title: In vitro evaluation of 4-phenyl-5-(4'-X-phenyl)-1,3,4-thiadiazolium-2-phenylaminide chlorides and 3[N-4'-X-phenyl]-1,2,3-oxadiazolium-5-olate derivatives on nitric oxide synthase and arginase activities of Leishmania amazonensis.
abstract: Leishmaniasis is a spectrum of infectious diseases caused by Leishmania protozoan parasites. The purpose of this study was to perform, in vitro, a comparative analysis of the activity amastigotes. Results showed excellent efficacy of all compounds against axenic amastigotes, compared to pentamidine isethionate, the reference drug used. The cytotoxic effect of these mesoionic compounds of six mesoionic compounds (three 1,3,4-thiadiazolium-2-aminide and three 1,2,3-oxadiazolium-5-olate class compounds) was evaluated in mouse peritoneal macrophages using MTT assay, low toxicity (≈ 10%) for these mammalian cells being observed. In an attempt to define a potential drug target, the activities of nitric oxide synthase (NOS) and arginase of the parasites treated with the mesoionic derivatives were evaluated. NOS was purified from a cell-free extract of infective promastigotes and axenic amastigotes and all derivatives tested were able to inhibit the enzyme as monitored by the decrease of NADPH consumption. Arginase activity from both stages of the parasite was measured using urea production and none of the compounds inhibited the enzyme activity of axenic amastigotes. However, the compounds without substituents (MI-H and SID-H) were able to inhibit arginase activity of these parasites.
authors.affiliation: Laboratory of Biochemistry of Trypanosomatids, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, RJ, Brazil.
authors.forename: Romulo J
authors.initials: RJ
authors.lastname: Soares-Bezerra
authors.forename: Leonor Laura
authors.initials: LL
authors.lastname: Leon
authors.forename: Aurea
authors.initials: A
authors.lastname: Echevarria
authors.forename: Camilla M
authors.initials: CM
authors.lastname: Reis
authors.forename: Liliane
authors.initials: L
authors.lastname: Gomes-Silva
authors.forename: Carla G
authors.initials: CG
authors.lastname: Agostinho
authors.forename: Renan A
authors.initials: RA
authors.lastname: Fernandes
authors.forename: Marilene M
authors.initials: MM
authors.lastname: Canto-Cavalheiro
authors.forename: Marcelo S
authors.initials: MS
authors.lastname: Genestra
mesh_terms: D000818:Animals; D001119:Arginase / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007894:Leishmania mexicana / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism*; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010529:Peritoneal Cavity / Q000166:cytology / Q000469:parasitology; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C116348:4-phenyl-5-(4-nitrocinnamoyl)-1,3,4-thiadiazolium-2-phenylamine; D002934:Cinnamates; D010069:Oxadiazoles; D013830:Thiadiazoles; D019001:Nitric Oxide Synthase; D001119:Arginase
keywords: Arginase; Axenic amastigote; Leishmania amazonensis; Mesoionic compounds; Nitric oxide synthase; Promastigote