C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00639792" target="_blank" >RIV/61388963:_____/25:00639792 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1002/cmdc.202500575" target="_blank" >https://doi.org/10.1002/cmdc.202500575</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cmdc.202500575" target="_blank" >10.1002/cmdc.202500575</a>

Jazyk výsledku

angličtina

Název v původním jazyce

C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase

Popis výsledku v původním jazyce

Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine-based C1 '-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1 ' atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest K i values for two of these inhibitors are 0.7 mu M for the human enzyme and 0.4 mu M for the parasite enzyme. The K i values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1 ' atom. A phosphonodiamidate prodrug of one of the compounds has an IC50 of 4.3 mu M against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.

Název v anglickém jazyce

C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase

Popis výsledku anglicky

Hypoxanthine-guanine-(xanthine) phosphoribosyltransferase [HG(X)PRT] is an excellent target for the development of new drugs to treat parasitic and bacterial infections as well as MYC-dependent triple-negative breast cancer. Inhibitors include compounds that mimic the transition state of the catalytic reaction and analogs of the two products of the reaction, the nucleoside monophosphates and pyrophosphate. One type of chemistry explored here is the design of purine-based C1 '-branched acyclic nucleoside phosphonates bearing diverse structural attachments (secondary linkers) on the C1 ' atom. Compounds where this secondary linker has either a terminal phosphonate or a hydroxyl group are submicromolar to single-digit micromolar inhibitors of human hypoxanthine-guanine phosphoribosyltransferase and Plasmodium falciparum HGXPRT. The lowest K i values for two of these inhibitors are 0.7 mu M for the human enzyme and 0.4 mu M for the parasite enzyme. The K i values of the prepared derivatives, however, cover a wide range and depend on the chemical structure of the attachment at the C1 ' atom. A phosphonodiamidate prodrug of one of the compounds has an IC50 of 4.3 mu M against a drug-sensitive strain of Plasmodium falciparum grown in human erythrocytes, showing in vitro activity and the merit of these new inhibitors as potential drug leads.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemMedChem

ISSN

1860-7179

e-ISSN

1860-7187

Svazek periodika

20

Číslo periodika v rámci svazku

19

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

19

Strana od-do

e202500575

Kód UT WoS článku

001563641200001

EID výsledku v databázi Scopus

2-s2.0-105013793363