- Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening
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Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments.
- Baulard, Alain R.,Biela, Alexandre,Blaise, Mickael,Bourbiaux, Kevin,Cantrelle, Francois-Xavier,Djaout, Kamel,Flipo, Marion,Frita, Rosangela,Hanoulle, Xavier,Herledan, Adrien,Kremer, Laurent,Leroux, Florence,Moune, Martin,Pintiala, Catalin,Piveteau, Catherine,Tanina, Abdalkarim,Vandeputte, Alexandre,Willand, Nicolas,Déprez, Benoit,Fa?on, Léo,Wintjens, René
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- A 3 - amino -2 - naphthalene armor acid compound preparation process (by machine translation)
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The invention discloses a 3 - amino - 2 - naphthalene armor acid compound preparation process, characterized in that in the phthaldialdehyde in three is made [...] condensed under the action of the 2, 3 - naphthalene carboxylic acid dimethyl ester; the alkaline hydrolysis is under the condition of 2, 3 - naphthalene carboxylic acid mono methyl ester; then through the DPPA reaction will be carboxyl group into amino, to obtain 3 - tert-butoxy-carboxamide yl - 2 - naphthalene carboxylic acid methyl ester; finally ester, and further takes off uncle butoxycarbonyl, to obtain 3 - amino - 2 - naphthoic acid. The method of mild reaction conditions, suitable for different substrate, without the need to use high temperature autoclave equipment, reduce the safety risk in the production process, to reduce the equipment investment, energy consumption can be reduced, which is suitable for large-scale production. (by machine translation)
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- Organocatalytic route to dihydrocoumarins and dihydroquinolinones in all stereochemical configurations
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A straightforward stereodivergent route to dihydrocoumarins and dihydroquinolinones based on cinchona alkaloid catalyzed addition reactions of monothiomalonates (MTMs) to functionalized nitroolefins followed by deprotection and chemoselective cyclization has been developed. The synthesis proceeds under mild conditions and yields heterocycles with adjacent quaternary and tertiary stereogenic centers in very high yields and stereoselectivities. Moreover, full control over the relative and absolute configuration is achieved by the use of (pseudo)enantiomeric catalysts and the difference in reactivity of thioester versus oxoester moieties. (Chemical Equation Presented).
- Engl, Oliver D.,Fritz, Sven P.,K?slin, Alexander,Wennemers, Helma
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supporting information
p. 5454 - 5457
(2015/02/05)
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- Design, synthesis, and biological evaluation of conformationally constrained analogues of naphthol AS-E as inhibitors of CREB-mediated gene transcription
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Cyclic AMP response element binding protein (CREB) is often dysregulated in cancer cells and is an attractive cancer drug target. Previously, we described naphthol AS-E (1) as a small molecule inhibitor of CREB-mediated gene transcription. To understand its bioactive conformation, a series of conformationally constrained analogues of 1 were designed and synthesized. Biological evaluation of these analogues suggests that the global energy minimum of 1 is the likely bioactive conformation.
- Jiang, Min,Li, Bingbing X.,Xie, Fuchun,Delaney, Frances,Xiao, Xiangshu
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supporting information; experimental part
p. 4020 - 4024
(2012/07/16)
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- GLYCOGEN PHOSPHORYLASE INHIBITOR COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF
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The invention relates to glycogen phosphorylase inhibitor compounds, pharmaceutical compositions of these compounds, methods of treatment using the pharmaceutical compositions to treat diabetes, conditions associated with diabetes, and/or tissue ischemia,
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Page/Page column 75
(2010/11/30)
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