Synthesis of carbocyclic pyrimidine nucleosides and their inhibitory activities against Plasmodium falciparum thymidylate kinase

• We synthesized enantioselective 2′,3′-dideoxycarbocyclic pyrimidine nucleosides.
• We screened several carbocyclic pyrimidine analogues for inhibitory activity against PfTMK.
• The fluorinated derivative exhibited the most potent inhibitory activity.

Plasmodium falciparum thymidylate kinase (PfTMK) is a promising antimalarial target due to its unique substrate specificity. Recently, we reported that 2′,3′-dideoxycarbocyclic thymidine showed moderate inhibitory activity and reported the related structure–activity relationship for inhibitors against PfTMK. In this study, we have designed and synthesized enantioselective 2′,3′-dideoxycarbocyclic pyrimidine nucleosides based on our previous results and screened them for inhibitory activity against PfTMK. The most potent inhibitor showed KiTMP and KidGMP values of 14 and 20 μM, respectively. The fluorinated dideoxy derivative (-)-7, exhibited lower KiTMP and higher KidGMP compared with that of the parent compound (KiTMP, KidGMP equals 20 and 7 μM, respectively). The modification of carbocyclic pyrimidine nucleosides is a promising strategy for developing powerful PfTMK inhibitors.

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