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
This paper reviews the current understanding of the toxicity of selenium (Se) to terrestrial mammalian and aquatic organisms. Adverse biological effects occur in the case of Se deficiencies, associated with this element having essential biological functions and a narrow window between essentiality and toxicity. Several inorganic species of Se (-2, 0, +4, and +6) and organic species (monomethylated and dimethylated) have been reported in aquatic systems. The toxicity of Se in any given sample depends not only on its speciation and concentration, but also on the concomitant presence of other compounds that may have synergistic or antagonistic effects, affecting the target organism as well, usually spanning 2 or 3 orders of magnitude for inorganic Se species. In aquatic ecosystems, indirect toxic effects, linked to the trophic transfer of excess Se, are usually of much more concern than direct Se toxicity. Studies on the toxicity of selenium nanoparticles indicate the greater toxicity of chemically generated selenium nanoparticles relative to selenium oxyanions for fish and fish embryos while oxyanions of selenium have been found to be more highly toxic to rats as compared to nano-Se. Studies on polymer coated Cd/Se quantum dots suggest significant differences in toxicity of weathered vs. non-weathered QD's as well as a significant role for cadmium with respect to toxicity.
- MeSH
- ekosystém MeSH
- krysa rodu rattus MeSH
- kvantové tečky toxicita MeSH
- látky znečišťující životní prostředí toxicita MeSH
- lidé MeSH
- organoselenové sloučeniny toxicita MeSH
- skot MeSH
- sloučeniny kadmia toxicita MeSH
- sloučeniny selenu toxicita MeSH
- synergismus léků MeSH
- vodní organismy účinky léků růst a vývoj MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
A number of cytotoxicity assays are currently available, each of them using specific approach to detect different aspects of cell viability, such as cell integrity, proliferation and metabolic functions. In this study we compared the potential of five commonly employed cytotoxicity assays (WST-1, XTT, MTT, Brilliant blue and Neutral red assay) to detect antiproliferative effects of three selenium compounds, sodium selenite, seleno-L-methionine (SeMet) and Se-(Methyl)selenocysteine (SeMCys) on three colorectal cancer cell lines in vitro. Cells were exposed to the selected selenium compounds in the concentration range of 0-256 microM during 48 h. WST-1 and XTT failed to detect cytotoxic effect, with the exception of the highest concentration of selenium compounds tested. Conversely, the metabolic activity of selenium treated cells measured by WST-1 and XTT significantly increased in comparison to untreated controls. MTT, Neutral red and Brilliant blue assays were more sensitive and yielded mutually comparable results, with significant decrease of measured parameters in a concentration-dependent manner. To a smaller extent, the results were affected by the different chemical nature of the selenium compounds tested as well as by the biological properties of individual cell lines.
- MeSH
- antikarcinogenní látky terapeutické užití toxicita MeSH
- cystein analogy a deriváty terapeutické užití toxicita MeSH
- cytotoxiny terapeutické užití toxicita MeSH
- lidé MeSH
- methionin analogy a deriváty terapeutické užití toxicita MeSH
- nádorové buněčné linie MeSH
- nádory tračníku farmakoterapie metabolismus prevence a kontrola MeSH
- organoselenové sloučeniny terapeutické užití toxicita MeSH
- proliferace buněk účinky léků MeSH
- seleničitan sodný terapeutické užití toxicita MeSH
- testy toxicity metody MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- MeSH
- antikarcinogenní látky terapeutické užití MeSH
- dítě MeSH
- dospělí MeSH
- glutathionperoxidasa fyziologie chemie MeSH
- lidé MeSH
- organoselenové sloučeniny imunologie toxicita MeSH
- renální insuficience metabolismus MeSH
- selen analýza imunologie toxicita MeSH
- sloučeniny selenu analýza imunologie MeSH
- těhotenství MeSH
- volné radikály antagonisté a inhibitory MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
