Exploring new inhibitors of Plasmodium falciparum purine nucleoside phosphorylase

Plasmodium falciparum purine nucleoside phosphorylase (PfPNP) has a central role in purine salvage and inhibitors of the enzyme have been shown to have antiplasmodial activity. The enzyme preferentially uses inosine as substrate (Km = 5 μM, kcat/Km = 7.4 × 104 M−1 s−1), but can also use uridine, albeit less efficiently (Km = 85 μM, kcat/Km = 306 M−1 s−1). In an effort to identify new PfPNP inhibitors, two series of compounds were prepared. Series 1 was based on known human uridine phosphorylase inhibitors whilst series 2 was uracil equivalents of purine-based PNP transition state inhibitors. These two series of compounds were assayed for inhibition of both PfPNP activity and growth of P. falciparum. The transition state analogues were found to be moderate inhibitors of PfPNP (most potent compound, Ki = 6 μM).

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide