Antimalarial activity of N6-substituted adenosine derivatives. Part 3 Original Research Article

A series of novel 3′-amido-3′-deoxy-N6-(1-naphthylmethyl)adenosines was synthesized applying a polymer-assisted solution phase (PASP) protocol and was tested for anti-malarial activity versus the Dd2 strain of Plasmodium falciparum. Further, this series and 62 adenosine derivatives were analyzed regarding 1-deoxy-d-xylulose 5-phospate (DOXP) reductoisomerase inhibition. Biological evaluations revealed that the investigated 3′,N6-disubstituted adenosine derivatives displayed moderate but significant activity against the P. falciparum parasite in the low-micromolar range. On the molecular level, DOXP reductoisomerase utilizing an adenosyl-containing substrate was identified as a promising metabolic target for ligands of adenosine binding motifs.