Acyclic nucleoside phosphonates with unnatural nucleobases, favipiravir and allopurinol, designed as potential inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases

0495494 - ÚOCHB 2019 RIV GB eng J - Journal Article
Klejch, Tomáš - Pohl, Radek - Janeba, Zlatko - Sun, M. - Keough, D. T. - Guddat, L. W. - Hocková, Dana
Acyclic nucleoside phosphonates with unnatural nucleobases, favipiravir and allopurinol, designed as potential inhibitors of the human and Plasmodium falciparum 6-oxopurine phosphoribosyltransferases.
Tetrahedron. Roč. 74, č. 40 (2018), s. 5886-5897. ISSN 0040-4020. E-ISSN 1464-5416
R&D Projects: GA ČR(CZ) GA16-06049S
Institutional support: RVO:61388963
Keywords : hypoxanthine-guanine-xanthine phosphoribosyltransferase * regioselective Mitsunobu reaction * acyclic nucleotide analogues * enzyme inhibition
OECD category: Organic chemistry
Impact factor: 2.379, year: 2018

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a key enzyme of the purine salvage pathway and its activity is crucial for the survival of certain parasites e.g. Plasmodium falciparum (Pf). Acyclic nucleoside phosphonates (ANPs) containing either guanine or hypoxanthine as the purine base are inhibitors of this enzyme. In this part of a SAR study, these two naturally-occurring nucleobases attached to an acyclic moiety were replaced by allopurinol or favipiravir. Both allopurinol and favipiravir ANPs were prepared via Mitsunobu reaction. The alkylation of favipiravir was optimized to yield both N- and O- regioisomers but the N-regioisomers were unstable under deprotection conditions. Thus, only the ANPs containing the O-isomer of favipiravir and those containing allopurinol were evaluated as potential inhibitors of human HGPRT and PfHGXPRT. Two ANPs with allopurinol as the base have K-i values of 10 mu M and 30 mu M for PfHGXPRT but do not inhibit human HGPRT activity at concentrations of 100-150 mu M.
Permanent Link: http://hdl.handle.net/11104/0288465