Exploring the gyrase ATPase domain for tailoring newer anti-tubercular drugs: hit to lead optimization of a novel class of thiazole inhibitors.
Bioorg Med Chem
; 23(3): 588-601, 2015 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-25541204
ABSTRACT
Gyrase ATPase domain, the pharmaceutical underexploited segment of DNA gyrase, the sole Type II topoisomerase present in Mycobacterium tuberculosis represents an attractive target for anti-tubercular drug discovery. Here we report, the development of a novel series of MTB DNA gyraseB inhibitor identified through a medium throughput screening (MTS) of BITS in-house chemical library (3000 compounds). The MTS hit was further remodeled by chemical synthesis to identify the most potent analogue 27 exhibiting an in vitro gyrB inhibitory IC50 of 0.15 µM. The series also demonstrated well correlating gyrase super coiling activity and in vitro anti-mycobacterial potency against MTB H37Rv strain. Furthermore the compounds displayed good safety profile in their subsequent cytotoxicity and hERG toxicity evaluations, to be worked out from a pharmaceutical point of view as potential anti-tubercular agents.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tiazóis
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Adenosina Trifosfatases
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DNA Girase
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Inibidores da Topoisomerase II
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Antituberculosos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Índia
País de publicação:
ENGLAND
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ESCOCIA
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GB
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GREAT BRITAIN
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INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM