title: Leishmania donovani: differential activities of classical topoisomerase inhibitors and antileishmanials against parasite and host cells at the level of DNA topoisomerase I and in cytotoxicity assays.
abstract: Different classes of topoisomerase (TOP) inhibitors and antitrypanosomatid agents exhibited variable efficacies against Leishmania donovani parasites and human mononuclear cells both at the level of DNA topoisomerase I (TOPI) catalytic activity and in cytotoxicity assays. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high efficacies against parasite and host enzymes as well as against parasite and mononuclear cells, but pentamidine showed around 2 orders of magnitude greater specificity for Leishmania TOPI and amastigote cells (P<0.05). The protoberberine coralyne and the flavonoid quercetin were highly potent, but non-selective, inhibitors in vitro, although the latter showed slight selectivity for parasite TOPI. Camptothecin was selective for mononuclear cells at both levels (P<0.05) and sodium stibogluconate was selective only at the enzyme level displaying 30-fold greater potency against parasite TOPI (P<0.05). These data suggest that at least part of pentamidines' leishmanicidal activity may be mediated through TOPI inhibition, and support the feasibility of exploiting differences between Leishmania and human TOPs to develop modified compounds with improved selectivity.
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Biochemistry and Molecular Biology Unit, Avenida 1 Norte No. 3-03, AA 5390, Cali, Valle de Cauca, Colombia.
authors.forename: Valerie
authors.initials: V
authors.lastname: Jean-Moreno
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rojas
authors.forename: Diego
authors.initials: D
authors.lastname: Goyeneche
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.forename: John
authors.initials: J
authors.lastname: Walker
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D000967:Antimony Sodium Gluconate / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology; D002460:Cell Line; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004133:Diminazene / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D049409:Luciferases, Firefly / Q000235:genetics; D049408:Luminescent Agents; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000469:parasitology*; D010419:Pentamidine / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors
chemical_list: D000981:Antiprotozoal Agents; D001562:Benzimidazoles; D001600:Berberine Alkaloids; D004791:Enzyme Inhibitors; D049408:Luminescent Agents; D059004:Topoisomerase I Inhibitors; D010419:Pentamidine; C000666:coralyne; D011794:Quercetin; D049409:Luciferases, Firefly; D000135:Acid Phosphatase; D004264:DNA Topoisomerases, Type I; C003915:diminazene aceturate; D006690:Bisbenzimidazole; C017807:bisbenzimide ethoxide trihydrochloride; D000967:Antimony Sodium Gluconate; D002166:Camptothecin; D004133:Diminazene