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Discovery of Novel Pyridone-Conjugated Monosulfactams as Potent and Broad-Spectrum Antibiotics for Multidrug-Resistant Gram-Negative Infections
Tan, Liang,Tao, Yunliang,Wang, Ting,Zou, Feng,Zhang, Shuhua,Kou, Qunhuan,Niu, Ao,Chen, Qian,Chu, Wenjing,Chen, Xiaoyan,Wang, Haidong,Yang, Yushe
, p. 2669 - 2684 (2017)
Conjugating a siderophore to an antibiotic is a promising strategy to overcome the permeability-mediated resistance of Gram-negative pathogens. On the basis of the structure of BAL30072, novel pyridone-conjugated monosulfactams incorporating diverse substituents into the methylene linker between the 1,3-dihydroxypyridin-4(1H)-one and the aminothiazole oxime were designed and synthesized. Structure-activity relationship studies revealed that a variety of substituents were tolerated, with isopropyl (compound 12c) and methylthiomethyl (compound 16a) showing the best efficacy against multidrug-resistant (MDR) Gram-negative pathogens. In addition, compound 12c exhibits a good free fraction rate in an in vitro human plasma protein binding test, along with a low clearance and favorable plasma exposure in vivo. In a murine systemic infection model with MDR Klebsiella pneumoniae, compound 12c shows an ED50 of 10.20 mg/kg. Taken together, the results indicate that compound 12c is a promising drug candidate for the treatment of serious infections caused by MDR Gram-negative pathogens.
NEW 2-AMIDOTHIADIAZOLE DERIVATIVES
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Page/Page column 64, (2010/04/30)
New 2-amidothiadiazole derivatives having the chemical structure of formula (I) or pharmaceutically acceptable salts or N-oxides thereof as agonists of S1P1 receptors.