title: 5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene.
abstract: Chagas disease represents a serious public health problem in South America. The first line of treatment is Nifurtimox and Benznidazole which generate toxic effects in treated patients. We have recently shown that a number of 5-nitrofuranes possess activity against Trypanosoma cruzi through oxidative stress and inhibition of parasite ergosterol biosynthesis, specifically at the level of squalene epoxidase. Here, we identify new 5-nitrofuranes and the thia-analogues with excellent effects on the viability of T. cruzi and adequate parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated, during 120h, with the compounds showed that some of them accumulated squalene suggesting the squalene epoxidase activity inhibition of the parasite. Nifurtimox was able to accumulate squalene only at lower incubation times. Due to this fact some derivatives were also tested as antifungal agents. Quantitative structure-activity relationship studies were also performed showing relevant features for further new derivatives design. Taken together, the results obtained in the present work point to a more general effect of 5-nitrofuranes and 5-nitrothiophenes in trypanosomatids, opening potential therapeutic possibilities of them for these infectious diseases.
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gerpe
authors.forename: Guzmán
authors.initials: G
authors.lastname: Alvarez
authors.forename: Diego
authors.initials: D
authors.lastname: Benítez
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Martín
authors.initials: M
authors.lastname: Quiroga
authors.forename: Paola
authors.initials: P
authors.lastname: Hernández
authors.forename: Maximiliano
authors.initials: M
authors.lastname: Sortino
authors.forename: Susana
authors.initials: S
authors.lastname: Zacchino
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D051379:Mice; D009581:Nitrofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D013185:Squalene / Q000378:metabolism*; D050603:Squalene Monooxygenase / Q000378:metabolism; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D009581:Nitrofurans; D013876:Thiophenes; D014344:Trypanocidal Agents; D013185:Squalene; D050603:Squalene Monooxygenase