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C-2 苯基取代以获得强效喹啉基 NorA 抑制剂。

C-2 phenyl replacements to obtain potent quinoline-based NorA inhibitors.

机构信息

Department of Pharmaceutical Sciences, Chemistry and Technology of the Drug Section, Università degli Studi di Perugia, Perugia, Italy.

Department of Life and Environmental Sciences, Università Politecnica delle Marche, Ancona, Italy.

出版信息

J Enzyme Inhib Med Chem. 2020 Dec;35(1):584-597. doi: 10.1080/14756366.2020.1719083.

DOI:10.1080/14756366.2020.1719083
PMID:31992093
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7034129/
Abstract

NorA is the most studied efflux pump of and is responsible for high level resistance towards fluoroquinolone drugs. Although along the years many NorA efflux pump inhibitors (EPIs) have been reported, poor information is available about structure-activity relationship (SAR) around their nuclei and reliability of data supported by robust assays proving NorA inhibition. In this regard, we focussed efforts on the 2-phenylquinoline as a promising chemotype to develop potent NorA EPIs. Herein, we report SAR studies about the introduction of different aryl moieties on the quinoline C-2 position. The new derivative showed an improved EPI activity (16-fold) with respect to the starting hit . Moreover, compound exhibited a high potential in time-kill curves when combined with ciprofloxacin against SA-1199B (. Also, exhibited poor non-specific effect on bacterial membrane polarisation and showed an improvement in terms of "selectivity index" in comparison to .

摘要

NorA 是研究最为透彻的 外排泵，负责对氟喹诺酮类药物产生高水平耐药性。尽管多年来已经报道了许多 NorA 外排泵抑制剂（EPIs），但有关其核周围的结构-活性关系（SAR）以及通过可靠的测定法支持 NorA 抑制作用的可靠数据的信息仍然有限。在这方面，我们专注于 2-苯基喹啉作为开发有效 NorA EPIs 的有前途的化学型。在此，我们报告了关于在喹啉 C-2 位置引入不同芳基部分的 SAR 研究。与起始命中物 相比，新型衍生物 显示出改善的 EPI 活性（16 倍）。此外，化合物 与环丙沙星联合使用时对 SA-1199B 表现出很高的杀菌活性（时间杀伤曲线）。此外，与 相比，化合物 对细菌膜极化的非特异性作用较小，并且在“选择性指数”方面有所提高。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/3d0bbbe29722/IENZ_A_1719083_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/a10813ee3d68/IENZ_A_1719083_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/7fa1fd097d97/IENZ_A_1719083_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/9bf618336468/IENZ_A_1719083_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/6dd5bec27f05/IENZ_A_1719083_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/d56111404f28/IENZ_A_1719083_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/75f5b30fa2e1/IENZ_A_1719083_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/3d0bbbe29722/IENZ_A_1719083_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/a10813ee3d68/IENZ_A_1719083_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/7fa1fd097d97/IENZ_A_1719083_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/9bf618336468/IENZ_A_1719083_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/6dd5bec27f05/IENZ_A_1719083_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/d56111404f28/IENZ_A_1719083_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/75f5b30fa2e1/IENZ_A_1719083_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d83/7034129/3d0bbbe29722/IENZ_A_1719083_F0006_C.jpg

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