title: Antichagasic and trichomonacidal activity of 1-substituted 2-benzyl-5-nitroindazolin-3-ones and 3-alkoxy-2-benzyl-5-nitro-2H-indazoles.
abstract: Two series of new 5-nitroindazole derivatives, 1-substituted 2-benzylindazolin-3-ones (6-29, series A) and 3-alkoxy-2-benzyl-2H-indazoles (30-37, series B), containing differently functionalized chains at position 1 and 3, respectively, have been synthesized starting from 2-benzyl-5-nitroindazolin-3-one 5, and evaluated against the protozoan parasites Trypanosoma cruzi and Trichomonas vaginalis, etiological agents of Chagas disease and trichomonosis, respectively. Many indazolinones of series A were efficient against different morphological forms of T. cruzi CL Brener strain (compounds 6, 7, 9, 10 and 19-21: IC50 = 1.58-4.19 μM for epimastigotes; compounds 6, 19-21 and 24: IC50 = 0.22-0.54 μM for amastigotes) being as potent as the reference drug benznidazole. SAR analysis suggests that electron-donating groups at position 1 of indazolinone ring are associated with an improved antichagasic activity. Moreover, compounds of series A displayed low unspecific toxicities against an in vitro model of mammalian cells (fibroblasts), which were reflected in high values of the selectivity indexes (SI). Compound 20 was also very efficient against amastigotes from Tulahuen and Y strains of T. cruzi (IC50 = 0.81 and 0.60 μM, respectively), showing low toxicity towards cardiac cells (LC50 > 100 μM). In what concerns compounds of series B, some of them displayed moderate activity against trophozoites of a metronidazole-sensitive isolate of T. vaginalis (35 and 36: IC50 = 9.82 and 7.25 μM, respectively), with low unspecific toxicity towards Vero cells. Compound 36 was also active against a metronidazole-resistant isolate (IC50 = 9.11 μM) and can thus be considered a good prototype for the development of drugs directed to T. vaginalis resistant to 5-nitroimidazoles.
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Fonseca-Berzal
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ibáñez-Escribano
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Reviriego
authors.affiliation: Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Cumella
authors.affiliation: Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Morales
authors.affiliation: Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain.
authors.forename: Nadine
authors.initials: N
authors.lastname: Jagerovic
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Nogal-Ruiz
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Escario
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, 21040-900, Rio de Janeiro, Brazil.
authors.forename: Patricia Bernardino
authors.initials: PB
authors.lastname: da Silva
authors.affiliation: Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, 21040-900, Rio de Janeiro, Brazil.
authors.forename: Maria de Nazaré C
authors.initials: Mde N
authors.lastname: Soeiro
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040, Madrid, Spain. Electronic address: agbarrio@ucm.es.
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/Juan de la Cierva 3, 28006, Madrid, Spain. Electronic address: vjaran@iqm.csic.es.
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship; D014244:Trichomonas / Q000187:drug effects*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D007191:Indazoles
keywords: Antiprotozoal drug; Indazole; Nitroheterocycle; Trichomonas vaginalis; Trypanosoma cruzi