In vitro and in vivo activities of 1,3,4-thiadiazole-2-arylhydrazone derivatives of megazol against Trypanosoma cruzi.
From a series of 1,3,4-thiadiazole-2-arylhydrazone derivatives of megazol screened in vitro against Trypanosoma cruzi, eight (S1 to S8) were selected for in vivo screening by single-dose oral administration (200 mg/kg of body weight) to infected mice at 5 days postinfection (dpi). Based on significant decreases in both parasitemia levels and mortality rates, S2 and S3 were selected for further assays. Despite having no in vivo effect, S1 was included since it was 2-fold more potent against trypomastigotes than megazol in vitro. Trypomastigotes treated with S1, S2, or S3 showed alterations of the flagellar structure and of the nuclear envelope. When assayed on intracellular amastigotes, the selectivity index (SI) for macrophages was in the range of >27 to >63 and for cardiac cells was >32 for S1 and >48 for megazol. In noninfected mice, S1 did not alter the levels of glutamic oxalacetic transaminase (GOT), glutamate pyruvate transaminase (GPT), or urea. S2 led to an increase in GOT, S3 to increases in GOT and GPT, and megazol to an increase in GOT. Infected mice were treated with each derivative at 50 and 100 mg/kg from dpi 6 to 15: S1 did not interfere with the course of infection or reduce the number of inflammatory foci in the cardiac tissue, S2 led to a significant decrease of parasitemia, and S3 decreased mortality. There was no direct correlation between the in vitro effect on trypomastigotes and amastigotes and the results of the treatment in experimental models, as S1 showed a high potency in vitro while, in two different schemes of in vivo treatment, no decrease of parasitemia or mortality was observed.
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil.
K
K
Salomão
E M
EM
de Souza
S A
SA
Carvalho
E F
EF
da Silva
C A M
CA
Fraga
H S
HS
Barbosa
S L
SL
de Castro
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight; D002478:Cells, Cultured; D014355:Chagas Disease / Q000188:drug therapy* / Q000401:mortality / Q000469:parasitology; D006835:Hydrazones / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000469:parasitology; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning; D032383:Myocytes, Cardiac / Q000166:cytology / Q000469:parasitology; D018512:Parasitemia / Q000188:drug therapy / Q000401:mortality / Q000469:parasitology; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D014508:Urea / Q000097:blood
D000981:Antiprotozoal Agents; D006835:Hydrazones; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole; C013378:megazol; D014508:Urea; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase