Antitubercular polyhalogenated phenothiazines and phenoselenazine with reduced binding to CNS receptors

Eur J Med Chem. 2020 Sep 1:201:112420. doi: 10.1016/j.ejmech.2020.112420. Epub 2020 Jun 5.


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.

Keywords: Halogenated-phenothiazines; NDH-2; Phenoselenazine; Phenothiazines; Respiratory chain; Tuberculosis.

MeSH terms

  • Animals
  • Antitubercular Agents / chemical synthesis
  • Antitubercular Agents / metabolism
  • Antitubercular Agents / pharmacology*
  • Antitubercular Agents / toxicity
  • Chlorocebus aethiops
  • Drug Synergism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / toxicity
  • HEK293 Cells
  • Humans
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Mycobacterium smegmatis / drug effects
  • Mycobacterium tuberculosis / drug effects
  • NADH Dehydrogenase / antagonists & inhibitors
  • Organoselenium Compounds / chemical synthesis
  • Organoselenium Compounds / metabolism
  • Organoselenium Compounds / pharmacology*
  • Organoselenium Compounds / toxicity
  • Parasitic Sensitivity Tests
  • Phenothiazines / chemical synthesis
  • Phenothiazines / metabolism
  • Phenothiazines / pharmacology*
  • Phenothiazines / toxicity
  • Protein Binding
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / metabolism
  • Structure-Activity Relationship
  • Vero Cells


  • Antitubercular Agents
  • Enzyme Inhibitors
  • Organoselenium Compounds
  • Phenothiazines
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • NADH dehydrogenase II
  • NADH Dehydrogenase