Aza-acyclic Nucleoside Phosphonates Containing a Second Phosphonate Group As Inhibitors of the Human, Plasmodium falciparum and vivax 6-Oxopurine Phosphoribosyltransferases and Their Prodrugs As Antimalarial Agents

Abstract

Hypoxanthine-guanine-[xanthine] phosphoribosyltransferase (HG[X]PRT) is considered an important target for antimalarial chemotherapy as it is the only pathway for the synthesis of the purine nucleoside monophosphates required for DNA/RNA production. Thus, inhibition of this enzyme should result in cessation of replication. The aza-acyclic nucleoside phosphonates (aza-ANPs) are good inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT), with Ki values as low as 0.08 and 0.01 μM for Plasmodium vivax HGPRT (PvHGPRT). Prodrugs of these aza-ANPs exhibit antimalarial activity against Pf lines with IC50 values (0.8-6.0 μM) and have low cytotoxicity against human cells. Crystal structures of six of these compounds in complex with human HGPRT have been determined. These suggest that the different affinities of these aza-ANPs could be due to the flexibility of the loops surrounding the active site as well as the flexibility of the inhibitors, allowing them to adapt to fit into three binding pockets of the enzyme(s).

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

“…31 For Series 1, 2 and 3 the addition of a bromine atom at position 8 in the purine ring led to an increase in K i values ( Table 1 derivative was due to a rotation of the purine ring which resulted in increased interactions between the phosphonyl oxygens and active site residues (PDB codes: 4RAB and 4RAD). 39 Clearly, this has not occurred with the ANbPs and it is concluded that the decrease in inhibition constant is due to the fact that the orientation of the base with a bromine attached at position 8 resulted in a decrease in such interactions.…”

“…19 However, phosphoramidate prodrugs (Scheme 4) of aza-ANPs have been shown to possess antimalarial activity 39,40 so prodrugs of these new compounds were synthesised (Scheme 4) to evaluate their effectiveness in vitro. The results of these in vitro tests are summarized in Table 2.…”

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).…”