title: Betulin derivatives impair Leishmania braziliensis viability and host-parasite interaction.
abstract: Leishmaniasis is a public health problem in tropical and subtropical areas of the world, including Venezuela. The incidence of treatment failure and the number of cases with Leishmania-HIV co-infection underscore the importance of developing alternative, economical and effective therapies against this disease. The work presented here analyzed whether terpenoids derived from betulin are active against New World Leishmania parasites. Initially we determined the concentration that inhibits the growth of these parasites by 50% or IC50, and subsequently evaluated the chemotactic effect of four compounds with leishmanicidal activity in the sub-micromolar and micromolar range. That is, we measured the migratory capacity of Leishmania (V.) braziliensis in the presence of increasing concentrations of compounds. Finally, we evaluated their cytotoxicity against the host cell and their effect on the infectivity of L. (V.) braziliensis. The results suggest that (1) compounds 14, 17, 18, 25 and 27 are active at concentrations lower than 10 μM; (2) compound 26 inhibits parasite growth with an IC50 lower than 1 μM; (3) compounds 18, 26 and 27 inhibit parasite migration at pico- to nanomolar concentrations, suggesting that they impair host-parasite interaction. None of the tested compounds was cytotoxic against J774.A1 macrophages thus indicating their potential as starting points to develop compounds that might affect parasite-host cell interaction, as well as being leishmanicidal.
authors.affiliation: Laboratorio de Fisiología Molecular, IME, Universidad Central de Venezuela, Venezuela.
authors.forename: Wilmer
authors.initials: W
authors.lastname: Alcazar
authors.affiliation: Laboratorio de Fisiología Molecular, IME, Universidad Central de Venezuela, Venezuela.
authors.forename: Adrian Silva
authors.initials: AS
authors.lastname: López
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Sami
authors.initials: S
authors.lastname: Alakurtti
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland; VTT Technical Research Centre of Finland, Espoo, Finland.
authors.forename: Maija-Liisa
authors.initials: ML
authors.lastname: Tuononen
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Yli-Kauhaluoma
authors.affiliation: Laboratorio de Fisiología Molecular, IME, Universidad Central de Venezuela, Venezuela. Electronic address: aiponte@gmail.com.
authors.forename: Alicia
authors.initials: A
authors.lastname: Ponte-Sucre
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006790:Host-Parasite Interactions / Q000187:drug effects*; D006801:Humans; D007892:Leishmania braziliensis / Q000187:drug effects* / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology*; D051379:Mice; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D000981:Antiprotozoal Agents; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid
keywords: Betulin derivatives; Host–parasite interaction; Leishmania; Susceptibility