Derivatives Against Leishmania amazonensis Promastigotes and Amastigotes. -14 1,3,4-Thiadiazolium-2-phenylamine derivatives, among them 4 new compounds, e.g. (IIIa) and (IIIb), are prepared and tested against promastigote and amastigote forms of Leishmania amazonensis. -(DA SILVA, E. F.; CANTO-CAVALHEIRO, M. M.; BRAZ, V. R.; CYSNE-FINKELSTEIN, L.; LEON, L. L.; ECHEVARRIA*, A.; Eur.
The efficacy of two mesoionic derivatives (MI-H-H and MI-4-OCH 3 ) was evaluated in CBA/J mice infected with Leishmania amazonensis. Treatment with these compounds demonstrated that the MI-4-OCH 3 derivative and the reference drug meglumine antimoniate (Glucantime) presented significant activity relative to an untreated control. No apparent hepatic or renal toxicity due to these mesoionic compounds was found.
L-arginine is involved in the production of both nitric oxide (NO), mediated by nitric oxide synthase (NOS) and L-ornithine, by arginase activity. It is generally accepted that NO regulation occurs mainly at the transcriptional level of NOS. In a previous work we purported that there is evidence that Leishmania sp. can produce NO from L-arginine. An arginase activity in its gene sequence has also been reported in Leishmania parasites. In a search for intracellular targets as potential antileishmanicidal agents, such as the L-arginine metabolism, we used 1,3,4-thiadiazolium mesoionic compounds, that have been demonstrated to be cytotoxic to the Leishmania amazonensis, when compared to Pentamidine isethionate as a reference drug. Parasites were assayed in absence/presence of 4 0 -and 3 0 -methoxy mesoionic derivatives in order to verify the effect on NO production and arginase activity in L. amazonensis. The results indicated that the drugs reduce from 70 to 90% of the NO production by the parasite and act on a soluble nitric oxide synthase purified from L. amazonensis promastigotes and axenic amastigotes.
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