Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase

Abstract

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme.

Solution structure of ligands involved in purine salvage pathway

“…Thus, enzymes of the salvage pathway are identified as potential therapeutic targets against these parasites [1][2][3][4]. Therapeutic intervention that targets these enzymes requires development of effective analogues of the natural substrates and on-enzyme intermediates [5,6]. As a first step, a thorough understanding of the structure of the natural substrates and intermediates is essential.…”

1‐Amino‐3‐(1H‐1,2,3‐triazol‐1‐yl)propylphosphonates as Acyclic Analogs of Nucleotides

“…Among various nitrogen‐containing nucleotides 8 – 10 obtained by Zhou, only analog 10 ( B = Gua) showed slight inhibitory activity against HSV‐1, HSV‐2, and CMV . Aza‐nucleotide 11 with nitrogen incorporated into the phosphonoalkyl residue and its N ‐branched derivative 12 appeared to be selective inhibitors of phosphoribosyltransferase P f HGXPRT, a key enzyme for the growth of Plasmodium falciparum , and at the same time did not show detectable inhibitory activity against human HGPRT. Moreover, it was shown that the protection of the amino functionalities in 13 with bulky groups such as tert ‐butoxycarbonyl (Boc) or benzoyl (Bz) leads to the enhancement of antiviral activities of the protected compounds .…”

Plasmodium Purine Metabolism and Its Inhibition by Nucleoside and Nucleotide Analogues

“…122 Biological studies on Pf and human PRT enzymes revealed that CPME analogues were inactive, in agreement with the fact that a five-atom chain is optimal for tight interactions at the active site. 123,124 Concerning HPEP derivatives, again the nature of the nucleobase was found to be crucial as only the 8-bromoguanine, guanine and hypoxanthine analogues showed some affinity (with Ki in the low micromolar range), but only the guanine HPEP ANP presented a 6-fold better selectivity for the parasite enzyme. CPEE derivatives exhibited similar activities against both enzymes, and in this case only the hypoxanthine derivatives appeared to be more selective for Pf HGXPRT than for human HGPRT.…”