Discovery of dual GyrB/ParE inhibitors active against Gram-negative bacteria

被引：12

作者：

Ho, Soo Yei ^{[1
]}

Wang, Weiling ^{[1
]}

Ng, Fui Mee ^{[1
]}

Wong, Yun Xuan ^{[1
]}

Poh, Zhi Ying ^{[1
]}

Tan, Sum Wai Eldwin ^{[1
]}

Ang, Shi Hua ^{[1
]}

Liew, Si Si ^{[1
]}

Wong, Yin Sze Joyner ^{[1
]}

Tan, Yvonne ^{[1
]}

Poulsen, Anders ^{[1
]}

Pendharkar, Vishal ^{[1
]}

Sangthongpitag, Kanda ^{[1
]}

Manchester, John ^{[2
,3
]}

Basarab, Gregory ^{[2
,4
]}

Hill, Jeffrey ^{[1
]}

Keller, Thomas H. ^{[1
]}

Cherian, Joseph ^{[1
]}

机构：

[1] Expt Therapeut Ctr, 13 Biopolis Way, Nanos 13866, Singapore

[2] AstraZeneca, 35 Gatehouse Dr, Waltham, MA 02451 USA

[3] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

[4] Univ Cape Town, Dept Chem, H3D,PD Hahn Bldg,Upper Campus, ZA-7700 Rondebosch, South Africa

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 157卷

关键词：

Gram-negative bacteria; Dual target inhibition; Gyrase B; ParE; Gyrase; TopoIV; TOPOISOMERASE-IV PARE; PSEUDOMONAS-AERUGINOSA; DNA; SUBUNIT; AVIBACTAM; SPECTRUM; BROAD; GYRB;

D O I：

10.1016/j.ejmech.2018.08.025

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Even though many GyrB and ParE inhibitors have been reported in the literature, few possess activity against Gram-negative bacteria. This is primarily due to limited permeability across Gram-negative bacterial membrane as well as bacterial efflux mechanisms. Permeability of compounds across Gramnegative bacterial membranes depends on many factors including physicochemical properties of the inhibitors. Herein, we show the optimization of pyridylureas leading to compounds with potent activity against Gram-negative bacterial species such as P.aeruginosa, E.coli and A.baumannii. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：610 / 621

页数：12

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