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A novel series of ANPs, analogues of previously reported 2\u2010(phosphonoethoxy)ethyl (PEE) and (<jats:italic>R<\/jats:italic>,<jats:italic>S<\/jats:italic>)\u20103\u2010hydroxy\u20102\u2010(phosphonomethoxy)propyl (HPMP) derivatives, were designed and synthesized to evaluate their ability to act as inhibitors of these enzymes and to extend our ongoing antimalarial structure\u2013activity relationship studies. In this series, (<jats:italic>S<\/jats:italic>)\u20103\u2010hydroxy\u20102\u2010(phosphonoethoxy)propyl (HPEP), (<jats:italic>S<\/jats:italic>)\u20102\u2010(phosphonomethoxy)propanoic acid (CPME), or (<jats:italic>S<\/jats:italic>)\u20102\u2010(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, (<jats:italic>S<\/jats:italic>)\u20103\u2010hydroxy\u20102\u2010(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for <jats:italic>Pf<\/jats:italic>HGXPRT, with a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> value of 0.1\u2005\u03bc<jats:sc>M<\/jats:sc> and a <jats:italic>K<\/jats:italic><jats:sub>i<\/jats:sub> value for human HGPRT of 0.6\u2005\u03bc<jats:sc>M<\/jats:sc>. The crystal structures of HPEPG and HPEPHx (where Hx=hypoxanthine) in complex with human HGPRT were obtained, showing specific interactions with active site residues. Prodrugs for the HPEP and CPEE analogues were synthesized and tested for in vitro antimalarial activity. The lowest IC<jats:sub>50<\/jats:sub> value (22\u2005\u03bc<jats:sc>M<\/jats:sc>) in a chloroquine\u2010resistant strain was observed for the bis\u2010amidate prodrug of HPEPG.<\/jats:p>","DOI":"10.1002\/cmdc.201500322","type":"journal-article","created":{"date-parts":[[2015,8,25]],"date-time":"2015-08-25T10:11:43Z","timestamp":1440497503000},"page":"1707-1723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of <i>Plasmodium falciparum<\/i> and Human 6\u2010Oxopurine Phosphoribosyltransferases"],"prefix":"10.1002","volume":"10","author":[{"given":"Martin 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