Drug Targeting of Natural Products: the Example of Antileishmanial Quinolines

Leishmaniases are a complex of tropical and sub-tropical diseases caused by parasites of the genus Leishmania and transmitted by the bite of an insect vector, the sandfly. Quinolines of natural origin have shown interesting antileishmanial activities on several experimental leishmaniasis models. A classical daily treament with 2-n-propylquinoline (2-n-PQ) on five consecutive days in mice model is not sufficient to cure the mice infected with Leishmania donovani and the activity requires a 10-day treatment duration whatever the route (oral, parenteral) because of a short half-life elimination of the drug.

Therefore, 2-n-PQ derivatives were bound to soluble polysaccharides to improve their solubility, delay their elimination half-life and therefore enhance the activity. In vitro release at 37ºC in phosphate buffer was performed in various conditions and showed that around 65% of the compound was released in 24 h. In vitro, the most active conjugate was the dextran-2PQA conjugate exhibiting an IC₅₀ value at 12 µg/mL on Leishmania donovani intramacrophage amastigotes. However, this system did not allow a sufficient release of the active principle explaining the lack of in vivo activity.

Another approach consisted in administering 2-n-PQ intravenously. Two systems were successful both in vitro and in vivo : a liposomal formulation named 2-n-PQ-LIP and a hydroxypropyl beta-cyclodextrin inclusion complex designated as 2-n-PQ-HPC. The most interesting one was the liposomal formulation, active on the L. donovani Balb/c mouse model, by reducing the parasite burden by more than 80% after an intravenous treatment regimen of 3 mg equivalent 2-n-PQ/kg/day given on five consecutive days. No synergistic activity between 2-n-PQ and Amphotericin B was monitored either in vitro or in vivo.

These formulations should be studied further on other leishmaniasis models and for toxicological considerations.

Acknowledgements

This work was supported by a grant from the Indo-French Centre of Advanced Research, New Delhi (CEFIPRA) (No. 4803-04) and Kaluvu Balaraman was recipient of a CEFIPRA postdoctoral fellowship.