Premium
Synthesis and Evaluation of Novel Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium falciparum and Human 6‐Oxopurine Phosphoribosyltransferases
Author(s) -
Kaiser Martin M.,
Hocková Dana,
Wang TzuHsuan,
Dračínský Martin,
PoštováSlavětínská Lenka,
Procházková Eliška,
Edstein Michael D.,
Chavchich Marina,
Keough Dianne T.,
Guddat Luke W.,
Janeba Zlatko
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500322
Subject(s) - chemistry , stereochemistry , prodrug , hypoxanthine , plasmodium falciparum , propanoic acid , phosphoribosyltransferase , enzyme , hypoxanthine guanine phosphoribosyltransferase , biochemistry , biology , mutant , malaria , immunology , gene
Acyclic nucleoside phosphonates (ANPs) are a promising class of antimalarial therapeutic drug leads that exhibit a wide variety of K i values for Plasmodium falciparum ( Pf ) and human hypoxanthine‐guanine‐(xanthine) phosphoribosyltransferases [HG(X)PRTs]. A novel series of ANPs, analogues of previously reported 2‐(phosphonoethoxy)ethyl (PEE) and ( R , S )‐3‐hydroxy‐2‐(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–activity relationship studies. In this series, ( S )‐3‐hydroxy‐2‐(phosphonoethoxy)propyl (HPEP), ( S )‐2‐(phosphonomethoxy)propanoic acid (CPME), or ( S )‐2‐(phosphonoethoxy)propanoic acid (CPEE) are the acyclic moieties. Of this group, ( S )‐3‐hydroxy‐2‐(phosphonoethoxy)propylguanine (HPEPG) exhibits the highest potency for Pf HGXPRT, with a K i value of 0.1 μ M and a K i value for human HGPRT of 0.6 μ M . 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 50 value (22 μ M ) in a chloroquine‐resistant strain was observed for the bis‐amidate prodrug of HPEPG.