title: Synthesis and evaluation of α-thymidine analogues as novel antimalarials.
abstract: Plasmodium falciparum thymidylate kinase (PfTMPK) is a key enzyme in pyrimidine nucleotide biosynthesis. 3-Trifluoromethyl-4-chloro-phenyl-urea-α-thymidine has been reported as an inhibitor of Mycobacterium tuberculosis TMPK (MtTMPK). Starting from this point, we designed, synthesized and evaluated a number of thymidine analogues as antimalarials. Both 5'-urea-α- and β-thymidine derivatives were moderate inhibitors of PfTMPK and furthermore showed moderate inhibition of parasite growth. The structure of several enzyme-inhibitor complexes provides a basis for improved inhibitor design. However, we found that certain 5'-urea-α-thymidine analogues had antimalarial activity where inhibition of PfTMPK is not the major mode of action. Optimization of this series resulted in a compound with potent antimalarial activity (EC(50) = 28 nM; CC(50) = 29 μM).
authors.affiliation: Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.
authors.forename: Huaqing
authors.initials: H
authors.lastname: Cui
authors.forename: Juana
authors.initials: J
authors.lastname: Carrero-Lérida
authors.forename: Ana P G
authors.initials: AP
authors.lastname: Silva
authors.forename: Jean L
authors.initials: JL
authors.lastname: Whittingham
authors.forename: James A
authors.initials: JA
authors.lastname: Brannigan
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruiz-Pérez
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Keith S
authors.initials: KS
authors.lastname: Wilson
authors.forename: Dolores
authors.initials: D
authors.lastname: González-Pacanowska
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D001798:Blood Proteins; D008024:Ligands; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D014508:Urea; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013890:Thiourea; D013936:Thymidine