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

Abstract

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.

Antimalarial activity of prodrugs of N-branched acyclic nucleoside phosphonate inhibitors of 6-oxopurine phosphoribosyltransferases

“…In addition, synthesis of six new aza-ANPs (4g, 4h, 4j and 5g, 5h, 5j) complementing the previously prepared 14,15 inhibitors of Pf, Pv and human HG(X)PRT is described, and their inhibitory activity (PfHGXPRT and human HGPRT) is reported to extend our published data. According our recent findings, phenylalanine prodrugs are more stable in plasma and their higher lipophilicity enable better penetration to the cells compared to alanine used in antivirals.…”

Novel nucleotide analogues bearing (1 H -1,2,3-triazol-4-yl)phosphonic acid moiety as inhibitors of Plasmodium and human 6-oxopurine phosphoribosyltransferases

“…[5][6][7][8][9] Importantly, the mode of action of the ANPs is different from the currently used drugs, so represents a new approach to developing antimalarial therapeutics. An efficient synthetic methodology to access the desired 6-oxopurine ANPs with the (1H-1,2,3-triazol-4-yl)phosphonic acid moiety has been developed and optimized.…”

“…1) and aza-ANPs ( Fig. 1) have antimalarial [5][6][7][8][9] and/or antimycobacterial [10][11] activity. Several different chemical types of ANPs, including modified PMEA analogues, have also been studied as potent inhibitors of bacterial adenylate cyclases, namely adenylate cyclase toxin from Bordetella pertussis and edema factor from Bacillus anthracis.…”

“…Inhibition of plasmodial hypoxanthine-guanine-(xanthine) phosphoribosyltransferases (HG(X)PRTs) by the ANPs is well-correlated with their antimalarial activity. [5][6][7][8][9] These enzymes catalyze the formation of the 6-oxopurine mononucleotides from the 6-oxopurine nucleobases and 5-phospho-α-D-ribosyl-1-pyrophosphate (Fig. 2).…”

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

“…A variety of different structural analogues of these phosphonate inhibitors have been synthesised, including the single chain ANPs, the ANbPs, the aza-ANPs, the pyrrolidine nucleoside phosphonates, the pyrrolidine nucleoside bisphosphonates and the acylic immucillin phosphonates. 24,25,26,27,28 The crystal structures of the single chain ANPs in complex with HG[X]PRT [20] suggested that the attachment of a second phosphonate group to the basic ANP scaffold may allow a single molecule to occupy three critical binding pockets in the active site. These include the sites for the purine base, the 5′-phosphate group and, possibly, the pyrophosphate product (Fig.…”