title: Synthesis and activity of new triphenylphosphonium derivatives of betulin and betulinic acid against Schistosoma mansoni in vitro and in vivo.
abstract: We studied the antischistosomal activity of betulin, betulinic acid and its 9 triphenylphosphonium derivatives characterized by a covalently linkage of the hydrophobic fragment of triterpenoid at C(2)- or C(30)-position with the triphenylphosphonium moiety via a hydrocarbon bridge. The triphenylphosphonium salts showed in vitro antischistosomal activity against newly transformed schistosomula (NTS) and adult worms of Schistosoma mansoni at low micromolar concentrations. In contrast betulin and betulinic acid were inactive against NTS and adult S. mansoni. Of the 9 triphenylphosphonium derivatives tested, the allyl salts 10 (IC50 of 0.76 μg/mL) and 11 (IC50 of 0.64 μg/mL) demonstrated the highest antischistosomal activity against adult S. mansoni. Low worm burden reductions of 22% were observed in vivo for these two compounds. In conclusion, triphenylphosphonium derivatives were obtained from available natural betulin by simple transformations, rendering it practical and useful for large scale application. However, further structural modifications are necessary to translate the promising antischistosomal in vitro activities into in vivo.
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
authors.forename: Anna Yu
authors.initials: AY
authors.lastname: Spivak
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse, 57, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Keiser
authors.affiliation: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Socinstrasse, 57, CH-4002 Basel, Switzerland; University of Basel, Petersplatz 1, CH-4003 Basel, Switzerland.
authors.forename: Mireille
authors.initials: M
authors.lastname: Vargas
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
authors.forename: Rinat R
authors.initials: RR
authors.lastname: Gubaidullin
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
authors.forename: Darya A
authors.initials: DA
authors.lastname: Nedopekina
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
authors.forename: Elvira R
authors.initials: ER
authors.lastname: Shakurova
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation.
authors.forename: Rezeda R
authors.initials: RR
authors.lastname: Khalitova
authors.affiliation: Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 prosp. Oktyabrya, 450075 Ufa, Russian Federation. Electronic address: odinokov@anrb.ru.
authors.forename: Victor N
authors.initials: VN
authors.lastname: Odinokov
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D053978:Pentacyclic Triterpenes; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000188:drug therapy* / Q000469:parasitology; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000094062:Betulinic Acid
chemical_list: D000871:Anthelmintics; D009943:Organophosphorus Compounds; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C002503:betulin; D000094062:Betulinic Acid
keywords: Betulin; Betulinic acid; In vitro; In vivo; Schistosoma mansoni; Triphenylphosphonium compounds