title: Novel nucleoside-based antimalarial compounds.
abstract: The malaria-causing parasite Plasmodium falciparum employs a salvage pathway for the biosynthesis of nucleotides, in contrast to de novo biosynthesis that is utilized by the human host. A series of twenty-two 2-, 6- and 5'-modified adenosine ribonucleosides was synthesized, with the expectation that these compounds would generate toxic metabolites instead of active nucleotides by the pathogen, while remaining inert in host cells. Bioassays with P. falciparum (K1 strain) indicated IC50 values as low as 110nM and a selectivity index with respect to cytotoxicity toward an L6 rat myoblast cell line of >1000 for the most potent analogue.
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Zhaoyan
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Huu-Anh
authors.initials: HA
authors.lastname: Tran
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Manivannan
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Xianghui
authors.initials: X
authors.lastname: Wen
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, 4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, PO Box, 4002 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Biochemical Genetics Lab, Alberta Children's Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A9, Canada. Electronic address: snyder@ucalgary.ca.
authors.forename: Floyd F
authors.initials: FF
authors.lastname: Snyder
authors.affiliation: Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada. Electronic address: tgback@ucalgary.ca.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Back
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008288:Malaria / Q000188:drug therapy*; D015394:Molecular Structure; D032446:Myoblasts / Q000187:drug effects* / Q000469:parasitology; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D009705:Nucleosides
keywords: Antimalarial compounds; Nucleosides; Purine salvage pathways