title: 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.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Yuri
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Makoto
authors.initials: M
authors.lastname: Tashiro
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kataoka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kandeel
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kitade
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005461:Fluorine / Q000737:chemistry; D016778:Malaria, Falciparum / Q000188:drug therapy*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011741:Pyrimidine Nucleosides; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives
chemical_list: C585686:2',3'-dideoxycarbocyclic thymidine; D000962:Antimalarials; D015224:Dideoxynucleosides; D004791:Enzyme Inhibitors; D011741:Pyrimidine Nucleosides; D005461:Fluorine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine