Leishmaniasis is a vector-borne Neglected Tropical Disease, caused by protozoan parasites of the genus Leishmania. There are approximately 1.3 million new cases of leishmaniasis world-wide each year claiming a significant number of lives. This infectious disease primarily affects the world’s poorest countries and therefore antileishmanial treatments need to be affordable and accessible. However current treatments are challenged by poor efficacy, difficult modes of administration, toxicity and growing resistance. Consequently, there is an urgent need to develop a drug with a novel mode of action. Our group has identified the Leishmania major inositol phosphorylceramide synthase (LmjIPCS) as a potential drug target. This membrane-bound enzyme is involved in the biosynthesis of sphingolipids and has a role that differs from its mammalian orthologue which provides the potential to access selective drugs. Therefore, a library of 1040 known bioactive compounds was screened against LmjIPCS and the most active were tested against the parasite. From these screens the over-the-counter antihistamine clemastine was selected as the most promising compound to develop further. Clemastine has now shown submicromolar activity against species that cause cutaneous (L. major and L. amazonensis) and visceral leishmaniasis (L. donovani and L. infantum). In addition, clemastine was effective against L. amazonensis intramacrophage amastigote with an EC50 value of 0.4 mM and a selectivity index of 50. Successful in vitro studies led to progression of this compound into a mouse model of L. amazonensis infection. There was a significant reduction in parasite burden when clemastine was given via the IL route demonstrating its potential as a localised antileishmanial therapy. This presentation will share these findings together with details of synthetic studies towards new active and more accessible analogues.

Identifying and utilising new antileishmanial drug targets

256th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.