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Bioorg Med Chem Lett. 2014 Sep 1;24(17):4215-22. doi: 10.1016/j.bmcl.2014.07.037. Epub 2014 Jul 19.

Discovery and in vivo evaluation of alcohol-containing benzothiazoles as potent dual-targeting bacterial DNA supercoiling inhibitors.

Author information

1
Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia. Electronic address: j.palmer@biota.com.au.
2
Biota Scientific Management, 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
3
Biota Europe Ltd, Begbroke Science Park, Begbroke, Oxfordshire OX51PF, United Kingdom.
4
Jubliant Chemsys Ltd, B-34, Sector 58, Noida 201301, India.

Abstract

A series of dual-targeting, alcohol-containing benzothiazoles has been identified with superior antibacterial activity and drug-like properties. Early lead benzothiazoles containing carboxylic acid moieties showed efficacy in a well-established in vivo model, but inferior drug-like properties demanded modifications of functionality capable of demonstrating superior efficacy. Eliminating the acid group in favor of hydrophilic alcohol moieties at C(5), as well as incorporating solubilizing groups at the C(7) position of the core ring provided potent, broad-spectrum Gram-positive antibacterial activity, lower protein binding, and markedly improved efficacy in vivo.

KEYWORDS:

Antibacterial; DNA gyrase; Dual-targeting; In vivo; Synthesis; Topoisomerase

PMID:
25086682
DOI:
10.1016/j.bmcl.2014.07.037
[Indexed for MEDLINE]

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