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

Abstract

Naphthylisoquinoline alkaloids equipped with a N,C-hetero-'biaryl' axis, and, in particular, simplified synthetic analogues thereof, kill intracellular Leishmania major at concentrations in the low submicromolar 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 N-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 salt 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.