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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 <jats:italic>Thermotoga maritima<\/jats:italic> mPPase test system. We furthermore provide early structure\u2010activity relationships around a new scaffold having a pyrazolo[1,5\u2010<jats:italic>a<\/jats:italic>]pyrimidine core. The most promising pyrazolo[1,5\u2010<jats:italic>a<\/jats:italic>]pyrimidine congener was further investigated and found to inhibit <jats:italic>Plasmodium falciparum<\/jats:italic> mPPase in membranes as well as the growth of <jats:italic>P. falciparum<\/jats:italic> in an <jats:italic>ex vivo<\/jats:italic> survival assay.<\/jats:p>","DOI":"10.1002\/cmdc.202100392","type":"journal-article","created":{"date-parts":[[2021,8,30]],"date-time":"2021-08-30T04:29:16Z","timestamp":1630297756000},"page":"3360-3367","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Exploration of Pyrazolo[1,5\u2010<i>a<\/i>]pyrimidines as Membrane\u2010Bound Pyrophosphatase Inhibitors"],"prefix":"10.1002","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8226-4813","authenticated-orcid":false,"given":"Niklas G.","family":"Johansson","sequence":"first","affiliation":[{"name":"Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy University of Helsinki  P.O. 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Box 56 (Viikinkaari 9) 00014 Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3980-8379","authenticated-orcid":false,"given":"Ayman","family":"Khattab","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Division of Biochemistry University of Helsinki  P.O. 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Box 56 (Viikinkaari 9) 00014 Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2488-1506","authenticated-orcid":false,"given":"Alexandros","family":"Kiriazis","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0099-6085","authenticated-orcid":false,"given":"Gustav","family":"Boije af Genn\u00e4s","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9142-501X","authenticated-orcid":false,"given":"Seppo","family":"Meri","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8032-9700","authenticated-orcid":false,"given":"Adrian","family":"Goldman","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Division of Biochemistry University of Helsinki  P.O. Box 56 (Viikinkaari 9) 00014 Helsinki Finland"},{"name":"School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology University of Leeds, Clarendon Way  Leeds LS2 9JT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-7653","authenticated-orcid":false,"given":"Jari","family":"Yli\u2010Kauhaluoma","sequence":"additional","affiliation":[{"name":"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"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3000-7858","authenticated-orcid":false,"given":"Henri","family":"Xhaard","sequence":"additional","affiliation":[{"name":"Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy University of Helsinki  P.O. 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