title: Simple dialkyl pyrazole-3,5-dicarboxylates show in vitro and in vivo activity against disease-causing trypanosomatids.
abstract: The synthesis and antiprotozoal activity of some simple dialkyl pyrazole-3,5-dicarboxylates (compounds 2-6) and their sodium salts (pyrazolates) (compounds 7-9) against Trypanosoma cruzi, Leishmania infantum and Leishmania braziliensis are reported. In most cases the studied compounds showed, especially against the clinically significant amastigote forms, in vitro activities higher than those of the reference drugs (benznidazole for T. cruzi and glucantime for Leishmania spp.); furthermore, the low non-specific cytotoxicities against Vero cells and macrophages shown by these compounds led to good selectivity indexes, which are 8-72 times higher for T. cruzi amastigotes and 15-113 times higher for Leishmania spp. amastigotes than those of the respective reference drugs. The high efficiency of diethyl ester 3 and its sodium salt 8 against the mentioned protozoa was confirmed by further in vitro assays on infection rates and by an additional in vivo study in a murine model of acute and chronic Chagas disease. The inhibitory capacity of compounds 3 and 8 on the essential iron superoxide dismutase of the aforementioned parasites may be related to the observed anti-trypanosomatid activity. The low acute toxicity of compounds 3 and 8 in mice is also reported in this article.
authors.affiliation: Instituto de Química Médica, CSIC,c/Juan de la Cierva 3, 28006-Madrid,Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Reviriego
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios de Granada/Universidad de Granada,Granada,Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Olmo
authors.affiliation: Instituto de Química Médica, CSIC,c/Juan de la Cierva 3, 28006-Madrid,Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios de Granada/Universidad de Granada,Granada,Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Marín
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios de Granada/Universidad de Granada,Granada,Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Ramírez-Macías
authors.affiliation: Departamento de Química Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, Edificio de Institutos de Paterna,c/Profesor José Beltrán 22, 46980-Paterna (Valencia),Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: García-España
authors.affiliation: Departamento de Química Inorgánica, Instituto de Ciencia Molecular, Universidad de Valencia, Edificio de Institutos de Paterna,c/Profesor José Beltrán 22, 46980-Paterna (Valencia),Spain.
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Albelda
authors.affiliation: Departamento de Estadística, Facultad de Ciencias, Universidad de Granada,c/Severo Ochoa s/n, 18071-Granada,Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Gutiérrez-Sánchez
authors.affiliation: Departamento de Parasitología, Instituto de Investigación Biosanitaria (ibs.GRANADA), Hospitales Universitarios de Granada/Universidad de Granada,Granada,Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Sánchez-Moreno
authors.affiliation: Instituto de Química Médica, CSIC,c/Juan de la Cierva 3, 28006-Madrid,Spain.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D002522:Chlorocebus aethiops; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005260:Female; D007892:Leishmania braziliensis / Q000187:drug effects*; D018314:Leishmania infantum / Q000187:drug effects*; D008264:Macrophages; D051379:Mice; D008807:Mice, Inbred BALB C; D018512:Parasitemia; D011720:Pyrazoles / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D003998:Dicarboxylic Acids; D011720:Pyrazoles; D014344:Trypanocidal Agents; C031280:pyrazole
keywords: 
                 Leishmania
              ; 
                 Trypanosoma
              ; antichagasic activity; cytotoxicity; leishmanicidal activity; pyrazole