Abstract
Inhibition of membrane‐bound pyrophosphatase (mPPase) with small molecules offer a new approach in the fight against pathogenic protozoan parasites. mPPases are absent in humans, but essential for many protists as they couple pyrophosphate hydrolysis to the active transport of protons or sodium ions across acidocalcisomal membranes. So far, only few nonphosphorus inhibitors have been reported. Here, we explore the chemical space around previous hits using a combination of screening and synthetic medicinal chemistry, identifying compounds with low micromolar inhibitory activities in the Thermotoga maritima mPPase test system. We furthermore provide early structure‐activity relationships around a new scaffold having a pyrazolo[1,5‐a]pyrimidine core. The most promising pyrazolo[1,5‐a]pyrimidine congener was further investigated and found to inhibit Plasmodium falciparum mPPase in membranes as well as the growth of P. falciparum in an ex vivo survival assay.
Highlights
Parasitic human diseases, such as malaria, leishmaniasis, trypanosomiasis and toxoplasmosis, represent a severe global health concern
By screening of commercially available compounds as well as synthetic medicinal chemistry, we explored and identified several low micromolar hits.[24]
Starting from 2 and its congeners, we aimed to identify novel molecular scaffolds that would lead to gain in binding affinity
Summary
Parasitic human diseases, such as malaria, leishmaniasis, trypanosomiasis and toxoplasmosis, represent a severe global health concern. The life cycles of protozoan parasites, including Plasmodium spp., Leishmania spp., Trypanosoma spp. and Toxoplasma spp., are rather complex and typically comprise of transitions between hosts and vectors as well as intracellular and extracellular environments. To survive these changes, the protozoan cell must be able to adjust e. The key mechanism involves membranebound pyrophosphatases (mPPases).[1] These enzymes are located in the cell membrane of bacteria and archaea, but can be found in the protist acidocalcisome, and in the Golgi [b] Dr K.
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