Malaria is one of the most prevalent infectious diseases of the developing world, whose primary causative agent in humans is the protozoan parasite Plasmodium falciparum. It is currently responsible for nearly 0.5 million deaths per year, with both young children and pregnant women in sub-Saharan Africa particularly at risk. There is significant concern about widespread and rapidly growing resistance to current standard malaria drugs; hence the development of structurally and mechanistically novel malaria treatments is urgently required to maintain control and advance eradication of the disease. We have been developing a class of inhibitors of PfPKG, starting from previously reported compounds (such as 1) with activity against the Eimeria Tenella PKG homologue. Compound 1 showed several undesirable traits: a pyrrole, an unflanked 4-pyridyl, and potent activity against human p38a MAPK and PKA kinases and this poster will describe our efforts to moderate or remove these traits while retaining good anti-parasitical activity. Substitution of the pyrrole for a thiazole and SAR modifications on the side chains led to a series of potent anti-malarials. Analogues such as compound 2 possess potent enzyme affinity and in vitro anti-parasite activity, coupled with excellent selectivity against human kinases as well as good ADME properties.

Trisubstituted thiazoles as potent and selective inhibitors of Plasmodium falciparum protein kinase G (PfPKG)

252nd National Meeting (2016)

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