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Bioorg Med Chem Lett. 2014 Feb 1;24(3):870-9. doi: 10.1016/j.bmcl.2013.12.080. Epub 2013 Dec 25.

Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy.

Author information

1
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
2
Department of Biosciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
3
DMPK and Animal Sciences, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.
4
Discovery Sciences, AstraZeneca, Alderley Park, Macclesfield, UK.
5
Biosciences, Infection iMed, AstraZeneca, Waltham, MA, USA.
6
Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India. Electronic address: Sandeep.ghorpade@astrazeneca.com.

Abstract

Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.

KEYWORDS:

DNA gyrase; GyrB; Thiazolopyridone ureas; Tuberculosis

PMID:
24405701
DOI:
10.1016/j.bmcl.2013.12.080
[Indexed for MEDLINE]

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