Repurposing as a Strategy for the Discovery of a New Antileishmanial

Abstract

Leishmaniasis is a vector-borne Neglected Tropical Disease, caused by protozoan parasites of the genus Leishmania for which there is a shortage of effective and viable non-toxic drugs. There are approximately 1.3 million new cases of leishmaniasis each year with the greatest impact in the poorest communities. Therefore, repurposing is an important strategy as established medicines have cheaper and faster development times.
Leishmania major inositol phosphorylceramide synthase (LmjIPCS) is involved in the biosynthesis of sphingolipids and has been identified as a potential drug target by our group. A set of screens against LmjIPCS and the parasite were performed on a library of 1040 bioactive compounds. 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) as well as being effective against L. amazonensis intramacrophage amastigotes (EC50 = 0.4 M, SI = 50). Progression of clemastine into a mouse model of L. amazonensis infection showed significant reduction in parasite burden when given via the intralesional (IL) or intraperitoneal (IP) route. In order to optimise the antileishmanial activity, two series of clemastine analogues were synthesised. The first series, named nor-clemastine analogues, lack the clemastine quarternary methyl group. An enantioselective route was developed to show the role stereochemistry plays on antileishmanial activity with greatest activity residing in the (R, R)-configuration of nor-clemastine. The second series, named N-linked analogues, identified a more synthetically accessible and selective analogue against L. amazonensis intramacrophage amastigotes (EC50 value = 0.5 M, SI = 146). This compound was progressed into a mouse model infected with L. amazonensis and significantly reduced the parasite burden when given via the IL route. Overall, this thesis demonstrates the potential of drug repurposing as well as the development of new analogues in the search of a new antileishmanial therapy.