C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
C1′-Branched Acyclic Nucleoside Phosphonates as Inhibitors of Plasmodium Falciparum 6-Oxopurine Phosphoribosyltransferase
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ChemMedChem
ISSN
1860-7179
e-ISSN
1860-7187
Volume of the periodical
20
Issue of the periodical within the volume
19
Country of publishing house
US - UNITED STATES
Number of pages
19
Pages from-to
e202500575
UT code for WoS article
001563641200001
EID of the result in the Scopus database
2-s2.0-105013793363