naphthoquinones and Trypanosomiasis--African

A series of naphthoquinone derivatives has been synthesized and tested for its biological activity against human African trypanosomiasis. The use of reverse micellar medium not only enhanced the conversion rate, but also showed selectivity towards mono-coupled product in aryl chloride-aniline coupling reactions. Two derivatives of naphthoquinone (9b and 9c) exhibited potent activity against Trypanosoma brucei in vitro with low cytotoxicity.

Topics: Animals; Humans; Naphthoquinones; Structure-Activity Relationship; Trypanosomiasis, African

Topics: Chagas Disease; Drug Therapy, Combination; Heme; Humans; Melarsoprol; Naphthoquinones; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis, African

The inability of the bloodstream form of Trypanosoma brucei brucei to decompose hydrogen peroxide forms the basis of our attempt to develop new pharmacological agents to kill these organisms. Approximately 1-3% of the oxygen consumed by these parasites appears in the form of hydrogen peroxide. Our previous observation that free radical initiators such as heme and hematoporphyrin D proved to be trypanocidal in vitro and in vivo, respectively, prompted this investigation into the mechanism of action of this class of compounds to enhance their therapeutic efficacy. The locus of H2O2 production within the trypanosome was examined using cell-free homogenates. Experiments described herein suggest that H2O2 is formed by the alpha-glycerol phosphate dehydrogenase in an adventitious manner, and that no enzymatic means of disposing of this potentially toxic compound are present with the organisms. Naphthoquinones were found to substantially increase the rate of both oxygen consumption and H2O2 production by trypanosomal mitochondrial preparations. Presumably, the naphthoquinones are acting as coenzyme Q analogues. The addition of sublytic concentrations of both naphthoquinones and heme leads to a synergistic lysis of the organisms in vitro. Another approach to increasing the susceptibility of T. b. brucei to free radical damage involved reduction of the intracellular concentration of glutathione. This was accomplished through the use of trypanocidal arsenicals. Melarsenoxide and heme acted synergistically in vitro, an effect which was further enhanced via addition of a naphthoquinone. Moreover, hematoporphyrin D and tryparsamide were shown to have a synergistic effect in T. b. brucei-infected mice.

Topics: Animals; Free Radicals; Glycolysis; Heme; Hydrogen Peroxide; Mice; Mitochondria; Naphthoquinones; Oxygen Consumption; Porphyrins; Trypanosoma brucei brucei; Trypanosomiasis, African