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Exploration of Pyrazolo[1,5‐ a ]pyrimidines as Membrane‐Bound Pyrophosphatase Inhibitors
Author(s) -
Johansson Niklas G.,
Dreano Loïc,
Vidilaseris Keni,
Khattab Ayman,
Liu Jianing,
Lasbleiz Arthur,
Ribeiro Orquidea,
Kiriazis Alexandros,
Boije af Gennäs Gustav,
Meri Seppo,
Goldman Adrian,
YliKauhaluoma Jari,
Xhaard Henri
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100392
Subject(s) - pyrophosphatase , small molecule , membrane , biochemistry , chemistry , pyrimidine , nucleoside , inorganic pyrophosphatase , pyrophosphate , chemical biology , biology , stereochemistry , hydrolysis , enzyme
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.