Thiophene-Linked Nucleotide Analogues as Selective and Nanomolar Inhibitors of Plasmodial 6-Oxopurine Phosphoribosyltransferases

Abstract 6-Oxopurine phosphoribosyltransferases (HGXPRTs) are essential enzymes in the purine salvage pathway of Plasmodium parasites and attractive antimalarial targets. However, the high conservation of their active sites with the human homolog complicates selective inhibitor development. Here, we report thiophene-linked nucleotide analogues as potent and selective inhibitors of plasmodial HG(X)PRTs. Structure-based modeling and conformational analysis guided the incorporation of a rigid thiophene core to control the orientation of phosphate-mimicking groups. C5 sulfonyl substitution markedly enhanced potency, yielding low- to single-digit nanomolar inhibitors of Plasmodium falciparum HGXPRT (PfHGXPRT). Compound 66 emerged as a lead inhibitor (Ki = 7 nM), showing up to ∼3300-fold selectivity over the human enzyme. Compound 63 was the most potent against Plasmodium vivax HGPRT (Ki = 30 nM), highlighting species-dependent linker length effects. Cellular activity remained limited, emphasizing intracellular delivery and/or prodrug activation as key remaining challenges. These compounds establish a promising selective chemotype for further antimalarial development.