Exploration of Pyrazolo[1,5-a]pyrimidines as Membrane-Bound Pyrophosphatase Inhibitors |
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Authors: | Niklas G. Johansson Loïc Dreano Dr. Keni Vidilaseris Dr. Ayman Khattab Jianing Liu Arthur Lasbleiz Dr. Orquidea Ribeiro Dr. Alexandros Kiriazis Dr. Gustav Boije af Gennäs Prof. Seppo Meri Prof. Adrian Goldman Prof. Jari Yli-Kauhaluoma Dr. Henri Xhaard |
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Affiliation: | 1. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5 E), 00014 Helsinki, Finland;2. Department of Biosciences, Division of Biochemistry, University of Helsinki, P.O. Box 56 (Viikinkaari 9), 00014 Helsinki, Finland;3. Malaria Research Laboratory, Translational Immunology Research Program, Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, P.O. Box 21 (Haartmaninkatu 3), 00014 Helsinki, Finland |
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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. |
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Keywords: | membrane-bound pyrophosphatase antiprotozoal agents pyrazolo[1,5-a]pyrimidine inhibitor drug discovery |
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