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

ABSTRACT

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 K(i)(TMP) and K(i)(dGMP) values of 14 and 20 µM, respectively. The fluorinated dideoxy derivative (-)-7, exhibited lower K(i)(TMP) and higher K(i)(dGMP) compared with that of the parent compound (K(i)(TMP), K(i)(dGMP) equals 20 and 7 µM, respectively). The modification of carbocyclic pyrimidine nucleosides is a promising strategy for developing powerful PfTMK inhibitors.