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Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine\u2010based C1\u2032\u2010branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1\u2032 atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single\u2010digit micromolar inhibitors of human hypoxanthine\u2010guanine phosphoribosyltransferase and <jats:italic>Plasmodium falciparum<\/jats:italic> HGXPRT. The lowest <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> values for two of these inhibitors are 0.7\u2009\u00b5M for the human enzyme and 0.4\u2009\u00b5M for the parasite enzyme. The <jats:italic>K<\/jats:italic><jats:sub><jats:italic>i<\/jats:italic><\/jats:sub> values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1\u2032 atom. A phosphonodiamidate prodrug of one of the compounds has an IC<jats:sub>50<\/jats:sub> of 4.3\u2009\u2009\u00b5M against a drug\u2010sensitive strain of <jats:italic>Plasmodium falciparum<\/jats:italic> grown in human erythrocytes, showing in\u2009vitro activity and the merit of these new inhibitors as potential drug leads.<\/jats:p>","DOI":"10.1002\/cmdc.202500575","type":"journal-article","created":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T14:15:27Z","timestamp":1755872127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["C1\u2032\u2010Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6\u2010Oxopurine Phosphoribosyltransferase"],"prefix":"10.1002","volume":"20","author":[{"given":"Jan","family":"Frydrych","sequence":"first","affiliation":[{"name":"Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences  Flemingovo n\u00e1m. 2 160 00 Prague 6 Czech 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