The Potential of 2-Substituted Quinolines as Antileishmanial Drug Candidates

Author:

Loiseau Philippe M.ORCID,Balaraman KaluvuORCID,Barratt GillianORCID,Pomel Sébastien,Durand Rémy,Frézard Frédéric,Figadère Bruno

Abstract

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 µM 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.

Funder

Drugs for Neglected Diseases Initiative

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

Reference102 articles.

1. World Health Organizationhttps://www.who.int/data/gho/data/themes/topics/gho-ntd-leishmaniasis

2. https://dndi.org/diseases/visceral-leishmaniasis/facts/

3. Health Topics/Leishmaniasishttps://www.who.int/health-topics/leishmaniasis#tab=tab_1

4. Antileishmanial Drug Discovery and Development: Time to Reset the Model?

5. Estimated Research and Development Investment Needed to Bring a New Medicine to Market, 2009-2018

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