Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: Development of inhibitors with broad spectrum, Gram-negative antibacterial activity

被引：66

作者：

Trzoss, Micheal ^{[1
]}

Bensen, Daniel C. ^{[1
]}

Li, Xiaoming ^{[1
]}

Chen, Zhiyong ^{[1
]}

Thanh Lam ^{[1
]}

Zhang, Junhu ^{[1
]}

Creighton, Christopher J. ^{[1
]}

Cunningham, Mark L. ^{[1
]}

Kwan, Bryan ^{[1
]}

Stidham, Mark ^{[1
]}

Nelson, Kirk ^{[1
]}

Brown-Driver, Vickie ^{[1
]}

Castellano, Amanda ^{[1
]}

Shaw, Karen J. ^{[1
]}

Lightstone, Felice C. ^{[2
]}

Wong, Sergio E. ^{[2
]}

Nguyen, Toan B. ^{[2
]}

Finn, John ^{[1
]}

Tari, Leslie W. ^{[1
]}

机构：

[1] Trius Therapeut, San Diego, CA 92121 USA

[2] Lawrence Livermore Natl Lab, Phys & Life Sci Directorate, Livermore, CA 94550 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 05期

基金：

美国国家卫生研究院;

关键词：

Bacterial topoisomerases; Pyrrolopyrimidine; GyrB; ParE; Gram-negative antibacterial agents; Inhibitor; ANTIBIOTICS;

D O I：

10.1016/j.bmcl.2012.11.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity. (c) 2012 Elsevier Ltd. All rights reserved.

引用

页码：1537 / 1543

页数：7

共 28 条

[1] DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: Synthesis and antibacterial activity
East, Stephen P.
White, Clara Bantry
Barker, Oliver
Barker, Stephanie
Bennett, James
Brown, David
Boyd, E. Andrew
Brennan, Christopher
Chowdhury, Chandana
Collins, Ian
Convers-Reignier, Emmanuelle
Dymock, Brian W.
Fletcher, Rowena
Haydon, David J.
Gardiner, Mihaly
Hatcher, Stuart
Ingram, Peter
Lancett, Paul
Mortenson, Paul
Papadopoulos, Konstantinos
Smee, Carol
Thomaides-Brears, Helena B.
Tye, Heather
Workman, James
Czaplewski, Lloyd G.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (03) : 894 - 899
[2] Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity
Tari, Leslie W.
Trzoss, Michael
Bensen, Daniel C.
Li, Xiaoming
Chen, Zhiyong
Thanh Lam
Zhang, Junhu
Creighton, Christopher J.
Cunningham, Mark L.
Kwan, Bryan
Stidham, Mark
Shaw, Karen J.
Lightstone, Felice C.
Wong, Sergio E.
Nguyen, Toan B.
Nix, Jay
Finn, John
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (05) : 1529 - 1536
[3] Discovery of potent, dual targeting pyrrolopyrimidine inhibitors of bacterial DNA gyrase B and topoisomerase IV with broad spectrum antibacterial activity
Finn, John
Tari, L.
Bensen, D.
Trzoss, M.
Lam, T.
Zhang, J.
Li, X.
Chen, Z.
Creighton, C.
Cunningham, M.
Kwan, B.
Nelson, K.
Castellano, A.
Stidham, M.
Brown-Driver, V.
Shaw, K. J.
Lightstone, F.
Wong, S.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2012, 243
[4] DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: Synthesis and antibacterial activity (vol 19, pg 894, 2009)
East, Stephen P.
White, Clara Bantry
Barker, Oliver
Barker, Stephanie
Bennett, James
Brown, David
Boyd, E. Andrew
Brennan, Christopher
Chowdhury, Chandana
Collins, Ian
Convers-Reignier, Emmanuelle
Dymock, Brian W.
Fletcher, Rowena
Haydon, David J.
Gardiner, Mihaly
Hatcher, Stuart
Ingram, Peter
Lancett, Paul
Mortenson, Paul
Papadopoulos, Konstantinos
Smee, Carol
Thomaides-Brears, Helena B.
Tye, Heather
Workman, James
Czaplewski, Lloyd G.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (09) : 2606 - 2606
[5] Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: A review
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Thathan, Janarthanan
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BIOORGANIC CHEMISTRY, 2015, 62 : 41 - 63
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Durcik, M.
Nyerges, A.
Skok, Z.
Zidar, N.
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Zega, A.
Tammela, P.
Draskovitz, G.
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Kikelj, D.
Pal, C.
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FEBS OPEN BIO, 2021, 11 : 88 - 88
[7] Discovery, synthesis, and antibacterial activity of novel myrtucommulone analogs as inhibitors of DNA gyrase and topoisomerase IV
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Li, Jian
Wang, Bo-Lin
Yang, Xin-Ya
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2025, 283
[8] Novel, non-quinolone inhibitors of DNA gyrase and topoisomerase IV: Antibacterial activity and resistance mechanisms
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ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2012, 243
[9] Covalent DNA Binding Is Essential for Gram-Negative Antibacterial Activity of Broad Spectrum Pyrrolobenzodiazepines
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[10] Discovery of Pyrido[2,3-b]indole Derivatives with Gram-Negative Activity Targeting Both DNA Gyrase and Topoisomerase IV
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Zhu, Wei
Zhang, Weixing
Zhang, Zhiwei
Zhou, Chengang
Liu, Yongqiang
Ding, Xiao
Shen, Hong C.
Yan, S. Frank
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Wu, Waikwong
Zhai, Guanglei
Zhou, Zheng
Xu, Zhiheng
Ji, Ying
Lv, Hua
Jiang, Tianyi
Wang, Wen
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JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (17) : 9623 - 9649

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