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Title: Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids

Abstract

4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »;  [1] « less
  1. (Novartis)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1049580
Resource Type:
Journal Article
Journal Name:
J. Med. Chem.
Additional Journal Information:
Journal Volume: 54; Journal Issue: (23) ; 12, 2011; Journal ID: ISSN 0022-2623
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; AMIDES; ANTIBIOTICS; CHAINS; ELONGATION; IN VITRO; IN VIVO; OPTIMIZATION; SOLUBILITY; STABILITY; URETHANE

Citation Formats

LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Kerri, Brewer, Jason T., Bushell, Simon M., Dewhurst, Janetta M., Dzink-Fox, JoAnne, Gangl, Eric, Goldovitz, Julie, Jain, Akash, Mullin, Steve, Neckermann, Georg, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Whitehead, Lewis, and Yu, Donghui. Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids. United States: N. p., 2012. Web. doi:10.1021/jm200938f.
LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Kerri, Brewer, Jason T., Bushell, Simon M., Dewhurst, Janetta M., Dzink-Fox, JoAnne, Gangl, Eric, Goldovitz, Julie, Jain, Akash, Mullin, Steve, Neckermann, Georg, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Whitehead, Lewis, & Yu, Donghui. Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids. United States. doi:10.1021/jm200938f.
LaMarche, Matthew J., Leeds, Jennifer A., Amaral, Kerri, Brewer, Jason T., Bushell, Simon M., Dewhurst, Janetta M., Dzink-Fox, JoAnne, Gangl, Eric, Goldovitz, Julie, Jain, Akash, Mullin, Steve, Neckermann, Georg, Osborne, Colin, Palestrant, Deborah, Patane, Michael A., Rann, Elin M., Sachdeva, Meena, Shao, Jian, Tiamfook, Stacey, Whitehead, Lewis, and Yu, Donghui. Fri . "Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids". United States. doi:10.1021/jm200938f.
@article{osti_1049580,
title = {Antibacterial Optimization of 4-Aminothiazolyl Analogues of the Natural Product GE2270 A: Identification of the Cycloalkylcarboxylic Acids},
author = {LaMarche, Matthew J. and Leeds, Jennifer A. and Amaral, Kerri and Brewer, Jason T. and Bushell, Simon M. and Dewhurst, Janetta M. and Dzink-Fox, JoAnne and Gangl, Eric and Goldovitz, Julie and Jain, Akash and Mullin, Steve and Neckermann, Georg and Osborne, Colin and Palestrant, Deborah and Patane, Michael A. and Rann, Elin M. and Sachdeva, Meena and Shao, Jian and Tiamfook, Stacey and Whitehead, Lewis and Yu, Donghui},
abstractNote = {4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for their activity against Gram positive bacterial infections. Optimization efforts focused on improving the physicochemical properties (e.g., aqueous solubility and chemical stability) of the 4-aminothiazolyl natural product template while improving the in vitro and in vivo antibacterial activity. Structure-activity relationships were defined, and the solubility and efficacy profiles were improved over those of previous analogues and 1. These studies identified novel, potent, soluble, and efficacious elongation factor-Tu inhibitors, which bear cycloalkylcarboxylic acid side chains, and culminated in the selection of development candidates amide 48 and urethane 58.},
doi = {10.1021/jm200938f},
journal = {J. Med. Chem.},
issn = {0022-2623},
number = (23) ; 12, 2011,
volume = 54,
place = {United States},
year = {2012},
month = {11}
}