Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60461373%3A22340%2F20%3A43920214" target="_blank" >RIV/60461373:22340/20:43920214 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1016/j.ejmech.2020.112420" target="_blank" >https://doi.org/10.1016/j.ejmech.2020.112420</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2020.112420" target="_blank" >10.1016/j.ejmech.2020.112420</a>

Result language

angličtina

Original language name

Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors

Original language description

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.

Czech name

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Czech description

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Type

J_ost - Miscellaneous article in a specialist periodical

CEP classification

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OECD FORD branch

10401 - Organic chemistry

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

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Volume of the periodical

201

Issue of the periodical within the volume

1. 9. 2020

Country of publishing house

FR - FRANCE

Number of pages

13

Pages from-to

"112420-1"-"112420-13"

UT code for WoS article

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EID of the result in the Scopus database

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