new pyrido-fused pyrrolo[1,2-a][1,4]diazepinones
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Alkylation of l-prolinamide with 3-(chloromethyl)-2-halopyridines, followed by cyclization through an intramolecular Pd-catalysed amidation, provided an entry to the pyrido[2,3-e]pyrrolo[1,2-a][1,4]diazepin-10-one scaffold. Furthermore, a synthetic route towards diverse new pyrido[f]pyrrolo[1,2-a][1,4]diazepin-7-ones has been developed by acylation of contiguously substituted (aminomethyl)halopyridines with Boc-l-proline followed by intramolecular amination.
- Legerén, Loreto,Domínguez, Domingo
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scheme or table
p. 4053 - 4057
(2010/08/07)
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- FUSED HETEROCYCLIC COMPOUND AND USE THEREOF
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The present invention relates to a serotonin 5-HT2C receptor activator containing a compound represented by the formula wherein ring A is a 5- or 6-membered aromatic heterocycle optionally having substituent(s), and ring B is a 7- to 9-membered
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Page/Page column 74
(2009/02/10)
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- THIENO-PYRIDINE DERIVATIVES AS MEK INHIBITORS
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A series of thieno[2,3-b]pyridine derivatives which are substituted in the 2- position by a substituted anilino moiety, being selective inhibitors of human MEK (MAPKK) enzymes, are accordingly of benefit in medicine, for example in the treatment, of inflammatory, autoimmune, cardiovascular, proliferative (including oncological) and nociceptive conditions.
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Page/Page column 25
(2009/03/07)
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- THIENO-PYRIDINE DERIVATIVES AS MEK INHIBITORS
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The invention provides a series of thieno[2,3-b]pyridine derivatives wherein Y represents a linkage of formula C(O) or S(O)2; R1 represents hydrogen, halogen, cyano, nitro, C|-6 alkyl, trifluoromethyl, Ci.6 alkoxy, trifluoromethoxy,
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Page/Page column 24
(2009/09/05)
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- THIENO-PYRIDINE DERIVATIVES AS MEK INHIBITORS
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A series of thieno[2,3-6]pyridine derivatives, attached at the 2-position to a substituted anilino moiety, which are substituted in the 3-position by a carbonyl group linked to a pyrrolidin-1-yl ring which in turn forms part of a heteroatom-containing fus
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Page/Page column 35
(2010/01/12)
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- Aza-and polyaza-naphthalenly ketones useful as hiv integrase inhibitors
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Certain aza- and polyaza-naphthalenyl ketones including certain quinolinyl and naphthyridinyl ketones are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment or the delay in the onset of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.
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Page/Page column 47
(2010/02/10)
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- Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells
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Naphthyridine 7 inhibits the strand transfer of the integration process catalyzed by integrase with an IC50 of 10 nM and inhibits 95% of the spread of HIV-1 infection in cell culture at 0.39 μM. It does not exhibit cytotoxicity in cell culture
- Zhuang, Linghang,Wai, John S.,Embrey, Mark W.,Fisher, Thorsten E.,Egbertson, Melissa S.,Payne, Linda S.,Guare Jr., James P.,Vacca, Joseph P.,Hazuda, Daria J.,Felock, Peter J.,Wolfe, Abigail L.,Stillmock, Kara A.,Witmer, Marc V.,Moyer, Gregory,Schleif, William A.,Gabryelski, Lori J.,Leonard, Yvonne M.,Lynch Jr., Joseph J.,Michelson, Stuart R.,Young, Steven D.
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p. 453 - 456
(2007/10/03)
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