Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors.

European Journal of Medicinal Chemistry
Maria Giulia NiziOriana Tabarrini

Abstract

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 serotonergi...Continue Reading

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Citations

Jan 11, 2021·European Journal of Medicinal Chemistry·Milan UrbanLucie Brulíková
Jul 4, 2021·European Journal of Medicinal Chemistry·Hongyan ChuaiMinhang Xin
Aug 5, 2021·ACS Chemical Neuroscience·Beata GryzłoKatarzyna Kulig

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