title: Novel non-neuroleptic phenothiazines inhibit Mycobacterium tuberculosis replication.
abstract: OBJECTIVE
  Phenothiazines are a commercially available class of psychotropic drugs known to show antituberculosis activity. At clinically relevant bactericidal doses, however, the psychotropic drugs produce undesirable side effects in addition to their neuroleptic properties. This study aimed to evaluate rationally designed novel phenothiazines as antimycobacterial drug candidates.
  
  
  METHODS
  Remodelling of psychotropic drugs by substitution of characteristic N-alkylamine side chains, important for CNS activity, with N-alkylsulphonates gave novel drug candidates, which were then tested for post-synaptic receptor binding affinity in a radioligand displacement assay. The bactericidal activities were screened using green fluorescent protein (GFP) microplate assays, and the efficacy of intracellular bacillus killing was evaluated by cfu enumeration.
  
  
  RESULTS
  Of the four selected phenothiazine derivatives (PTZ3, PTZ4, PTZ31 and PTZ32) tested, PTZ31 displayed marginal serotonergic activity. The remaining three derivatives did not exhibit dopamine or serotonin receptor binding activity. In vitro results showed significant growth inhibition of virulent Mycobacterium tuberculosis with MICs of 12.5-25 mg/L. None of the phenothiazine derivatives displayed cytotoxicity in infected primary bone marrow-derived macrophages. Moreover, the phenothiazines showed significant antimycobacterial activity of between 40% and 60% against intracellular (ex vivo) M. tuberculosis.
  
  
  CONCLUSIONS
  We demonstrate that structural modification of the phenothiazine core is possible in a manner that does not affect the ability of the phenothiazine derivatives to inhibit M. tuberculosis, but that abolishes undesirable dopamine and serotonin receptor binding.
authors.affiliation: Division of Immunology, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Sumayah
authors.initials: S
authors.lastname: Salie
authors.affiliation: Division of Immunology, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
authors.forename: Nai-Jen
authors.initials: NJ
authors.lastname: Hsu
authors.affiliation: Department of Chemistry, Faculty of Science, University of Cape Town, Cape Town, South Africa.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Semenya
authors.affiliation: Department of Chemistry, Faculty of Science, University of Cape Town, Cape Town, South Africa.
authors.forename: Anwar
authors.initials: A
authors.lastname: Jardine
authors.affiliation: Division of Immunology, Department of Clinical Laboratory Sciences and Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa National Health Laboratory Service, Cape Town, South Africa muazzam.jacobs@uct.ac.za.
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry / Q000494:pharmacology; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology*; D010640:Phenothiazines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D000995:Antitubercular Agents; D010640:Phenothiazines; C031637:phenothiazine
keywords: antimycobacterial; chemotherapy; dopamine; serotonin; thioridazine