Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

0477558 - ÚOCHB 2018 RIV GB eng J - Článek v odborném periodiku
Špaček, Petr - Keough, D. T. - Chavchich, M. - Dračínský, Martin - Janeba, Zlatko - Naesens, L. - Edstein, M. D. - Guddat, L. W. - Hocková, Dana
Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs.
Bioorganic & Medicinal Chemistry. Roč. 25, č. 15 (2017), s. 4008-4030. ISSN 0968-0896. E-ISSN 1464-3391
Grant CEP: GA ČR(CZ) GA16-06049S
Institucionální podpora: RVO:61388963
Klíčová slova: enzyme inhibitors * nucleotide analogues * malaria
Obor OECD: Organic chemistry
Impakt faktor: 2.881, rok: 2017

Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N-9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower K-i values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest K-i values obtained for the two parasite enzymes were 0.1 mu M (Pf) and 0.2 mu M (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture with IC50 values of 0.8 and 1.5 mu M. These two compounds exhibited low cytotoxicity in human A549 cells having CC50 values of >300 mu M resulting in an excellent selectivity index.
Trvalý link: http://hdl.handle.net/11104/0273877