Journal of Medicinal Chemistry, volume 61, issue 8, pages 3325-3349

Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity

Skepper Colin K 1
Moreau Robert J 1
Appleton Brent A. 1
Benton Bret M. 1
Drumm Joseph E 1
Feng Brian Y 1
Geng Mei 1
Hu Cheng 1
Li Cindy 1
Lingel Andreas 1
Lu Yipin 1
Mamo Mulugeta 1
Mergo Wosenu 1
Mostafavi Mina 1
Rath Christopher M 1
Steffek Micah 1
Takeoka Kenneth T 1
Uehara Kyoko 1
Wang Lisha 1
Wei Jun Rong 1
Xie Lili 1
Xu Wenjian 1
Zhang Qiong 1
de Vicente Javier 1
1
 
Novartis Institutes for Biomedical Research, 5300 Chiron Way, Emeryville, California 94608, United States
Publication typeJournal Article
Publication date2018-03-18
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor7.3
ISSN00222623, 15204804
Drug Discovery
Molecular Medicine
Abstract
In the preceding manuscript [ Moreau et al. 2018 , 10.1021/acs.jmedchem.7b01691 ] we described a successful fragment-based lead discovery (FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase inhibitors (PPAT, CoaD). Following several rounds of optimization two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose our efforts to further optimize these two leads for on-target potency and Gram-negative cellular activity. Enabled by a robust X-ray crystallography system, our structure-based inhibitor design approach delivered compounds with biochemical potencies 4-5 orders of magnitude greater than their respective fragment starting points. Additional optimization was guided by observations on bacterial permeability and physicochemical properties, which ultimately led to the identification of PPAT inhibitors with cellular activity against wild-type E. coli.

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Skepper C. K. et al. Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 8. pp. 3325-3349.
GOST all authors (up to 50) Copy
Skepper C. K., Moreau R. J., Appleton B. A., Benton B. M., Drumm J. E., Feng B. Y., Geng M., Hu C., Li C., Lingel A., Lu Y., Mamo M., Mergo W., Mostafavi M., Rath C. M., Steffek M., Takeoka K. T., Uehara K., Wang L., Wei J. R., Xie L., Xu W., Zhang Q., de Vicente J. Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity // Journal of Medicinal Chemistry. 2018. Vol. 61. No. 8. pp. 3325-3349.
RIS |
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RIS Copy
TY - JOUR
DO - 10.1021/acs.jmedchem.7b01861
UR - https://doi.org/10.1021%2Facs.jmedchem.7b01861
TI - Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity
T2 - Journal of Medicinal Chemistry
AU - Appleton, Brent A.
AU - Benton, Bret M.
AU - Drumm, Joseph E
AU - Geng, Mei
AU - Hu, Cheng
AU - Li, Cindy
AU - Lu, Yipin
AU - Mamo, Mulugeta
AU - Mergo, Wosenu
AU - Mostafavi, Mina
AU - Rath, Christopher M
AU - Steffek, Micah
AU - Takeoka, Kenneth T
AU - Uehara, Kyoko
AU - Wang, Lisha
AU - Wei, Jun Rong
AU - Xie, Lili
AU - Xu, Wenjian
AU - Zhang, Qiong
AU - de Vicente, Javier
AU - Skepper, Colin K
AU - Moreau, Robert J
AU - Feng, Brian Y
AU - Lingel, Andreas
PY - 2018
DA - 2018/03/18 00:00:00
PB - American Chemical Society (ACS)
SP - 3325-3349
IS - 8
VL - 61
SN - 0022-2623
SN - 1520-4804
ER -
BibTex |
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BibTex Copy
@article{2018_Skepper
author = {Brent A. Appleton and Bret M. Benton and Joseph E Drumm and Mei Geng and Cheng Hu and Cindy Li and Yipin Lu and Mulugeta Mamo and Wosenu Mergo and Mina Mostafavi and Christopher M Rath and Micah Steffek and Kenneth T Takeoka and Kyoko Uehara and Lisha Wang and Jun Rong Wei and Lili Xie and Wenjian Xu and Qiong Zhang and Javier de Vicente and Colin K Skepper and Robert J Moreau and Brian Y Feng and Andreas Lingel},
title = {Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity},
journal = {Journal of Medicinal Chemistry},
year = {2018},
volume = {61},
publisher = {American Chemical Society (ACS)},
month = {mar},
url = {https://doi.org/10.1021%2Facs.jmedchem.7b01861},
number = {8},
pages = {3325--3349},
doi = {10.1021/acs.jmedchem.7b01861}
}
MLA
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MLA Copy
Skepper, Colin K., et al. “Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity.” Journal of Medicinal Chemistry, vol. 61, no. 8, Mar. 2018, pp. 3325-3349. https://doi.org/10.1021%2Facs.jmedchem.7b01861.
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