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Nature-Inspired (di)Azine-Bridged Bisindole Alkaloids with Potent Antibacterial In Vitro and In Vivo Efficacy against Methicillin-Resistant Staphylococcus aureus.
Rehberg, Nidja; Sommer, Gereon A; Drießen, Daniel; Kruppa, Marco; Adeniyi, Emmanuel T; Chen, Shang; Wang, Lin; Wolf, Karina; Tasch, Boris O A; Ioerger, Thomas R; Zhu, Kui; Müller, Thomas J J; Kalscheuer, Rainer.
Afiliación
  • Rehberg N; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • Sommer GA; Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
  • Drießen D; Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
  • Kruppa M; Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
  • Adeniyi ET; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • Chen S; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China.
  • Wang L; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • Wolf K; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • Tasch BOA; Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
  • Ioerger TR; Department of Computer Science, Texas A&M University, 710 Ross St., College Station, Texas 77843, United States.
  • Zhu K; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Veterinary Medicine, China Agricultural University, No. 2 Yuanmingyuan West Road, Beijing 100193, China.
  • Müller TJJ; Institute of Organic Chemistry and Macromolecular Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, D-40225 Düsseldorf, Germany.
  • Kalscheuer R; Institute of Pharmaceutical Biology and Biotechnology, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
J Med Chem ; 63(21): 12623-12641, 2020 11 12.
Article en En | MEDLINE | ID: mdl-33103423
Natural bisindole alkaloids such as Hyrtinadine A and Alocasin A, which are known to exhibit diverse bioactivities, provide promising chemical scaffolds for drug development. By optimizing the Masuda borylation-Suzuki coupling sequence, a library of various natural product-derived and non-natural (di)azine-bridged bisindoles was created. While unsubstituted bisindoles were devoid of antibacterial activity, 5,5'-chloro derivatives were highly active against methicillin-resistant Staphylococcus aureus (MRSA) and further Gram-positive pathogens at minimal inhibitory concentrations ranging from 0.20 to 0.78 µM. These compounds showed strong bactericidal killing effects but only moderate cytotoxicity against human cell lines. Furthermore, the two front-runner compounds 4j and 4n exhibited potent in vivo efficacy against MRSA in a mouse wound infection model. Although structurally related bisindoles were reported to specifically target pyruvate kinase in MRSA, antibacterial activity of 4j and 4n is independent of pyruvate kinase. Rather, these compounds lead to bacterial membrane permeabilization and cellular efflux of low-molecular-weight molecules.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alcaloides / Staphylococcus aureus Resistente a Meticilina / Indoles / Antibacterianos Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Alcaloides / Staphylococcus aureus Resistente a Meticilina / Indoles / Antibacterianos Límite: Animals / Female / Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2020 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos