Preclinical development of 3-hydroxypropaneamidine derivatives targeting Plasmodium falciparum

Approximately 228 million malaria infections were reported worldwide in 2018, of which an estimated 405,000 were fatal. Commonly, a combination therapy of a fast-acting artemisinin derivative with an antimalarial drug of a different class characterized by a significantly longer half-life (e.g. lumefantrine) is applied. However, malaria prophylaxis and treatment are impeded by the lack of a widely effective malaria vaccine and by parasite resistance. Today, resistance affects all classes of antimalarial drugs. Hence, new antimalarial drugs need to be introduced soon if malaria is to be contained. Besides other approaches, the structural optimization of existing antimalarial drug classes is one established and successful strategy for the clinical implementation of new antimalarial drugs. However, within the last 28 years only one new antimalarial, tafenoquine (2018), was approved, highlighting the need of further preclinical and clinical candidates to overcome current hurdles in malaria prophylaxis and treatment.Our preliminary work discovered 3-hydroxypropaneamidine derivatives as potential new drug leads characterized by very promising antiplasmodial properties. First generation compounds exerted nanomolar antiplasmodial in vitro activity against sensitive and resistant P. falciparum strains, virtually no cytotoxicity towards human cells, partially curative in vivo antimalarial activity in the P. berghei mouse model as well potent in vivo activity in a SCID mouse model of human P. falciparum malaria. The most active compound also affected free heme conversion, with accumulation of free heme and decreased hemozoin levels. Moreover, current results suggest that the current lead compound shows a genetic high barrier to resistance. This proposal aims at contributing to the preclinical development of a long acting candidate with a high barrier to resistance.