Pyrazolidine-3,5-diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase
Pyrazolidine-3,5-diones and 5-hydroxy-1H-pyrazol-3(2H)-ones, inhibitors of UDP-N-acetylenolpyruvyl glucosamine reductase
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DOI：
10.1021/jm060499t
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发表时间：
2006-10-05
影响因子：
7.3
通讯作者：
Katz, Alan H.
中科院分区：
文献类型：
--
作者：
Gilbert, Adam M.;Failli, Amedeo;Katz, Alan H.
合成了一系列吡唑烷-3，5-二酮和5-羟基-1H-吡唑-3（2 H）-酮类大肠杆菌UDP-N-乙酰烯醇式葡萄糖胺还原酶（MurB）抑制剂。5-羟基-1H-吡唑-3（2 H）酮与E相比显示出较低的微摩尔IC 50值。大肠杆菌MurB和对金黄色葡萄球菌GC 1131、粪肠球菌GC 2242、肺炎链球菌GC 1894和大肠杆菌的亚微摩尔最小抑菌浓度（MIC）。coliGC 4560 imp，一种具有增加的外膜通透性的菌株。这些化合物都没有显示出对白色念珠菌的抗微生物活性，白色念珠菌是真核生物毒性的标志。此外，这些化合物抑制肽聚糖生物合成，如通过测量表皮链球菌在与化合物孵育后产生的可溶性肽聚糖的量所评估的。对潜在结构的偏最小二乘投影分析表明，提高MurB效力和MIC值与5-羟基-1H-吡唑-3（2 H）-酮核心的C-4取代基的亲脂性增加相关。使用FLO和PharmDock的对接研究在MurB活性位点产生了这些分子的几种结合方向。
A series of pyrazolidine-3,5-dione and 5-hydroxy-1H-pyrazol-3(2H)-one inhibitors of Escherichia coli UDP-N-acetylenolpyruvyl glucosamine reductase (MurB) has been prepared. The 5-hydroxy-1H-pyrazol-3(2H)ones show low micromolar IC50 values versus E. coli MurB and submicromolar minimal inhibitory concentrations ( MIC) against Staphylococcus aureus GC 1131, Enterococcus faecalis GC 2242, Streptococcus pneumoniae GC 1894, and E. coli GC 4560 imp, a strain with increased outer membrane permeability. None of these compounds show antimicrobial activity against Candida albicans, a marker of eukaryotic toxicity. Moreover, these compounds inhibit peptidoglycan biosynthesis, as assessed by measuring the amount of soluble peptidoglycan produced by Streptococcus epidermidis upon incubation with compounds. A partial least squares projection to latent structures analysis shows that improving MurB potency and MIC values correlate with increasing lipophilicity of the C-4 substituent of the 5-hydroxy-1H-pyrazol-3(2H)-one core. Docking studies using FLO and PharmDock produced several binding orientations for these molecules in the MurB active site.