Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors

Jing Zhang; Qingyi Yang; Jason B. Cross; Jan Antoinette C. Romero; Katherine M. Poutsiaka; Felix Epie; Douglas Bevan; Bin Wang; Yanzhi Zhang; Ajit Chavan; Xin Zhang; Terence Moy; Anu Daniel; Kien Nguyen; Brian Chamberlain; Nicole Carter; Joseph Shotwell; Jared Silverman; Chester A. Metcalf; Dominic Ryan; Blaise Lippa; Roland E. Dolle

doi:10.1021/acs.jmedchem.5b00961

Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors

Jing Zhang, Qingyi Yang, Jason B. Cross, Jan Antoinette C. Romero, Katherine M. Poutsiaka, Felix Epie, Douglas Bevan, Bin Wang, Yanzhi Zhang, Ajit Chavan, Xin Zhang, Terence Moy, Anu Daniel, Kien Nguyen, Brian Chamberlain, Nicole Carter, Joseph Shotwell, Jared Silverman, Chester A. Metcalf, Dominic RyanBlaise Lippa, Roland E. Dolle

Center for Drug Discovery

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

Abstract

The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.

Original language	English
Pages (from-to)	8503-8512
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	21
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00961
State	Published - Oct 13 2015

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Zhang, J., Yang, Q., Cross, J. B., Romero, J. A. C., Poutsiaka, K. M., Epie, F., Bevan, D., Wang, B., Zhang, Y., Chavan, A., Zhang, X., Moy, T., Daniel, A., Nguyen, K., Chamberlain, B., Carter, N., Shotwell, J., Silverman, J., Metcalf, C. A., ... Dolle, R. E. (2015). Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors. Journal of Medicinal Chemistry, 58(21), 8503-8512. https://doi.org/10.1021/acs.jmedchem.5b00961

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title = "Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors",

abstract = "The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.",

author = "Jing Zhang and Qingyi Yang and Cross, {Jason B.} and Romero, {Jan Antoinette C.} and Poutsiaka, {Katherine M.} and Felix Epie and Douglas Bevan and Bin Wang and Yanzhi Zhang and Ajit Chavan and Xin Zhang and Terence Moy and Anu Daniel and Kien Nguyen and Brian Chamberlain and Nicole Carter and Joseph Shotwell and Jared Silverman and Metcalf, {Chester A.} and Dominic Ryan and Blaise Lippa and Dolle, {Roland E.}",

note = "Publisher Copyright: {\textcopyright} 2015 American Chemical Society.",

year = "2015",

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doi = "10.1021/acs.jmedchem.5b00961",

language = "English",

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Zhang, J, Yang, Q, Cross, JB, Romero, JAC, Poutsiaka, KM, Epie, F, Bevan, D, Wang, B, Zhang, Y, Chavan, A, Zhang, X, Moy, T, Daniel, A, Nguyen, K, Chamberlain, B, Carter, N, Shotwell, J, Silverman, J, Metcalf, CA, Ryan, D, Lippa, B & Dolle, RE 2015, 'Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors', Journal of Medicinal Chemistry, vol. 58, no. 21, pp. 8503-8512. https://doi.org/10.1021/acs.jmedchem.5b00961

TY - JOUR

T1 - Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors

AU - Zhang, Jing

AU - Yang, Qingyi

AU - Cross, Jason B.

AU - Romero, Jan Antoinette C.

AU - Poutsiaka, Katherine M.

AU - Epie, Felix

AU - Bevan, Douglas

AU - Wang, Bin

AU - Zhang, Yanzhi

AU - Chavan, Ajit

AU - Zhang, Xin

AU - Moy, Terence

AU - Daniel, Anu

AU - Nguyen, Kien

AU - Chamberlain, Brian

AU - Carter, Nicole

AU - Shotwell, Joseph

AU - Silverman, Jared

AU - Metcalf, Chester A.

AU - Ryan, Dominic

AU - Lippa, Blaise

AU - Dolle, Roland E.

PY - 2015/10/13

Y1 - 2015/10/13

N2 - The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.

AB - The emergence and spread of multidrug resistant bacteria are widely believed to endanger human health. New drug targets and lead compounds exempt from cross-resistance with existing drugs are urgently needed. We report on the discovery of azaindole ureas as a novel class of bacterial gyrase B inhibitors and detail the story of their evolution from a de novo design hit based on structure-based drug design. These inhibitors show potent minimum inhibitory concentrations against fluoroquinolone resistant MRSA and other Gram-positive bacteria.

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U2 - 10.1021/acs.jmedchem.5b00961

DO - 10.1021/acs.jmedchem.5b00961

M3 - Article

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SN - 0022-2623

VL - 58

SP - 8503

EP - 8512

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

Discovery of Azaindole Ureas as a Novel Class of Bacterial Gyrase B Inhibitors

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