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Design, synthesis and antitubercular potency of 4-hydroxyquinolin-2(1H)-ones.
de Macedo, Maíra Bidart; Kimmel, Roman; Urankar, Damijana; Gazvoda, Martin; Peixoto, Antonio; Cools, Freya; Torfs, Eveline; Verschaeve, Luc; Lima, Emerson Silva; Lycka, Antonín; Milicevic, David; Klásek, Antonín; Cos, Paul; Kafka, Stanislav; Kosmrlj, Janez; Cappoen, Davie.
Afiliación
  • de Macedo MB; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Kimmel R; Faculty of Technology, Tomas Bata University, Vavreckova 275, CZ-760 01 Zlín, Czech Republic.
  • Urankar D; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia.
  • Gazvoda M; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia.
  • Peixoto A; Centre National de la Recherche Scientifique, IPBS, UMR 5089, F-31077 Toulouse, France; Univ. Toulouse, UPS, F-31000 Toulouse, France.
  • Cools F; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Torfs E; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Verschaeve L; Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Lima ES; Faculty of Pharmaceutical Sciences, Federal Univeristy of Amazonas, Avenida General Rodrigo Otávio Campos de Jordão, 6200, Coroado, Manaus 69077-000, Amazonas, Brazil.
  • Lycka A; Faculty of Science, University of Hradec Králové, Rokitanského 62, CZ-500 03 Hradec Králové III, Czech Republic.
  • Milicevic D; Faculty of Technology, Tomas Bata University, Vavreckova 275, CZ-760 01 Zlín, Czech Republic.
  • Klásek A; Faculty of Technology, Tomas Bata University, Vavreckova 275, CZ-760 01 Zlín, Czech Republic.
  • Cos P; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium.
  • Kafka S; Faculty of Technology, Tomas Bata University, Vavreckova 275, CZ-760 01 Zlín, Czech Republic. Electronic address: Kafka@ft.utb.cz.
  • Kosmrlj J; Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia. Electronic address: Janez.Kosmrlj@fkkt.uni-lj.si.
  • Cappoen D; Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Universiteitsplein 1, B-2610 Wilrijk, Belgium. Electronic address: Davie.Cappoen@uantwerpen.be.
Eur J Med Chem ; 138: 491-500, 2017 Sep 29.
Article en En | MEDLINE | ID: mdl-28689097
In this study, a 50-membered library of substituted 4-hydroxyquinolin-2(1H)-ones and two closely related analogues was designed, scored in-silico for drug likeness and subsequently synthesized. Thirteen derivatives, all sharing a common 3-phenyl substituent showed minimal inhibitory concentrations against Mycobacterium tuberculosis H37Ra below 10 µM and against Mycobacterium bovis AN5A below 15 µM but were inactive against faster growing mycobacterial species. None of these selected derivatives showed significant acute toxicity against MRC-5 cells or early signs of genotoxicity in the Vitotox™ assay at the active concentration range. The structure activity study relation provided some insight in the further favourable substitution pattern at the 4-hydroxyquinolin-2(1H)-one scaffold and finally 6-fluoro-4-hydroxy-3-phenylquinolin-2(1H)-one (38) was selected as the most promising member of the library with a MIC of 3.2 µM and a CC50 against MRC-5 of 67.4 µM.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Quinolonas / Mycobacterium bovis / Mycobacterium tuberculosis / Antituberculosos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2017 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Francia
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Diseño de Fármacos / Quinolonas / Mycobacterium bovis / Mycobacterium tuberculosis / Antituberculosos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2017 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Francia