Systematic structure-activity studies on a diverse family of nucleoside phosphonic acids has led to the development of potent antiviral drugs such as HPMPC (CidofovirTM), PMEA (AdefovirTM), and PMPA (TenofovirTM), which are used in the treatment of CMV-induced retinitis, hepatitis B, and HIV, respectively. Here, we present the synthesis of a novel class of acyclic phosphonate nucleotides that have a locked conformation via a pyrrolidine ring. NMR analysis of these compounds revealed that the pyrrolidine ring has a constrained conformation when in the cis-form at pD < 10 via hydrogen bonding. Four of these compounds were tested as inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases. The most potent has a Ki of 0.6 μM for Plasmodium falciparum HGXPRT.
- MeSH
- adenin chemie MeSH
- antimalarika chemická syntéza MeSH
- farmaceutická chemie MeSH
- hypoxanthin chemie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- konformace proteinů MeSH
- kyslík chemie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- organofosfonáty chemie MeSH
- pentosyltransferasy antagonisté a inhibitory MeSH
- Plasmodium falciparum účinky léků MeSH
- pyrrolidiny chemie MeSH
- racionální návrh léčiv MeSH
- vodíková vazba MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
