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

Abstract

Abstract: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 µM (Pf) and 0.2 µM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture 2 with IC 50 values of 0.8 and 1.5 µM. These two compounds exhibited low cytotoxicity in human A549 cells having CC 50 values of >300 µM resulting in an excellent selectivity index.

Enzymatic Transition States and Drug Design

“…When converted to the phosphoramidate prodrugs to permit cellular entry, the IC 50 values for inhibition of P. falciparum growth in cultured erythrocytes were between 1.4 and 9.7 μM and showed low toxicity for human cell lines. 200…”

Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases

“…Acyclic nucleoside bisphosphonates were found to be inhibitors of the P. falciparum and showed anti-malarial activities [ 115 ]. Folate and nucleotide analogs are the two main categories of the TS enzyme.…”

Patent Highlights June–July 2017

“…For the most active compounds, K i values for human, Plasmodium and M. tuberculosis HGPRT were in the low nanomolar range; growth of Plasmodium strains was inhibited with micromolar IC 50 values. For peer review papers on these and related compounds, seeŠpaček et al [26] and Kaiser et al [27].…”