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Alterations on the structure of Leishmania major induced by N arylisoquinolines correlate with compound accumulation and disposition

¹ Universidad Central de Venezuela;

² The Scripps Research Institute, 10550 N. Torrey Pines Rd. La Jolla, CA 92037 USA;

³ Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, UCSD;

⁴ University of Wurzburg, Institute for Molecular Infection Biology, Rontgenring 11, 97070 Wurzburg;

⁵ Institute for Organic Chemistry, Am Hubland, 97074 Wurzburg, Germany

⁶ E-mail: bringman{at}chemie.uni-wuerzburg.de

Received July 10, 2009
Accepted September 4, 2009

Naphthylisoquinoline alkaloids equipped with an N,C-hetero-'biaryl' axis and, in particular, simplified synthetic analogs thereof, kill intracellular Leishmania major at concentrations in the low sub-micromolar range, while being significantly less toxic to their major host cell, the macrophage, at the same concentrations. To further investigate their mechanism of action we evaluated the morphological and ultrastructural changes induced by specific arylisoquinolines in L. major and the correlation of these changes with compound accumulation and disposition by the parasite. After 24 h of treatment with the synthetic arylisoquinolinium salts 3 or 4, dramatic structural changes and cell death were observed. Furthermore, the auto-fluorescent derivative 3 accumulates continually in intracellular compartments. Our results thus suggest that the leishmanicidal effect of arylisoquinolinium salts may involve their ability to accumulate and precipitate in intracellular organelles, form a huge vacuole and eventually promote cell lysis.