Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors.
Eur J Med Chem
; 201: 112420, 2020 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-32526553
ABSTRACT
Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADHmenaquinone 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phenothiazines
/
Organoselenium Compounds
/
Antitubercular Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2020
Document type:
Article
Affiliation country:
Italy
Publication country:
FR
/
FRANCE
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FRANCIA
/
FRANÇA