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 mu M, 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 mu M, respectively). The modification of carbocyclic pyrimidine nucleosides is a promising strategy for developing powerful PfTMK inhibitors. (C) 2013 Elsevier Ireland Ltd. All rights reserved.