C1′‐Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6‐Oxopurine Phosphoribosyltransferase

Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. 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-based C1'-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1' atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest K_i values for two of these inhibitors are 0.7 µM for the human enzyme and 0.4 µM for the parasite enzyme. The K_i values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1' atom. A phosphonodiamidate prodrug of one of the compounds has an IC₅₀ of 4.3 µM against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.