81168-17-4Relevant articles and documents
INHIBITORS OF ADENYLATE-FORMING ENZYME MENE
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, (2020/08/22)
Provided herein are compounds of Formula (I) and pharmaceutically acceptable salts or tautomers thereof which may inhibit adenylate-forming enzymes. Also provided are pharmaceutical compositions, kits, uses, and methods involving the inventive compounds for the treatment and/or prevention of an infectious disease (e.g., bacterial infection (e.g., tuberculosis, methicillin- resistant Staphylococcus aureus)).
Structure-Based Design, Synthesis, and Biological Evaluation of Non-Acyl Sulfamate Inhibitors of the Adenylate-Forming Enzyme MenE
Evans, Christopher E.,Si, Yuanyuan,Matarlo, Joe S.,Yin, Yue,French, Jarrod B.,Tonge, Peter J.,Tan, Derek S.
, p. 1918 - 1930 (2019/04/03)
N-Acyl sulfamoyladenosines (acyl-AMS) have been used extensively to inhibit adenylate-forming enzymes that are involved in a wide range of biological processes. These acyl-AMS inhibitors are nonhydrolyzable mimics of the cognate acyl adenylate intermediates that are bound tightly by adenylate-forming enzymes. However, the anionic acyl sulfamate moiety presents a pharmacological liability that may be detrimental to cell permeability and pharmacokinetic profiles. We have previously developed the acyl sulfamate OSB-AMS (1) as a potent inhibitor of the adenylate-forming enzyme MenE, an o-succinylbenzoate-CoA (OSB-CoA) synthetase that is required for bacterial menaquinone biosynthesis. Herein, we report the use of computational docking to develop novel, non-acyl sulfamate inhibitors of MenE. A m-phenyl ether-linked analogue (5) was found to be the most potent inhibitor (IC50 = 8 μM; Kd = 244 nM), and its X-ray co-crystal structure was determined to characterize its binding mode in comparison to the computational prediction. This work provides a framework for the development of potent non-acyl sulfamate inhibitors of other adenylate-forming enzymes in the future.
Synthetic method for ring formation intermediate of aromatic octatomic ring through biological orthogonal experiment
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Paragraph 0019-0021; 0028-0031, (2019/01/06)
The invention relates to a synthetic method for a ring formation intermediate of an aromatic octatomic ring through a biological orthogonal experiment. The synthetic method comprises the following steps: (a) mixing o-benzenedicarbinol, dichloromethane, imidazole and tert-butyldimethylsilyl chloride for reaction, and purifying by virtue of a chromatographic column, so as to obtain a compound II; (b) adding methyl toluenesulfonyl carbamate, triphenylphosphine and diethyl azodicarboxylate, concentrating, and carrying out column purification, so as to obtain a compound III; (c) dissolving the compound III into methanol, cooling to the temperature less than or equal to 0 DEG C, adding potassium carbonate for reaction, and adding water for quenching; (d) carrying out extraction for several timesby virtue of ethyl acetate, combining organic phases, drying by virtue of anhydrous sodium sulfate, concentrating, and purifying by virtue of the chromatographic column, so as to obtain a compound V;(e) concentrating, and purifying by virtue of the chromatographic column, so as to obtain a compound VI; and (f) concentrating, and purifying by virtue of the chromatographic column, so as to obtaina compound VII. According to the synthetic method, the redesign of a synthetic route for the ring formation intermediate of the aromatic octatomic ring is realized.
