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.
- 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
