期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 21, 页码 6297-6304出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.014
关键词
Betulin; Betulinic acid; Triphenylphosphonium compounds; Schistosoma mansoni; In vitro; In vivo
资金
- Program Presidium of Russian Academy of Sciences (Program of the Division of Chemistry and Materials Science of RAS 'Medicinal Chemistry: Molecular Design of Physiologically Active Compounds and Medicinal Drugs')
- RAS programs 'Basic sciences to medicine'
- European Research Council [ERC-2013-CoG 614739-A_HERO]
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 mu g/mL) and 11 (IC50 of 0.64 mu g/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. (C) 2014 Elsevier Ltd. All rights reserved.
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