Drug Targeting of Natural Products: the Example of Antileishmanial Quinolines

Philippe Loiseau, Kaluvu Balaraman, Nalia Mekarnia, Gillian Barratt, Sébastien Pomel, Sandrine Cojean, Venkitasamy Kesavan, Atipetha Jayakrishnan, Bruno Fidadère
2017 Proceedings of 3rd International Electronic Conference on Medicinal Chemistry   unpublished
Quinolines of natural origin have shown antileishmanial activities on several experimental leishmaniasis models. However, a classical daily treament with 2-npropylquinoline (2-n-PQ) on five consecutive days in mice model is not sufficient to cure the mice infected with Leishmania donovani as 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
more » ... es to improve their solubility, delay their elimination half-life and therefore enhance the activity. In vitro, the most active conjugate was the dextran-2PQA conjugate. 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. These formulations should be studied further on other leishmaniasis models and for toxicological considerations.
doi:10.3390/ecmc-3-04649 fatcat:n4pfi55vrjgs5kbgd6fcrrtacq