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Application of Virtual Screening to the Identification of New LpxC Inhibitor Chemotypes, Oxazolidinone and Isoxazoline.
Lee, Patrick S; Lapointe, Guillaume; Madera, Ann Marie; Simmons, Robert L; Xu, Wenjian; Yifru, Aregahegn; Tjandra, Meiliana; Karur, Subramanian; Rico, Alice; Thompson, Katherine; Bojkovic, Jade; Xie, Lili; Uehara, Kyoko; Liu, Amy; Shu, Wei; Bellamacina, Cornelia; McKenney, David; Morris, Laura; Tonn, George R; Osborne, Colin; Benton, Bret M; McDowell, Laura; Fu, Jiping; Sweeney, Zachary K.
Afiliação
  • Lee PS; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Lapointe G; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Madera AM; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Simmons RL; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Xu W; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Yifru A; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Tjandra M; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Karur S; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Rico A; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Thompson K; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Bojkovic J; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Xie L; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Uehara K; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Liu A; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Shu W; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Bellamacina C; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • McKenney D; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Morris L; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Tonn GR; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Osborne C; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Benton BM; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • McDowell L; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Fu J; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
  • Sweeney ZK; Novartis Institutes for Biomedical Research , 5300 Chiron Way , Emeryville , California 94608 , United States.
J Med Chem ; 61(20): 9360-9370, 2018 10 25.
Article em En | MEDLINE | ID: mdl-30226381
ABSTRACT
This report summarizes the identification and synthesis of novel LpxC inhibitors aided by computational methods that leveraged numerous crystal structures. This effort led to the identification of oxazolidinone and isoxazoline inhibitors with potent in vitro activity against P. aeruginosa and other Gram-negative bacteria. Representative compound 13f demonstrated efficacy against P. aeruginosa in a mouse neutropenic thigh infection model. The antibacterial activity against K. pneumoniae could be potentiated by Gram-positive antibiotics rifampicin (RIF) and vancomycin (VAN) in both in vitro and in vivo models.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazolidinonas / Amidoidrolases / Isoxazóis Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxazolidinonas / Amidoidrolases / Isoxazóis Tipo de estudo: Diagnostic_studies / Screening_studies Limite: Animals Idioma: En Revista: J Med Chem Assunto da revista: QUIMICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos