Journal of Medicinal Chemistry, volume 61, issue 10, pages 4456-4475
Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria
Gerasyuto Aleksey I
1
,
Arnold Michael A.
1
,
Wang Jiashi
1
,
Chen Guangming
1
,
Zhang Xiaoyan
1
,
Smith Sean
1
,
Woll Matthew G
1
,
Baird John
1
,
Zhang Nanjing
1
,
Almstead Neil G.
1
,
NARASIMHAN Jana
1
,
Peddi Srinivasa
1
,
Dumble Melissa
1
,
Sheedy Josephine
1
,
Weetall Marla
1
,
Branstrom Arthur A.
1
,
Prasad J V N
1
,
Karp Gary M
1
1
PTC Therapeutics, Inc., 100 Corporate Court, South Plainfield, New Jersey 07080, United States
|
Publication type: Journal Article
Publication date: 2018-05-04
Journal:
Journal of Medicinal Chemistry
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 7.3
ISSN: 00222623, 15204804
PubMed ID:
29727185
Drug Discovery
Molecular Medicine
Abstract
There exists an urgent medical need to identify new chemical entities (NCEs) targeting multidrug resistant (MDR) bacterial infections, particularly those caused by Gram-negative pathogens. 4-Hydroxy-2-pyridones represent a novel class of nonfluoroquinolone inhibitors of bacterial type II topoisomerases active against MDR Gram-negative bacteria. Herein, we report on the discovery and structure–activity relationships of a series of fused indolyl-containing 4-hydroxy-2-pyridones with improved in vitro antibacterial activity against fluoroquinolone resistant strains. Compounds 6o and 6v are representative of this class, targeting both bacterial DNA gyrase and topoisomerase IV (Topo IV). In an abbreviated susceptibility screen, compounds 6o and 6v showed improved MIC90 values against Escherichia coli (0.5–1 μg/mL) and Acinetobacter baumannii (8–16 μg/mL) compared to the precursor compounds. In a murine septicemia model, both compounds showed complete protection in mice infected with a lethal dose of E. coli.
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- We do not take into account publications that without a DOI.
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- Statistics recalculated weekly.
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Gerasyuto A. I. et al. Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 10. pp. 4456-4475.
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Gerasyuto A. I., Arnold M. A., Wang J., Chen G., Zhang X., Smith S., Woll M. G., Baird J., Zhang N., Almstead N. G., NARASIMHAN J., Peddi S., Dumble M., Sheedy J., Weetall M., Branstrom A. A., Prasad J. V. N., Karp G. M. Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 10. pp. 4456-4475.
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TY - JOUR
DO - 10.1021/acs.jmedchem.8b00114
UR - https://doi.org/10.1021%2Facs.jmedchem.8b00114
TI - Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria
T2 - Journal of Medicinal Chemistry
AU - Gerasyuto, Aleksey I
AU - Wang, Jiashi
AU - Smith, Sean
AU - Woll, Matthew G
AU - Baird, John
AU - Almstead, Neil G.
AU - NARASIMHAN, Jana
AU - Peddi, Srinivasa
AU - Dumble, Melissa
AU - Sheedy, Josephine
AU - Branstrom, Arthur A.
AU - Prasad, J V N
AU - Karp, Gary M
AU - Arnold, Michael A.
AU - Chen, Guangming
AU - Zhang, Xiaoyan
AU - Zhang, Nanjing
AU - Weetall, Marla
PY - 2018
DA - 2018/05/04 00:00:00
PB - American Chemical Society (ACS)
SP - 4456-4475
IS - 10
VL - 61
PMID - 29727185
SN - 0022-2623
SN - 1520-4804
ER -
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@article{2018_Gerasyuto,
author = {Aleksey I Gerasyuto and Jiashi Wang and Sean Smith and Matthew G Woll and John Baird and Neil G. Almstead and Jana NARASIMHAN and Srinivasa Peddi and Melissa Dumble and Josephine Sheedy and Arthur A. Branstrom and J V N Prasad and Gary M Karp and Michael A. Arnold and Guangming Chen and Xiaoyan Zhang and Nanjing Zhang and Marla Weetall},
title = {Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {may},
url = {https://doi.org/10.1021%2Facs.jmedchem.8b00114},
number = {10},
pages = {4456--4475},
doi = {10.1021/acs.jmedchem.8b00114}
}
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Gerasyuto, Aleksey I., et al. “Discovery and Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II DNA Topoisomerase Inhibitors Active against Multidrug Resistant Gram-negative Bacteria.” Journal of Medicinal Chemistry, vol. 61, no. 10, May. 2018, pp. 4456-4475. https://doi.org/10.1021%2Facs.jmedchem.8b00114.