title: Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents.
abstract: Two series of ten novel 7-nitroquinoxalin-2-ones and ten 6-nitroquinoxaline-2,3-diones with diverse substituents at positions 1 and 4 were synthesized and evaluated against the sexually transmitted parasite Trichomonas vaginalis. Furthermore, diverse molecular and drug-likeness properties were analyzed to predict the oral bioavailability following the Lipinski's "rule of five". 7-Nitroquinoxalin-2-one derivatives displayed moderate to high in vitro activity while the efficiency of most nitroquinoxaline-2,3-diones was rather low; both kinds of compounds did not show cytotoxic effects in mammalian cells. 7-Nitro-4-(3-piperidinopropyl)quinoxalin-2-one 9 achieved the highest trichomonacidal activity (IC50 = 18.26 μM) and was subsequently assayed in vivo in a murine model of trichomonosis. A 46.13% and a 50.70% reduction of pathogenic injuries were observed in the experimental groups treated orally during 7 days with 50 mg/kg and 100 mg/kg doses. The results obtained in the biological assays against T. vaginalis indicate that compounds with ω-(dialkylamino)alkyl substituents and a keto group at positions 4 and 2 of quinoxaline ring, respectively, provide interesting structural cores to develop novel prototypes to enhance the nitroquinoxalinones activity as trichomonacidal agents with interesting ADME properties according to virtual screening analysis.
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), CSIC, c/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Reviriego
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: Centro de Bioactivos Químicos, Universidad Central de Las Villas, 54830 Santa Clara, Villa Clara, Cuba.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Meneses-Marcel
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: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
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: escario@ucm.es.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Escario
authors.affiliation: Moncloa Campus of International Excellence (UCM-UPM & CSIC), Spain; Instituto de Química Médica (IQM), 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; D000994:Antitrichomonal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014245:Trichomonas Infections / Q000188:drug therapy*; D014246:Trichomonas vaginalis / Q000187:drug effects*; D014709:Vero Cells
chemical_list: D000994:Antitrichomonal Agents; D011810:Quinoxalines
keywords: Antiprotozoal drugs; Lipinski's rule; Nitroheterocycles; Quinoxaline; Trichomonas vaginalis