title: Synthesis and activity of nucleoside-based antiprotozoan compounds.
abstract: Parasitic protozoa employ a salvage pathway to synthesize purines and generate essential active nucleotides, whereas mammals are capable of their de novo biosynthesis. This difference provides opportunity for the design of potential new antiprotozoan compounds. A series of 47 adenosine analogues was prepared with modifications at the 2-, 6- and 5'-positions, based on the hypothesis that such compounds would serve as substrates for protozoan nucleoside salvage enzymes, while remaining refractory in mammalian cells. The nucleosides were designed to produce toxic metabolites upon cleavage to the corresponding purine base by the parasite. Three 7-deazaguanosine derivatives were prepared with similar objectives. All of these compounds were tested in vitro against T. brucei (African sleeping sickness), T. cruzi (Chagas' disease), L. donovani (leishmaniasis) and P. falciparum (malaria). In order to determine the therapeutic selectivity indices (SI) of the antiprotozoan nucleosides, their cytotoxicities toward a rat myoblast cell line were also determined. One adenosine derivative proved highly effective against P. falciparum (IC50=110nM and SI=1010, while a modified guanosine displayed potent activities against L. donovani (IC50=60nM, SI=2720) and T. brucei (IC50=130nM, SI=1250), as well as moderate activity against T. cruzi (IC50=3.4µM, SI=48). These results provide proof of concept for the nucleoside-based antiprotozoan strategy, as well as potential lead compounds for further optimization and validation.
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: 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: Xianghui
authors.initials: X
authors.lastname: Wen
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: Arnaud
authors.initials: A
authors.lastname: Pastor
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical and Public Health Institute, Socinstrasse 57, P.O. Box, 4002 Basel, Switzerland; University of Basel, Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Departments of Medical Genetics & Biochemistry and Molecular Biology, University of Calgary, Calgary T2N 4N1, 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; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D066244:Proton Magnetic Resonance Spectroscopy; D013055:Spectrophotometry, Infrared; D014346:Trypanosoma brucei brucei / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000981:Antiprotozoal Agents
keywords: Antiprotozoan compounds; Nucleosides; Purine salvage pathways