Leishmania panamensis: Comparative inhibition of nuclear DNA topoisomerase II enzymes from promastigotes and human macrophages reveals anti-parasite selectivity of fluoroquinolones, flavonoids and pentamidine

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.