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

Micheal Trzoss, Daniel C. Bensen, Xiaoming Li, Zhiyong Chen, Thanh Lam, Junhu Zhang, Christopher J. Creighton, Mark L. Cunningham, Bryan Kwan, Mark Stidham, Kirk Nelson, Vickie Brown-Driver, Amanda Castellano, Karen J. Shaw, Felice C Lightstone, Sergio E. Wong, Toan B. Nguyen, John Finn, Leslie W. Tari

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1537-1543
Number of pages7
JournalBioorganic and Medicinal Chemistry Letters
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Fingerprint

DNA Topoisomerase IV
Topoisomerase II Inhibitors
Type I DNA Topoisomerase
DNA Gyrase
Acinetobacter baumannii
Bacterial DNA
Pathogens
Pseudomonas aeruginosa
Escherichia coli
Anti-Bacterial Agents
pyrrolopyrimidine

Keywords

  • Bacterial topoisomerases
  • Gram-negative antibacterial agents
  • GyrB
  • Inhibitor
  • ParE
  • Pyrrolopyrimidine

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II : Development of inhibitors with broad spectrum, Gram-negative antibacterial activity. / Trzoss, Micheal; Bensen, Daniel C.; Li, Xiaoming; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Creighton, Christopher J.; Cunningham, Mark L.; Kwan, Bryan; Stidham, Mark; Nelson, Kirk; Brown-Driver, Vickie; Castellano, Amanda; Shaw, Karen J.; Lightstone, Felice C; Wong, Sergio E.; Nguyen, Toan B.; Finn, John; Tari, Leslie W.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 23, No. 5, 01.03.2013, p. 1537-1543.

Research output: Contribution to journalArticle

Trzoss, M, Bensen, DC, Li, X, Chen, Z, Lam, T, Zhang, J, Creighton, CJ, Cunningham, ML, Kwan, B, Stidham, M, Nelson, K, Brown-Driver, V, Castellano, A, Shaw, KJ, Lightstone, FC, Wong, SE, Nguyen, TB, Finn, J & Tari, LW 2013, 'Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: Development of inhibitors with broad spectrum, Gram-negative antibacterial activity', Bioorganic and Medicinal Chemistry Letters, vol. 23, no. 5, pp. 1537-1543. https://doi.org/10.1016/j.bmcl.2012.11.073
Trzoss, Micheal ; Bensen, Daniel C. ; Li, Xiaoming ; Chen, Zhiyong ; Lam, Thanh ; Zhang, Junhu ; Creighton, Christopher J. ; Cunningham, Mark L. ; Kwan, Bryan ; Stidham, Mark ; Nelson, Kirk ; Brown-Driver, Vickie ; Castellano, Amanda ; Shaw, Karen J. ; Lightstone, Felice C ; Wong, Sergio E. ; Nguyen, Toan B. ; Finn, John ; Tari, Leslie W. / Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II : Development of inhibitors with broad spectrum, Gram-negative antibacterial activity. In: Bioorganic and Medicinal Chemistry Letters. 2013 ; Vol. 23, No. 5. pp. 1537-1543.
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