Mitochondrial disruption and DNA fragmentation in Trypanosoma cruzi induced by naphthoimidazoles synthesized from beta-lapachone.
Three naphthoimidazoles presenting aromatic groups attached to the imidazole ring were the most active against trypomastigotes of Trypanosoma cruzi between 45 derivatives from beta-lapachone. N1 is active against the three forms of the parasite. In this work, we investigated N2 and N3 and analyzed the effect of the three derivatives on metacyclogenesis, endocytosis, and cell cycle. In epimastigotes, N2 and N3 blocked the cell cycle, inhibited succinate cytochrome c reductase, metacyclogenesis, and induced damage to mitochondrion, Golgi, and reservosomes. In treated trypomastigotes, there were alterations in the mitochondrion, nucleus and kinetoplast, and DNA fragmentation. Preincubation with cysteine protease inhibitors reversed the effect of N1, N2, and N3. Such reversion and ultrastructural alterations suggest the involvement of autophagy in parasite death. Ultrastructural, flow cytometry, and biochemical studies suggest that naphthoimidazoles interferes with the energetic metabolism and induces DNA fragmentation.
Menna-Barreto
R F S
RF
Departamento de Ultra-estrutura e Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, 21045-900 Rio de Janeiro, RJ, Brazil.
Corrêa
J R
JR
Pinto
A V
AV
Soares
M J
MJ
de Castro
S L
SL
D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D029402:Bignoniaceae / Q000737:chemistry*; D002453:Cell Cycle / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008855:Microscopy, Electron, Scanning; D008928:Mitochondria / Q000187:drug effects*; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D014349:Trypanosoma cruzi / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure
D000981:Antiprotozoal Agents; D004272:DNA, Mitochondrial; D007093:Imidazoles; D009285:Naphthoquinones; C508726:naphthoimidazole N1