The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

There is a need for new, cost-effective drugs to treat leishmaniasis. A strategy based on traditional medicine practiced in Bolivia led to the discovery of the 2-substituted quinoline series as a source of molecules with antileishmanial activity and low toxicity. This review documents the development of the series from the first isolated natural compounds through several hundred synthetized molecules to an optimized compound exhibiting an in vitro IC50 value of 0.2 mu M against Leishmania donovani, and a selectivity index value of 187, together with in vivo activity on the L. donovani/hamster model. Attempts to establish structure-activity relationships are described, as well as studies that have attempted to determine the mechanism of action. For the latter, it appears that molecules of this series act on multiple targets, possibly including the immune system, which could explain the observed lack of drug resistance after in vitro drug pressure. We also show how nanotechnology strategies could valorize these drugs through adapted formulations and how a mechanistic targeting approach could generate new compounds with increased activity.

Automated summary

This review documents the development of the 2-substituted quinoline series as a potential treatment for leishmaniasis. The series has shown promising antileishmanial activity with low toxicity, and attempts have been made to establish structure-activity relationships and determine the mechanism of action. The molecules in this series appear to act on multiple targets, including the immune system, which may explain the lack of drug resistance observed after in vitro drug pressure. Nanotechnology strategies and mechanistic targeting approaches may enhance the activity of these drugs.