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New direct inhibitors of InhA with antimycobacterial activity based on a tetrahydropyran scaffold.
Pajk, Stane; Zivec, Matej; Sink, Roman; Sosic, Izidor; Neu, Margarete; Chung, Chun-Wa; Martínez-Hoyos, María; Pérez-Herrán, Esther; Álvarez-Gómez, Daniel; Álvarez-Ruíz, Emilio; Mendoza-Losana, Alfonso; Castro-Pichel, Julia; Barros, David; Ballell-Pages, Lluís; Young, Robert J; Convery, Maire A; Encinas, Lourdes; Gobec, Stanislav.
Affiliation
  • Pajk S; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
  • Zivec M; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
  • Sink R; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
  • Sosic I; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia.
  • Neu M; Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
  • Chung CW; Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
  • Martínez-Hoyos M; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Pérez-Herrán E; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Álvarez-Gómez D; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Álvarez-Ruíz E; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Mendoza-Losana A; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Castro-Pichel J; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Barros D; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Ballell-Pages L; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain.
  • Young RJ; Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
  • Convery MA; Medicines Research Centre, GlaxoSmithKline, Stevenage, Hertfordshire, UK.
  • Encinas L; DPU TB Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain. Electronic address: lourdes.p.encinas-prieto@gsk.com.
  • Gobec S; University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. Electronic address: stanislav.gobec@ffa-uni-lj.si.
Eur J Med Chem ; 112: 252-257, 2016 Apr 13.
Article in En | MEDLINE | ID: mdl-26900657
ABSTRACT
Tetrahydropyran derivative 1 was discovered in a high-throughput screening campaign to find new inhibitors of mycobacterial InhA. Following initial in-vitro profiling, a structure-activity relationship study was initiated and a focused library of analogs was synthesized and evaluated. This yielded compound 42 with improved antimycobacterial activity and low cytotoxicity. Additionally, the crystal structure of InhA in complex with inhibitor 1 was resolved, to reveal the binding mode and provide hints for further optimization.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oxidoreductases / Pyrans / Bacterial Proteins / Mycobacterium tuberculosis / Antitubercular Agents Limits: Humans Language: En Journal: Eur J Med Chem Year: 2016 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Oxidoreductases / Pyrans / Bacterial Proteins / Mycobacterium tuberculosis / Antitubercular Agents Limits: Humans Language: En Journal: Eur J Med Chem Year: 2016 Document type: Article Affiliation country: