- Discovery of Novel UDP- N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors with Activity against Pseudomonas aeruginosa
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This study describes a novel series of UDP-N-acetylglucosamine acyltransferase (LpxA) inhibitors that was identified through affinity-mediated selection from a DNA-encoded compound library. The original hit was a selective inhibitor of Pseudomonas aeruginosa LpxA with no activity against Escherichia coli LpxA. The biochemical potency of the series was optimized through an X-ray crystallography-supported medicinal chemistry program, resulting in compounds with nanomolar activity against P. aeruginosa LpxA (best half-maximal inhibitory concentration (IC50) 20 μM and MIC > 128 μg/mL). The mode of action of analogues was confirmed through genetic analyses. As expected, compounds were active against multidrug-resistant isolates. Further optimization of pharmacokinetics is needed before efficacy studies in mouse infection models can be attempted. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa.
- Andersen, Ole A.,Barbeau, Olivier R.,Barker, John,Cain, Ricky,Centrella, Paolo A.,Clark, Matthew A.,Compper, Christel,Corbett, David,Cuozzo, John W.,Dejob, Magali,Dejonge, Boudewijn L. M.,Deng, Boer,Dickie, Anthony P.,Dorali, Alain,Etheridge, Donnya,Evans, Sian,Faulkner, Adele,Gadouleau, Elise,Gorman, Timothy,Haase, Denes,Holbrow-Wilshaw, Maisie,Hunt, Avery,Keefe, Anthony D.,Krulle, Thomas,Li, Xianfu,Lumley, Christopher,Mertins, Barbara,Napier, Spencer,Odedra, Rajesh,Papadopoulos, Kostas,Parkes, Alastair L.,Roumpelakis, Vasileios,Ryan, M. Dominic,Sanzone, Angelo,Sigel, Eric A.,Southey, Michelle,Soutter, Holly T.,Spear, Kate,Stein, Daniel B.,Thommes, Pia,Trimby, Emily,Troast, Dawn M.,Williams, Jennifer,Zahn, Michael,Zhang, Ying
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p. 14377 - 14425
(2021/10/25)
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- A facile synthesis of sulfonylureas: Via water assisted preparation of carbamates
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A novel and simple approach to the synthesis of sulfonylureas has been reported. It involved the reaction of various amines with diphenyl carbonate to yield the corresponding carbamates, which subsequently reacted with different sulphonamides to produce different sulfonylureas in excellent yields. The first reaction of diphenyl carbonate with amines was carried out in aqueous:organic (H2O:THF, 90:10) medium at room temperature to produce carbamates that paved a straightforward route to sulfonylureas after reaction with sulfonamides. The above process avoided traditional multistep protocols and the use of hazardous, irritant, toxic and moisture sensitive reagents such as phosgene, isocyanates and/or chloroformates.
- Tanwar, Dinesh Kumar,Ratan, Anjali,Gill, Manjinder Singh
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p. 4992 - 4999
(2017/07/11)
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- Efficient synthesis of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate: A versatile precursor to o-benzyne
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(Chemical Equation Presented) An efficient procedure for the gram-scale preparation of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate, a versatile precursor to o-benzyne, is presented. The three-step sequence utilizes phenol as the starting material, requires only one chromatographic purification, and ultimately delivers the desired silyltriflate in 66% overall yield. 2009 American Chemical Society.
- Bronner, Sarah M.,Garg, Neil K.
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experimental part
p. 8842 - 8843
(2010/02/28)
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- Facile preparation of 2-iodophenyl trifluoromethanesulfonates: Superior aryne precursors
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A comparative study of 3-methoxyaryne precursors revealed 2-iodo-3-methoxyphenyl triflate as the most effective in nonpolar solvent. Use of Hoppe's N-isopropyl carbamate allows for the systematic preparation of a variety of 2-iodophenyl triflates via a directed ortho-lithiation-iodination- decarbamation sequence. These steps are possible without isolation of the intermediate iodophenyl carbamates. Georg Thieme Verlag Stuttgart.
- Ganta, Ashok,Snowden, Timothy S.
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p. 2227 - 2231
(2008/02/10)
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- PROCESS FOR THE PREPARATION OF HIGHLY PURE TORSEMIDE
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The present invention provides a novel process for the preparation of highly pure torsemide [1] by reacting of 4-m-tolylamino-3-pyridinesulfonamide [2] with phenyl isopropylcarbamate in the presence of lithium base (F I, II). The present invention also provides a novel intermediate - torsemide lithium, also in hydrate or solvate form - which is a stable, solid compound, and may be simply isolated from the reaction mixture to give after acidification practically pure torsemide [1] without further purification steps.
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Page/Page column 30
(2010/02/07)
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- Synthesis of substituted phenols by directed ortho-lithiation of in situ N-silyl-protected O-aryl N-monoalkylcarbamates
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A simple, high-yield procedure has been developed for the ortho-lithiation and subsequent ortho-substitution of phenols by a manifold of electrophiles. N,C-Dilithiation of O-aryl N-monoalkylcarbamates proved to be impossible due to a cleavage reaction of
- Kauch, Matthias,Hoppe, Dieter
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p. 1736 - 1746
(2007/10/03)
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- A highly-efficient synthesis of benzoxazine-2,4-diones
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Base-promoted reaction of salicylate esters with isocyanates provides a highly efficient route to benzoxazine-2,4-diones.
- Boontheung, Pinmanee,Perlmutter, Patrick
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p. 2629 - 2630
(2007/10/03)
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- α-Haloalkyl Haloformates and Related Compounds 1. A Convenient Synthesis of Carbamates via Chloromethyl Carbamates
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The preparation of carbamates under mild conditions utilizing a new class of activated carbonates (containing chloromethyl function) is described.
- Patonay, Tamas,Patonay-Peli, Erzsebet,Mogyorodi, Ferenc
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p. 2865 - 2885
(2007/10/02)
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- 1,2,3-Thiadiazole-3-in-5-ylidene-urea derivatives, process for making the same and compositions containing the same having growth regulating activity for plants
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1,2,3-Thiadiazole-3-in-5-ylidene-urea derivative of the formula STR1 in which R1 is hydrogen or alkyl which may be substituted in one or several places by oxygen or sulfur and wherein R2 and R3 have the meaning as given in the attached specification and wherein X is oxygen or sulfur. The compounds have properties suited for controlling the natural growth and natural development of plants and in addition have a superior defoliating property without accompanying unpleasant odors.
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- 1,2,3-Thiadiazole-2-id derivatives, process for making the same and composition containing the same having a growth regulating activity for plants
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1,2,3-Thiadiazole-2-id-derivative of the formula STR1 in which R1 is hydrogen or alkyl which may be substituted in one or several places by oxygen or sulfur and wherein R1 has the meaning as given in the attached specification and wherein X is oxygen or sulfur and B is a univalent metal atom. The compounds have properties suited for controlling the natural growth and natural development of plants and in addition have a superior defoliating property.
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- Process for preparing alkyl isocyanates
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Alkylisocyanates are prepared by reacting a phenol or substituted phenol and phosgene in a halogenated hydrocarbon solvent with aqueous alkali metal hydroxide to produce a corresponding chloroformate, reacting the resulting chloroformate solution with aqueous alkylamine to give a corresponding N-alkylcarbamate which, after solvent is stripped, is then pyrolyzed to yield the alkyl isocyanate. Solvent and the starting phenol may be recovered and recycled to the process.
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