title: Zinc(II)-Dipicolylamine Coordination Complexes as Targeting and Chemotherapeutic Agents for Leishmania major.
abstract: Cutaneous leishmaniasis is a neglected tropical disease that causes painful lesions and severe disfigurement. Modern treatment relies on a few chemotherapeutics with serious limitations, and there is a need for more effective alternatives. This study describes the selective targeting of zinc(II)-dipicolylamine (ZnDPA) coordination complexes toward Leishmania major, one of the species responsible for cutaneous leishmaniasis. Fluorescence microscopy of L. major promastigotes treated with a fluorescently labeled ZnDPA probe indicated rapid accumulation of the probe within the axenic promastigote cytosol. The antileishmanial activities of eight ZnDPA complexes were measured using an in vitro assay. All tested complexes exhibited selective toxicity against L. major axenic promastigotes, with 50% effective concentration values in the range of 12.7 to 0.3 μM. Similar toxicity was observed against intracellular amastigotes, but there was almost no effect on the viability of mammalian cells, including mouse peritoneal macrophages. In vivo treatment efficacy studies used fluorescence imaging to noninvasively monitor changes in the red fluorescence produced by an infection of mCherry-L. major in a mouse model. A ZnDPA treatment regimen reduced the parasite burden nearly as well as the reference care agent, potassium antimony(III) tartrate, and with less necrosis in the local host tissue. The results demonstrate that ZnDPA coordination complexes are a promising new class of antileishmanial agents with potential for clinical translation.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Rice
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Vacchina
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA.
authors.forename: Brianna
authors.initials: B
authors.lastname: Norris-Mullins
authors.affiliation: Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA smith.115@nd.edu miguel.morales@nd.edu.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Morales
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA smith.115@nd.edu miguel.morales@nd.edu.
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Smith
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D005260:Female; D018320:Leishmania major / Q000187:drug effects* / Q000472:pathogenicity; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009942:Organometallic Compounds / Q000627:therapeutic use*; D010847:Picolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D010847:Picolines; C509592:zinc(II) dipicolylamine