- Linker-switch approach towards new ATP binding site inhibitors of DNA gyrase B
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Due to increasing emergence of bacterial resistance, compounds with new mechanisms of action are of paramount importance. One of modestly researched therapeutic targets in the field of antibacterial discovery is DNA gyrase B. In the present work we synthesized a focused library of potential DNA gyrase B inhibitors composed of two key pharmacophoric moieties linked by three types of sp3-rich linkers to obtain three structural classes of compounds. Using molecular docking, molecular dynamics and analysis of conserved waters in the binding site, we identified a favourable binding mode for piperidin-4-yl and 4-cyclohexyl pyrrole-2-carboxamides while predicting unfavourable interactions with the active site for piperazine pyrrole-2-carboxamides. Biological evaluation of prepared compounds on isolated enzyme DNA gyrase B confirmed our predictions and afforded multiple moderately potent inhibitors of DNA gyrase B. Namely trans-4-(4,5-dibromo-1H-pyrrole-2-carboxamide)cyclohexyl)glycine and 4-(4-(3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamido)piperidin-1-yl)-4-oxobutanoic acid with an IC50value of 16 and 0.5?μM respectively.
- Juki?, Marko,Ila?, Janez,Brvar, Matja?,Kikelj, Danijel,Cesar, Jo?ko,Anderluh, Marko
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supporting information
p. 500 - 514
(2016/10/04)
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- Discovery of N-benzyl-N′-(4-pipyridinyl)urea CCR5 antagonists as anti-HIV-1 agents (I): Optimization of the amine portion
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Several series of carbamate, urea and carboxamide-based CCR5 antagonists have been discovered via optimizations at the amine portion of lead compound 2. All compounds were evaluated for their antiviral activities. Lead urea 29 showed good pharmacokinetic properties, justifying further development of this series.
- Duan, Maosheng,Peckham, Jennifer,Edelstein, Mark,Ferris, Robert,Kazmierski, Wieslaw M.,Spaltenstein, Andrew,Wheelan, Pat,Xiong, Zhiping
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scheme or table
p. 7397 - 7400
(2011/02/23)
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- Studies on the structure-activity relationship of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists. Part 2: Discovery of highly potent anti-HIV agents
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Modification of 1,3,3,4-tetra-substituted pyrrolidine embodied CCR5 receptor antagonists revealed that introducing a fluoro group at the 3-position of the 3-phenyl group to reduce metabolism did not adversely affect the high potency against HIV infection, and that replacing the piperidine ring with a tropane ring could deliver the most potent anti-HIV agents. Stereochemistry of the substituted tropane ring is essential for maintaining the potent anti-HIV activity because only exo-isomers displayed subnanomolar whole cell activity.
- Li, Ben,Jones, Eric Dale,Zhou, Enkun,Chen, Li,Baylis, Dean Cameron,Yu, Shanghai,Wang, Miao,He, Xing,Coates, Jonathan Alan Victor,Rhodes, David Ian,Pei, Gang,Deadman, John Joseph,Xie, Xin,Ma, Dawei
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scheme or table
p. 5334 - 5336
(2010/10/03)
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- PYROLLIDINE-BASED COMPOUNDS
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The present invention discloses the compounds of formula ( I ) or a pharmaceutically acceptable derivative, salt or prodrug thereof, which can inhibit HIV replication.
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Page/Page column 59
(2009/08/16)
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- PYROLLIDINE-BASED COMPOUNDS
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A compound of formula (I) or a pharmaceutically acceptable derivative, salt or prodrug thereof, which can inhibit HIV replication.
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Page/Page column 59
(2009/09/05)
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- Pyrrolidine modulators of chemokine receptor activity
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The present invention is directed to pyrrolidine compounds of the formula I: (wherein R1, R2, R3, R4, R5, R6and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-5 and/or CCR-3.
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- Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4: Synthesis and structure-activity relationships for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(N-(alkyl)-N- (benzyloxycarbonyl)amino)piperidin-1-yl)butanes
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(2S)-2-(3-Chlorophenyl)-1-[N-(methyl)-N-(phenylsulfonyl)amino]-4-[spiro (2,3-dihydrobenzthiophene-3,4′-piperidin-1′-yl)]butane S-oxide (1b) has been identified as a potent CCR5 antagonist having an IC50 = 10 nM. Herein, structure-activity relationship studies of non-spiro piperidines are described, which led to the discovery of 4-(N-(alkyl)-N-(benzyloxycarbonyl)amino)piperidine derivatives (3-5) as potent CCR5 antagonists.
- Finke, Paul E.,Oates, Bryan,Mills, Sander G.,MacCoss, Malcolm,Malkowitz, Lorraine,Springer, Martin S.,Gould, Sandra L.,DeMartino, Julie A.,Carella, Anthony,Carver, Gwen,Holmes, Karen,Danzeisen, Renee,Hazuda, Daria,Kessler, Joseph,Lineberger, Janet,Miller, Michael,Schleif, William A.,Emini, Emilio A.
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p. 2475 - 2479
(2007/10/03)
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- Cyclic amine modulators of chemokine receptor activity
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The present invention is directed to cyclic amines of the formula I: (wherein R1, R2, R3, m and n are defined herein) which are useful as modulators of chemokine receptor activity. In particular, these compounds are useful as modulators of the chemokine receptors CCR-1, CCR-2, CCR-2A, CCR-2B, CCR-3, CCR-4, CCR-5, CXCR-3, and/or CXCR-4.
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