Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in anEx VivoModel System Is Selectively Enhanced by the Addition of Divalent Metal Ions

Abstract

ABSTRACTCurrent 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 anex vivosystem 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-Leishmaniaactivity 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. Thein vitrotherapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, againstL. majorwhen combined with ZnCl2. The combination of disulfiram with ZnSO4resulted in a 1.8-fold increase in IVTI againstL. 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.