title: In vitro activity of salinomycin and monensin derivatives against Trypanosoma brucei.
abstract: African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells.
  
  
  
  Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2-trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50 % growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 μM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250.
  
  
  
  The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti-trypanosomal drug development.
authors.affiliation: Bob Champion Research & Education Building, Norwich Medical School, University of East Anglia, Norwich, UK. dsteverding@hotmail.com.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Steverding
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Antoszczak
authors.affiliation: Faculty of Chemistry, Adam Mickiewicz University, Poznań, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Huczyński
mesh_terms: D018922:HL-60 Cells; D006801:Humans; D008985:Monensin / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000469:parasitology*; D000095662:Polyether Polyketides
chemical_list: D008985:Monensin; D011714:Pyrans; D014344:Trypanocidal Agents; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: African trypanosomaisis; Drug screening; Monensin derivatives; Salinomycin derivatives; Trypanosoma brucei