Design of Plasmodium vivax Hypoxanthine-Guanine Phosphoribosyltransferase Inhibitors as Potential Antimalarial Therapeutics

Abstract

Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) are the foremost causative agents of malaria. Due to the development of resistance to current antimalarial medications, new drugs for this parasitic disease need to be discovered. The activity of hypoxanthine-guanine-[xanthine]-phosphoribosyltransferase, HG[X]PRT, is reported to be essential for the growth of both of these parasites, making it an excellent target for antimalarial drug discovery. Here, we have used rational structure-based methods to design an inhibitor, [3R,4R]-4-guanin-9-yl-3-((S)-2-hydroxy-2-phosphonoethyl)oxy-1-N-(phosphonopropionyl)pyrrolidine, of PvHGPRT and PfHGXPRT that has K values of 8 and 7 nM, respectively, for these two enzymes. The crystal structure of PvHGPRT in complex with this compound has been determined to 2.85 Å resolution. The corresponding complex with human HGPRT was also obtained to allow a direct comparison of the binding modes of this compound with the two enzymes. The tetra-(ethyl l-phenylalanine) tetraamide prodrug of this compound was synthesized, and it has an IC of 11.7 ± 3.2 μM against Pf lines grown in culture and a CC in human A549 cell lines of 102 ± 11 μM, thus giving it a ∼10-fold selectivity index.

Pyrrolidine nucleoside bisphosphonates as antituberculosis agents targeting hypoxanthine-guanine phosphoribosyltransferase

“…18 The genesis for these potential anti-TB drugs is based on structure of the successful antiviral agent tenofovir that was developed by Antonin Holý and colleagues. 18 Prodrugs of the ANPs arrest the growth of Pf in cell culture [19][20][21] highlighting the possibility that selective design could lead to the development of chemotherapeutics against Mt where the activity of this enzyme also appears to be essential for the survival and reproduction of this organism.…”

“…Escherichia coli, XGPRT and HPRT, 22 Plasmodium falciparum HGXPRT 19 , Plasmodium vivax HGPRT 19 and human HGPRT. 19,22 In these compounds, a purine base is attached to a phosphonate moiety via a pyrrolidine ring in the linker which connects the two functional groups. The five membered pyrrolidine ring is connected to the N 9 atom of the purine base ( Fig.…”

Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

“…Cordycepin (3-deoxy-adenosine) 67 Inhibitors of Pf IMPDH 60,70 Ribavirin derivatives screened by Raza et al 60 Adenosine analogues tested against Pf GMPS by Bhat et al 62 Pyrrolidine nucleoside mono-and bisphosphonates 73 Tubercidin and derivatives 74…”

“…d. PNBPs -Pyrrolidine nucleoside bisphosphonatesInitially synthesized and tested for their ability to inhibit E. coli, 6-oxopurine phosphoribosyltransferases,78 pyrrolidine nucleoside phosphonates (Table 1)were subsequently assessed as potential inhibitors of PvHGPRT and PfHGXPRT. The design of such compounds was based on a central 5-membered ring skeleton, bearing three substituents anchored through free rotation bonds, thus allowing to adopt the best conformation at the active site of the enzyme 73.…”

Facile Substituent Exchange at H‐Phosphonate Diesters Limiting an Effective Synthesis of D‐Phosphonate Diesters

“…H ‐phosphonate diesters are useful synthons in a variety of reactions . Selected specific examples include, reactants in the catalytic cross coupling of P−N, P−O−P, P−P, P−F, P−C, P−O−C, P−Se and P−S bonds, base‐catalyzed hydrophosphination of azobenzene to form N−N−P units, organophosphorus ligands in metal complexes, in addition to precursors to phosphines, P−Cl, and biologically active phosphorus compounds . Furthermore, H ‐phosphonate diesters are reactants in transesterification, alkylation reactions and in P−O−Si polymer synthesis .…”