Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

Basic Information

ID: ALA4342516

Journal: ACS Med Chem Lett

Title: Discovery of Membrane-Bound Pyrophosphatase Inhibitors Derived from an Isoxazole Fragment.

Authors: Johansson NG, Turku A, Vidilaseris K, Dreano L, Khattab A, Ayuso Pérez D, Wilkinson A, Zhang Y, Tamminen M, Grazhdankin E, Kiriazis A, Fishwick CWG, Meri S, Yli-Kauhaluoma J, Goldman A, Boije Af Gennäs G, Xhaard H.

Abstract: Membrane-bound pyrophosphatases (mPPases) regulate energy homeostasis in pathogenic protozoan parasites and lack human homologues, which makes them promising targets in e.g. malaria. Yet only few nonphosphorus inhibitors have been reported so far. Here, we explore an isoxazole fragment hit, leading to the discovery of small mPPase inhibitors with 6-10 μM IC50 values in the Thermotoga maritima test system. Promisingly, the compounds retained activity against Plasmodium falciparum mPPase in membranes and inhibited parasite growth.

CiteXplore: 32292570

DOI: 10.1021/acsmedchemlett.9b00537

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