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Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors
MG. Nizi, J. Desantis, Y. Nakatani, S. Massari, MA. Mazzarella, G. Shetye, S. Sabatini, ML. Barreca, G. Manfroni, T. Felicetti, R. Rushton-Green, K. Hards, G. Latacz, G. Satała, AJ. Bojarski, V. Cecchetti, MH. Kolář, J. Handzlik, GM. Cook, SG....
Jazyk angličtina Země Francie
Typ dokumentu časopisecké články
Odkazy
PubMed
32526553
DOI
10.1016/j.ejmech.2020.112420
Knihovny.cz E-zdroje
- MeSH
- antituberkulotika chemická syntéza metabolismus farmakologie toxicita MeSH
- Cercopithecus aethiops MeSH
- fenothiaziny chemická syntéza metabolismus farmakologie toxicita MeSH
- HEK293 buňky MeSH
- inhibitory enzymů chemická syntéza metabolismus farmakologie toxicita MeSH
- jaterní mikrozomy metabolismus MeSH
- lidé MeSH
- molekulární struktura MeSH
- Mycobacterium smegmatis účinky léků MeSH
- Mycobacterium tuberculosis účinky léků MeSH
- NADH-dehydrogenasa antagonisté a inhibitory MeSH
- organoselenové sloučeniny chemická syntéza metabolismus farmakologie toxicita MeSH
- parazitické testy citlivosti MeSH
- receptory dopaminu D2 metabolismus MeSH
- receptory serotoninové metabolismus MeSH
- synergismus léků MeSH
- vazba proteinů MeSH
- Vero buňky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
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.
Department of Microbiology and Immunology University of Otago Dunedin New Zealand
Department of Pharmaceutical Sciences University of Perugia Via Del Liceo 1 Perugia 06100 Italy
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