Anti-leishmanial activity of betulin derivatives.
Leishmanicidal activity of 24 derivatives of naturally occurring and abundant triterpenes belonging to the lupane series, betulin, betulinic acid and betulonic acid, is described in this study. The easily modified positions of the lupane skeleton, the hydroxy groups of C-3 and C-28, as well as the carbon-carbon double bond C-20-C-29 were used as a starting point to prepare a library of triterpenoid derivatives for bioactivity studies. The compounds were evaluated against Leishmania donovani axenic amastigotes on a microplate assay at 50 microM. GI(50) values of the most effective compounds were evaluated, as well as their cytotoxicity on the human macrophage cell line THP-1, and anti-leishmanial activity against L. donovani-infected THP-1 macrophages was determined. Betulonic acid was the most potent derivative, yielding a GI(50) value of 14.6 microM. Promising and distinct structure-activity relationships were observed, and these compounds can be regarded as significant lead molecules for further improvement and optimization.
Faculty of Pharmacy, Division of Pharmaceutical Chemistry, University of Helsinki, Helsinki, Finland.
Sami
S
Alakurtti
Pia
P
Bergström
Nina
N
Sacerdoti-Sierra
Charles L
CL
Jaffe
Jari
J
Yli-Kauhaluoma
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D053978:Pentacyclic Triterpenes; D013329:Structure-Activity Relationship; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000094062:Betulinic Acid
D000981:Antiprotozoal Agents; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C118308:betulonic acid; D009828:Oleanolic Acid; C002503:betulin; D000094062:Betulinic Acid