Synthesis of Novel N-Branched Acyclic Nucleoside Phosphonates As Potent and Selective Inhibitors of Human, Plasmodium falciparum and Plasmodium vivax 6-Oxopurine Phosphoribosyltransferases

• Published in: Journal of medicinal chemistry 2012-07, Vol.55 (13), p.6209-6223
• Main Authors: Hocková, Dana, Keough, Dianne T, Janeba, Zlatko, Wang, Tzu-Hsuan, de Jersey, John, Guddat, Luke W
• Format: Article
• Language: English
• Subjects: Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hypoxanthine Phosphoribosyltransferase - antagonists & inhibitors; Malaria - drug therapy; Models, Molecular; Molecular Conformation; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Organophosphonates - chemical synthesis; Organophosphonates - chemistry; Organophosphonates - pharmacology; Pentosyltransferases - antagonists & inhibitors; Plasmodium falciparum - drug effects; Plasmodium falciparum - enzymology; Plasmodium vivax - drug effects; Plasmodium vivax - enzymology; Protein Binding; Substrate Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300662d

Hypoxanthine–guanine–(xanthine) phosphoribosyltransferase (HG(X)PRT) is crucial for the survival of malarial parasites Plasmodium falciparum (Pf) and Plasmodium vivax (Pv). Acyclic nucleoside phosphonates (ANPs) are inhibitors of HG(X)PRT and arrest the growth of Pf in cell culture. Here, a novel class of ANPs containing trisubstituted nitrogen (aza-ANPs) has been synthesized. These compounds have a wide range of K i values and selectivity for human HGPRT, PfHGXPRT, and PvHGPRT. The most selective and potent inhibitor of PfHGXPRT is 9-[N-(3-methoxy-3-oxopropyl)-N-(2-phosphonoethyl)-2-aminoethyl]hypoxanthine (K i = 100 nM): no inhibition could be detected against the human enzyme. This compound exhibits the highest ever reported selectivity for PfHGXPRT compared to human HGPRT. For PvHGPRT, 9-[N-(2-carboxyethyl)-N-(2-phosphonoethyl)-2-aminoethyl]guanine has a K i of 50 nM, the best inhibitor discovered for this enzyme to date. Docking of these compounds into the known structures of human HGPRT in complex with ANP-based inhibitors suggests reasons for the variations in affinity, providing insights for the design of antimalarial drug candidates.