European Journal of Medicinal Chemistry, volume 124, pages 129-137
Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities
Zunhua Yang
1
,
Yan Liu
1
,
Jongsam Ahn
2
,
Zhen Qiao
1
,
Jennifer L. Endres
2
,
Nagsen Gautam
1
,
Yunlong Huang
3
,
Jerry Li
1
,
Jialin Zheng
4
,
Yazen Alnouti
1
,
Kenneth W. Bayles
5
,
Rongshi Li
6
1
UNMC Center for Drug Discovery and Department of Pharmaceutical Sciences, United States.
|
2
Department of Pathology and Microbiology, United States
|
3
Department of Pharmacology and Experimental Neuroscience, United States
|
4
Department of Pharmacology and Experimental Neuroscience
5
Center for Staphylococcal Research
6
Fred & Pamela Buffett Cancer Center
Publication type: Journal Article
Publication date: 2016-11-01
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 6.7
ISSN: 02235234, 17683254
Organic Chemistry
Drug Discovery
General Medicine
Pharmacology
Abstract
Staphylococcus aureus (SA) is a major cause of hospital- and community-associated bacterial infections in the U.S. and around the world. These infections have become increasingly difficult to treat due to the propensity to develop antibiotic resistance and form biofilm. To date, no antibiofilm agents are available for clinical use. To add to the repertoire of antibiotics for clinical use and to provide novel agents for combating both SA and biofilm infections, we previously reported marinopyrroles as potent anti-SA agents. In this study, we used fragment-based and bioisostere approaches to design and synthesize a series of novel fluorinated pyrrolomycins for the first time, performed analyses of their physicochemical and drug-like properties, and investigated structure activity relationships and pharmacokinetics. These promising fluorinated pyrrolomycins demonstrate potent antibacterial activity against SA with favorable drug-like properties and pharmacokinetic profiles. Importantly, these compounds kill staphylococcal biofilm-associated cells with a lack of mammalian cell cytotoxicity and no occurrence of bacterial resistance. Our novel fluorinated pyrrolomycin 4 has a clogP value of 4.1, an MIC of 73 ng/mL, MBC of 4 μg/mL, kill staphylococcal-associated biofilm at 8 μg/mL, bioavailability of 35%, and the elimination half-life of 6.04 h and 6.75 h by intravenous and oral administration, respectively. This is the first report of comprehensive drug discovery studies on pyrrolomycin-based antibiotics.
Top-30
Citations by journals
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1 publication, 5.26%
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1 publication, 5.26%
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1 publication, 5.26%
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Citations by publishers
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1
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3
4
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American Society for Microbiology
4 publications, 21.05%
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3 publications, 15.79%
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2 publications, 10.53%
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2 publications, 10.53%
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1 publication, 5.26%
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1 publication, 5.26%
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1 publication, 5.26%
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1 publication, 5.26%
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1 publication, 5.26%
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Springer Nature
1 publication, 5.26%
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Autonomous Non-profit Organization Editorial Board of the journal Uspekhi Khimii
1 publication, 5.26%
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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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Yang Z. et al. Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities // European Journal of Medicinal Chemistry. 2016. Vol. 124. pp. 129-137.
GOST all authors (up to 50)
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Yang Z., Liu Y., Ahn J., Qiao Z., Endres J. L., Gautam N., Huang Y., Li J., Zheng J., Alnouti Y., Bayles K. W., Li R. Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities // European Journal of Medicinal Chemistry. 2016. Vol. 124. pp. 129-137.
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TY - JOUR
DO - 10.1016/j.ejmech.2016.08.017
UR - https://doi.org/10.1016/j.ejmech.2016.08.017
TI - Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities
T2 - European Journal of Medicinal Chemistry
AU - Yang, Zunhua
AU - Liu, Yan
AU - Ahn, Jongsam
AU - Qiao, Zhen
AU - Endres, Jennifer L.
AU - Gautam, Nagsen
AU - Huang, Yunlong
AU - Li, Jerry
AU - Zheng, Jialin
AU - Alnouti, Yazen
AU - Bayles, Kenneth W.
AU - Li, Rongshi
PY - 2016
DA - 2016/11/01 00:00:00
PB - Elsevier
SP - 129-137
VL - 124
SN - 0223-5234
SN - 1768-3254
ER -
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@article{2016_Yang,
author = {Zunhua Yang and Yan Liu and Jongsam Ahn and Zhen Qiao and Jennifer L. Endres and Nagsen Gautam and Yunlong Huang and Jerry Li and Jialin Zheng and Yazen Alnouti and Kenneth W. Bayles and Rongshi Li},
title = {Novel fluorinated pyrrolomycins as potent anti-staphylococcal biofilm agents: Design, synthesis, pharmacokinetics and antibacterial activities},
journal = {European Journal of Medicinal Chemistry},
year = {2016},
volume = {124},
publisher = {Elsevier},
month = {nov},
url = {https://doi.org/10.1016/j.ejmech.2016.08.017},
pages = {129--137},
doi = {10.1016/j.ejmech.2016.08.017}
}