Journal of Medicinal Chemistry, volume 57, issue 21, pages 9078-9095
Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization
Gregory S. Basarab
1
,
Patrick Brassil
1
,
Peter Doig
1
,
Vincent Galullo
1
,
Howard B Haimes
1
,
Gunther Kern
1
,
Amy Kutschke
1
,
John McNulty
1
,
Virna J.A. Schuck
1
,
Gregory G. Stone
1
,
Madhusudhan Gowravaram
1
1
Infection Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States
|
Publication type: Journal Article
Publication date: 2014-10-17
Journal:
Journal of Medicinal Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 7.3
ISSN: 00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
The compounds described herein with a spirocyclic architecture fused to a benzisoxazole ring represent a new class of antibacterial agents that operate by inhibition of DNA gyrase as corroborated in an enzyme assay and by the inhibition of precursor thymidine into DNA during cell growth. Activity resided in the configurationally lowest energy (2S,4R,4aR) diastereomer. Highly active compounds against Staphylococcus aureus had sufficiently high solubility, high plasma protein free fraction, and favorable pharmacokinetics to suggest that in vivo efficacy could be demonstrated, which was realized with compound (−)-1 in S. aureus mouse infection models. A high drug exposure NOEL on oral dosing in the rat suggested that a high therapeutic margin could be achieved. Importantly, (−)-1 was not cross-resistant with other DNA gyrase inhibitors such as fluoroquinolone and aminocoumarin antibacterials. Hence, this class shows considerable promise for the treatment of infections caused by multidrug resistant bacteria, including S. aureus.
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Citations by publishers
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14
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American Chemical Society (ACS)
13 publications, 29.55%
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2 publications, 4.55%
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1 publication, 2.27%
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Frontiers Media S.A.
1 publication, 2.27%
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American Society for Biochemistry and Molecular Biology
1 publication, 2.27%
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Oxford University Press
1 publication, 2.27%
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Autonomous Non-profit Organization Editorial Board of the journal Uspekhi Khimii
1 publication, 2.27%
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- We do not take into account publications without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Basarab G. S. et al. Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization // Journal of Medicinal Chemistry. 2014. Vol. 57. No. 21. pp. 9078-9095.
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Basarab G. S., Brassil P., Doig P., Galullo V., Haimes H. B., Kern G., Kutschke A., McNulty J., Schuck V. J., Stone G. G., Gowravaram M. Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization // Journal of Medicinal Chemistry. 2014. Vol. 57. No. 21. pp. 9078-9095.
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TY - JOUR
DO - 10.1021/jm501174m
UR - https://doi.org/10.1021/jm501174m
TI - Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization
T2 - Journal of Medicinal Chemistry
AU - Brassil, Patrick
AU - Doig, Peter
AU - Galullo, Vincent
AU - Haimes, Howard B
AU - Kern, Gunther
AU - Kutschke, Amy
AU - McNulty, John
AU - Schuck, Virna J.A.
AU - Gowravaram, Madhusudhan
AU - Basarab, Gregory S.
AU - Stone, Gregory G.
PY - 2014
DA - 2014/10/17 00:00:00
PB - American Chemical Society (ACS)
SP - 9078-9095
IS - 21
VL - 57
SN - 0022-2623
SN - 1520-4804
ER -
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@article{2014_Basarab,
author = {Patrick Brassil and Peter Doig and Vincent Galullo and Howard B Haimes and Gunther Kern and Amy Kutschke and John McNulty and Virna J.A. Schuck and Madhusudhan Gowravaram and Gregory S. Basarab and Gregory G. Stone},
title = {Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization},
journal = {Journal of Medicinal Chemistry},
year = {2014},
volume = {57},
publisher = {American Chemical Society (ACS)},
month = {oct},
url = {https://doi.org/10.1021/jm501174m},
number = {21},
pages = {9078--9095},
doi = {10.1021/jm501174m}
}
Cite this
MLA
Copy
Basarab, Gregory S., et al. “Novel DNA Gyrase Inhibiting Spiropyrimidinetriones with a Benzisoxazole Scaffold: SAR and in Vivo Characterization.” Journal of Medicinal Chemistry, vol. 57, no. 21, Oct. 2014, pp. 9078-9095. https://doi.org/10.1021/jm501174m.