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Antimicrobial Agents and Chemotherapy, January 2007, p. 188-194, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00936-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activities of Naphthylisoquinoline Alkaloids and Synthetic Analogs against Leishmania major{triangledown}

Alicia Ponte-Sucre,1,3 Johan H. Faber,2 Tanja Gulder,2 Inga Kajahn,2 Sarah E. H. Pedersen,2 Martina Schultheis,1 Gerhard Bringmann,2 and Heidrun Moll1*

University of Würzburg, Institute for Molecular Infection Biology, Röntgenring 11, 97070 Würzburg, Germany,1 Institute for Organic Chemistry, Hubland, 97074 Würzburg, Germany,2 Laboratory of Molecular Physiology, Universidad Central de Venezuela, Caracas, Venezuela3

Received 28 July 2006/ Returned for modification 5 October 2006/ Accepted 28 October 2006

The current treatments for leishmaniasis are unsatisfactory due to their toxic side effects, high costs, and increasing problems with drug resistance. Thus, there is an urgent need for alternative drugs against leishmaniasis. Different approaches have been used to identify novel pharmacophores against Leishmania sp. parasites, and one strategy has been the analysis of naturally occurring plant-derived compounds, including naphthylisoquinoline alkaloids. In the present study, we examined the abilities of these alkaloids to inhibit the growth of Leishmania major promastigotes and evaluated their effects on macrophages, dendritic cells, and fibroblasts. Furthermore, we determined the efficacy of selected compounds in decreasing the infection rate of macrophages and regulating their production of cytokines and nitric oxide. Our results demonstrate that the naphthylisoquinoline alkaloids ancistrocladiniums A and B (compounds 10 and 11) and the synthetic isoquinolinium salt (compound 14) were effective against intracellular amastigotes in the low submicromolar range, while toxicity against mammalian cells was observed at concentrations that were significantly higher than those needed to impair parasite replication. The activities of compounds 11 and 14 were mainly directed against the amastigote stage of L. major. This effect was not associated with the stimulation of host macrophages to produce nitric oxide or secrete cytokines relevant for the leishmanicidal function. In conclusion, our data suggest that ancistrocladiniums A and B (compounds 10 and 11) and the synthetically prepared isoquinolinium salt (compound 14) are promising candidates to be considered as lead compounds for leishmanicidal drugs.

* Corresponding author. Mailing address: Institute for Molecular Infection Biology, University of Würzburg, Röntgenring 11, 97070 Würzburg, Germany. Phone: 49 931 312627. Fax: 49 931 312578. E-mail: heidrun.moll{at}mail.uni-wuerzburg.de.

{triangledown} Published ahead of print on 6 November 2006.

Antimicrobial Agents and Chemotherapy, January 2007, p. 188-194, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00936-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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