Abstract
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 μM. GI50 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 GI50 value of 14.6 μM. Promising and distinct structure–activity relationships were observed, and these compounds can be regarded as significant lead molecules for further improvement and optimization.
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Acknowledgements
This study was supported by the Finnish Funding Agency for Technology and Innovation (Tekes), the Foundation for Research of Natural Resources in Finland, Marjatta ja Eino Kollin Säätiö and the European Commission (Contract nos LSHB-CT-2004-503467 and EU-KBBE-227239-ForestSpeCs). We thank Mrs Anja Salakari and Mr Erkki Metsälä for their excellent technical assistance. Dr Salme Koskimies is thanked for valuable discussions. CLJ holds the Michael and Penny Feiwel Chair in Dermatology and is grateful to the American Friends of Hebrew University for financial support of this project.
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Alakurtti, S., Bergström, P., Sacerdoti-Sierra, N. et al. Anti-leishmanial activity of betulin derivatives. J Antibiot 63, 123–126 (2010). https://doi.org/10.1038/ja.2010.2
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DOI: https://doi.org/10.1038/ja.2010.2
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