title: Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in an Ex Vivo Model System Is Selectively Enhanced by the Addition of Divalent Metal Ions.
abstract: Current treatments for cutaneous and visceral leishmaniasis are toxic, expensive, difficult to administer, and limited in efficacy and availability. Disulfiram has primarily been used to treat alcoholism. More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used an ex vivo system to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-Leishmania activity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 μM, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 μM. The in vitro therapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, against L. major when combined with ZnCl2. The combination of disulfiram with ZnSO4 resulted in a 1.8-fold increase in IVTI against L. donovani. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and/or oral therapies for treatment of cutaneous and visceral leishmaniasis.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA Escuela de Ciencias Básicas, Facultad de Salud, Universidad del Valle, Cali, Colombia.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Peniche
authors.affiliation: Small Molecule Discovery Center, Center for Discovery and Innovation in Parasitic Diseases, and Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Adam R
authors.initials: AR
authors.lastname: Renslo
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Melby
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas, USA Center for Tropical Diseases, University of Texas Medical Branch, Galveston, Texas, USA brltravi@utmb.edu.
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Travi
mesh_terms: D000818:Animals; D002413:Cations, Divalent; D002460:Cell Line; D002712:Chlorides / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects / Q000254:growth & development; D018320:Leishmania major / Q000187:drug effects / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D013893:Thiram / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D017967:Zinc Compounds / Q000494:pharmacology*; D019287:Zinc Sulfate / Q000494:pharmacology*
chemical_list: D002413:Cations, Divalent; D002712:Chlorides; D014344:Trypanocidal Agents; D017967:Zinc Compounds; D013893:Thiram; D019287:Zinc Sulfate; C016837:zinc chloride; D004221:Disulfiram