Thiazolopyridone ureas as DNA gyrase B inhibitors: optimization of antitubercular activity and efficacy.
Bioorg Med Chem Lett
; 24(3): 870-9, 2014 Feb 01.
Article
en En
| MEDLINE
| ID: mdl-24405701
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.
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Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Piridonas
/
Tiazoles
/
Urea
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Inhibidores de Topoisomerasa II
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Mycobacterium tuberculosis
Límite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2014
Tipo del documento:
Article
País de afiliación:
India