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Title

Synthesis and in vitro and in vivo biological evaluation of substituted nitroquinoxalin-2-ones and 2,3-diones as novel trichomonacidal agents

AuthorsIbáñez-Escribano, Alexandra; Reviriego, Felipe ; Nogal-Ruiz, Juan José; Meneses-Marcel, Alfredo; Gómez-Barrio, Alicia; Escario, José Antonio; Arán, Vicente J.
KeywordsTrichomonas vaginalis
Quinoxaline
Nitroheterocycles
Antiprotozoal drugs
Lipinski's rule
Issue Date2015
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 94: 276-283 (2015)
AbstractTwo 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.
URIhttp://hdl.handle.net/10261/113129
DOI10.1371/journal.pone.0085706
Identifiersdoi: 10.1371/journal.pone.0085706
issn: 1768-3254
e-issn: 1768-3254
Appears in Collections:(IQM) Artículos
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