title: Symmetrical choline-derived dications display strong anti-kinetoplastid activity.
abstract: OBJECTIVE
  to investigate the anti-kinetoplastid activity of choline-derived analogues with previously reported antimalarial efficacy.
  
  
  METHODS
  from an existing choline analogue library, seven antimalarial compounds, representative of the first-, second- and third-generation analogues previously developed, were assessed for activity against Trypanosoma and Leishmania spp. Using a variety of techniques, the effects of choline analogue exposure on the parasites were documented and a preliminary investigation of their mode of action was performed.
  
  
  RESULTS
  the activities of choline-derived compounds against Trypanosoma brucei and Leishmania mexicana were determined. The compounds displayed promising anti-kinetoplastid activity, particularly against T. brucei, to which 4/7 displayed submicromolar EC(50) values for the wild-type strain. Low micromolar concentrations of most compounds cleared trypanosome cultures within 24-48 h. The compounds inhibit a choline transporter in Leishmania, but their entry may not depend only on this carrier; T. b. brucei lacks a choline carrier and the mode of uptake remains unclear. The compounds had no effect on the overall lipid composition of the cells, cell cycle progression or cyclic adenosine monophosphate production or short-term effects on intracellular calcium levels. However, several of the compounds, displayed pronounced effects on the mitochondrial membrane potential; this action was not associated with production of reactive oxygen species but rather with a slow rise of intracellular calcium levels and DNA fragmentation.
  
  
  CONCLUSIONS
  the choline analogues displayed strong activity against kinetoplastid parasites, particularly against T. b. brucei. In contrast to their antimalarial activity, they did not act on trypanosomes by disrupting choline salvage or phospholipid metabolism, instead disrupting mitochondrial function, leading to chromosomal fragmentation.
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK.
authors.forename: Hasan M S
authors.initials: HM
authors.lastname: Ibrahim
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Al-Salabi
authors.forename: Nasser
authors.initials: N
authors.lastname: El Sabbagh
authors.forename: Neils B
authors.initials: NB
authors.lastname: Quashie
authors.forename: Abdulsalam A M
authors.initials: AA
authors.lastname: Alkhaldi
authors.forename: Roger
authors.initials: R
authors.lastname: Escale
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002413:Cations, Divalent / Q000494:pharmacology*; D002794:Choline / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053938:DNA Fragmentation; D007894:Leishmania mexicana / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D014346:Trypanosoma brucei brucei / Q000187:drug effects*
chemical_list: D000981:Antiprotozoal Agents; D002413:Cations, Divalent; D002794:Choline