Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation

0510479 - ÚOCHB 2020 RIV FR eng J - Článek v odborném periodiku
Klejch, Tomáš - Keough, D. T. - Chavchich, M. - Travis, J. - Skácel, Jan - Pohl, Radek - Janeba, Zlatko - Edstein, M. D. - Avery, V. M. - Guddat, L. W. - Hocková, Dana
Sulfide, sulfoxide and sulfone bridged acyclic nucleoside phosphonates as inhibitors of the Plasmodium falciparum and human 6-oxopurine phosphoribosyltransferases: Synthesis and evaluation.
European Journal of Medicinal Chemistry. Roč. 183, Dec 1 (2019), č. článku 111667. ISSN 0223-5234. E-ISSN 1768-3254
Grant CEP: GA ČR(CZ) GA16-06049S
Institucionální podpora: RVO:61388963
Klíčová slova: hypoxanthine-guanine-xanthine phosphoribosyltransferase * sulfur-containing drugs * sulfide oxidation * Plasmodium falciparum * acyclic nucleoside phosphonates
Obor OECD: Organic chemistry
Impakt faktor: 5.573, rok: 2019
Způsob publikování: Omezený přístup
https://www.sciencedirect.com/science/article/abs/pii/S0223523419308116?via%3Dihub

Hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) is a recognized target for antimalarial chemotherapeutics. It synthesises all of the 6-oxopurine nucleoside monophosphates, IMP, GMP and XMP needed by the malarial parasite, Plasmodium falciparum (Pf). PfHGXPRT is also indirectly responsible for the synthesis of the adenosine monophosphate, AMP. The acyclic nucleoside phosphonates (ANPs) are a class of PfHGXPRT inhibitors. Prodrugs of these compounds are able to arrest the growth of Pf in cell culture. In the search for new inhibitors of PfHGXPRT, a series of sulfur containing ANPs (thia-ANPs) has been designed and synthesized. These compounds are based on the structure of 2-(phosphonoethoxy)ethylguanine (PEEG) and PEEHx which consist of a purine base (i.e. guanine or hypoxanthine) linked to a phosphonate group by five atoms i.e. four carbons and one oxygen. Here, PEEG and PEEHx were modified by substituting a sulfide, sulfoxide or a sulfone bridge for the oxygen atom in the linker. The effect of these substitutions on the Ki values for human HGPRT and PfHGXPRT was investigated and showed that most of the thia-ANPs distinctively favour PfHGXPRT. For example, the thia-analogue of PEEHx has a Ki value of 0.2 μM for PfHGXPRT, a value 25-fold lower than for the human counterpart. Prodrugs of these compounds have IC50 values in the 4–6 μM range in antimalarial cell-based assays, making them attractive compounds for further development as antimalarial drug leads.
Trvalý link: http://hdl.handle.net/11104/0300951