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Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors.
Nizi, Maria Giulia; Desantis, Jenny; Nakatani, Yoshio; Massari, Serena; Mazzarella, Maria Angela; Shetye, Gauri; Sabatini, Stefano; Barreca, Maria Letizia; Manfroni, Giuseppe; Felicetti, Tommaso; Rushton-Green, Rowena; Hards, Kiel; Latacz, Gniewomir; Satala, Grzegorz; Bojarski, Andrzej J; Cecchetti, Violetta; Kolár, Michal H; Handzlik, Jadwiga; Cook, Gregory M; Franzblau, Scott G; Tabarrini, Oriana.
Afiliación
  • Nizi MG; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Desantis J; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Nakatani Y; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • Massari S; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Mazzarella MA; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Shetye G; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
  • Sabatini S; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Barreca ML; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Manfroni G; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Felicetti T; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Rushton-Green R; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • Hards K; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • Latacz G; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
  • Satala G; Department of Medicinal Chemistry May Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland.
  • Bojarski AJ; Department of Medicinal Chemistry May Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, 31-343, Kraków, Poland.
  • Cecchetti V; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy.
  • Kolár MH; Department of Physical Chemistry, University of Chemistry and Technology, Technicka 5, 16628, Prague, Czech Republic.
  • Handzlik J; Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
  • Cook GM; Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand.
  • Franzblau SG; Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
  • Tabarrini O; Department of Pharmaceutical Sciences, University of Perugia, Via Del Liceo 1, Perugia, 06100, Italy. Electronic address: oriana.tabarrini@unipg.it.
Eur J Med Chem ; 201: 112420, 2020 Sep 01.
Article en En | MEDLINE | ID: mdl-32526553
Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotiazinas / Compuestos de Organoselenio / Antituberculosos Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fenotiazinas / Compuestos de Organoselenio / Antituberculosos Límite: Animals / Humans Idioma: En Revista: Eur J Med Chem Año: 2020 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Francia