title: Leishmania panamensis: comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine.
abstract: Certain model inhibitors exerted selective action against the catalytic activity of nuclear DNA topoisomerase II (TOPII) of Leishmania panamensis promastigotes. The second-generation fluoroquinolones enoxacin and ciprofloxacin exhibited extraordinarily high anti-parasite selectivity displaying 582- and 40-fold greater potencies against L. panamensis TOPII as compared with the human macrophage enzyme. The flavonoids quercetin and ellagic acid showed inverse specificities, the former being 161-fold more potent against L. panamensis TOPII, and the latter 15.7-fold more active against macrophage TOPII. The protoberberine coralyne was a potent inhibitor of both Leishmania and macrophage TOPII. Bis-benzimidazoles and the diamidine diminazene aceturate exhibited uniformly high potencies against parasite and host TOPII, but a second diamidine pentamidine showed 17.6-fold greater specificity for Leishmania TOPII. The antimonial sodium stibogluconate was an ineffective inhibitor of parasite TOPII showing 4.3-fold greater potency against the macrophage enzyme. These findings suggest that the leishmanicidal activities of certain fluoroquinolones and pentamidine may be mediated partly through TOPII inhibition.
authors.affiliation: Centro Internacional de Entrenamiento e Investigaciones Medicas, Cali, Colombia.
authors.forename: Tania M
authors.initials: TM
authors.lastname: Cortázar
authors.forename: Graham H
authors.initials: GH
authors.lastname: Coombs
authors.forename: John
authors.initials: J
authors.lastname: Walker
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology; D002939:Ciprofloxacin / Q000494:pharmacology; D004610:Ellagic Acid / Q000494:pharmacology; D015365:Enoxacin / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D018334:Leishmania guyanensis / Q000187:drug effects / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D010419:Pentamidine / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors
chemical_list: D000890:Anti-Infective Agents; D000981:Antiprotozoal Agents; D005419:Flavonoids; D024841:Fluoroquinolones; D059005:Topoisomerase II Inhibitors; D004610:Ellagic Acid; D015365:Enoxacin; D002939:Ciprofloxacin; D010419:Pentamidine; D011794:Quercetin