title: In vitro leishmanicidal activity of imidazole- or pyrazole-based benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis species.
abstract: OBJECTIVE
  To evaluate the in vitro leishmanicidal activity of imidazole-based (1-4) and pyrazole-based (5-6) benzo[g]phthalazine derivatives against Leishmania infantum and Leishmania braziliensis.
  
  
  METHODS
  The in vitro activity of compounds 1-6 was assayed on extracellular promastigote and axenic amastigote forms, and on intracellular amastigote forms of the parasites. Infectivity and cytotoxicity tests were performed on J774.2 macrophage cells using meglumine antimoniate (Glucantime) as the reference drug. The mechanisms of action were analysed by iron superoxide dismutase (Fe-SOD) and copper/zinc superoxide dismutase (CuZn-SOD) inhibition, metabolite excretion and transmission electronic microscopy (TEM).
  
  
  RESULTS
  Compounds 1-6 were more active and less toxic than meglumine antimoniate. Data on infection rates and amastigote mean numbers showed that 2, 4 and 6 were more active than 1, 3 and 5 in both L. infantum and L. braziliensis. The inhibitory effect of these compounds on the antioxidant enzyme Fe-SOD of promastigote forms of the parasites was remarkable, whereas inhibition of human CuZn-SOD was negligible. The ultrastructural alterations observed in treated promastigote forms confirmed the greater cell damage caused by the most active compounds 2, 4 and 6. The modifications observed by (1)H-NMR in the nature and amounts of catabolites excreted by the parasites after treatment with 1-6 suggested that the catabolic mechanisms could depend on the structure of the side chains linked to the benzo[g]phthalazine moiety.
  
  
  CONCLUSIONS
  All the compounds assayed were active in vitro against the two Leishmania species and were less toxic against mammalian cells than the reference drug, but the monosubstituted compounds were significantly more effective and less toxic than their disubstituted counterparts.
authors: Instituto de Biotecnología, Facultad de Ciencias, Universidad de Granada, 18071 Granada,  Spain.
authors: Manuel
authors: M
authors: Sánchez-Moreno
authors: Fernando
authors: F
authors: Gómez-Contreras
authors: Pilar
authors: P
authors: Navarro
authors: Clotilde
authors: C
authors: Marín
authors: Inmaculada
authors: I
authors: Ramírez-Macías
authors: Francisco
authors: F
authors: Olmo
authors: Ana María
authors: AM
authors: Sanz
authors: Lucrecia
authors: L
authors: Campayo
authors: Carmen
authors: C
authors: Cano
authors: María J R
authors: MJ
authors: Yunta
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007892:Leishmania braziliensis / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D008264:Macrophages / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D021261:Parasitic Sensitivity Tests; D010793:Phthalazines / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D007093:Imidazoles; D010793:Phthalazines; D011720:Pyrazoles; C031280:pyrazole; C029899:imidazole; C043388:phthalazine; D013482:Superoxide Dismutase