Effect of mesoionic 4-phenyl-5-(cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivative salts on the activities of the nitric oxide synthase and arginase of Leishmania amazonensis.
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'- and 3'-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.
Soares-Bezerra
Rômulo José
RJ
Department of Immunology-Oswaldo Cruz Institute, Rio de Janeiro, Brazil.
da Silva
Edson F
EF
Echevarria
Aurea
A
Gomes-da-Silva
Liliane
L
Cysne-Finkelstein
Léa
L
Monteiro
Fabiane Pereira
FP
Leon
Leonor L
LL
Genestra
Marcelo
M
D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001119:Arginase / Q000187:drug effects*; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000032:analysis; D012492:Salts; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry* / Q000494:pharmacology*
D000814:Aniline Compounds; D009573:Nitrites; D012492:Salts; D013830:Thiadiazoles; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D001119:Arginase