Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes

Raisa Haavikko; Abedelmajeed Nasereddin; Nina Sacerdoti-Sierra; Dmitry Kopelyanskiy; Sami Alakurtti; Mari Tikka; Charles L. Jaffe; Jari Yli-Kauhaluoma

doi:10.1039/c3md00282a

Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes

Raisa Haavikko, Abedelmajeed Nasereddin, Nina Sacerdoti-Sierra, Dmitry Kopelyanskiy, Sami Alakurtti, Mari Tikka, Charles L. Jaffe, Jari Yli-Kauhaluoma^*

^*Corresponding author for this work

Department of Microbiology and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

54 Scopus citations

Abstract

The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC₅₀ values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.

Original language	English
Pages (from-to)	445-451
Number of pages	7
Journal	MedChemComm
Volume	5
Issue number	4
DOIs	https://doi.org/10.1039/c3md00282a
State	Published - Apr 2014

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title = "Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes",

abstract = "The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.",

author = "Raisa Haavikko and Abedelmajeed Nasereddin and Nina Sacerdoti-Sierra and Dmitry Kopelyanskiy and Sami Alakurtti and Mari Tikka and Jaffe, {Charles L.} and Jari Yli-Kauhaluoma",

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doi = "10.1039/c3md00282a",

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AU - Haavikko, Raisa

AU - Nasereddin, Abedelmajeed

AU - Sacerdoti-Sierra, Nina

AU - Kopelyanskiy, Dmitry

AU - Alakurtti, Sami

AU - Tikka, Mari

AU - Jaffe, Charles L.

AU - Yli-Kauhaluoma, Jari

PY - 2014/4

Y1 - 2014/4

N2 - The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.

AB - The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.

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Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes

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