Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors.
Structure-activity relationships of a novel pyranopyridine series of Gram-negative bacterial efflux pump inhibitors.
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DOI：
10.1016/j.bmc.2015.03.016
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发表时间：
2015-05-01
影响因子：
3.5
通讯作者：
Opperman TJ
中科院分区：
文献类型：
--
作者：
Nguyen ST;Kwasny SM;Ding X;Cardinale SC;McCarthy CT;Kim HS;Nikaido H;Peet NP;Williams JD;Bowlin TL;Opperman TJ
最近我们报道了一种新型的肠杆菌科RND型外排泵的吡喃并吡啶抑制剂(MBX2319)。(3，3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3，4-dihydro-1H-pyrano[3，4-c]pyridine)在结构上不同于其他已知的革兰氏阴性外排泵抑制剂(EPI)，如1-(1-萘甲基)-哌嗪(NMP)、苯丙氨基精氨酸-β-萘胺(PAβN)、D13-9001和吡啶衍生物。在这里，我们报道了60个新的MBX2319类似物的合成和生物活性评价，这些类似物旨在探索吡喃并吡啶类支架的构效关系(SARS)。这些研究的结果产生了支架的分子活性图谱，其中确定了对外流抑制活性至关重要的区域，以及那些可以被修饰以提高效力、代谢稳定性和溶解性的区域。一些化合物，如22d-f、22i和22k，在增强左氧氟沙星和哌拉西林对大肠杆菌的抗菌活性方面明显优于MBX2319。
Recently we described a novel pyranopyridine inhibitor (MBX2319) of RND-type efflux pumps of the Enterobacteriaceae. MBX2319 (3,3-dimethyl-5-cyano-8-morpholino-6-(phenethylthio)-3,4-dihydro-1H-pyrano[3,4-c]pyridine) is structurally distinct from other known Gram-negative efflux pump inhibitors (EPIs), such as 1-(1-naphthylmethyl)-piperazine (NMP), phenylalanylarginine-β-naphthylamide (PAβN), D13-9001, and the pyridopyrimidine derivatives. Here, we report the synthesis and biological evaluation of 60 new analogs of MBX2319 that were designed to probe the structure activity relationships (SARs) of the pyranopyridine scaffold. The results of these studies produced a molecular activity map of the scaffold, which identifies regions that are critical to efflux inhibitory activities and those that can be modified to improve potency, metabolic stability and solubility. Several compounds, such as 22d–f, 22i and 22k, are significantly more effective than MBX2319 at potentiating the antibacterial activity of levofloxacin and piperacillin against Escherichia coli.
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影响因子：
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