title: Naftifine-analogues as anti-Trypanosoma cruzi agents.
abstract: Chagas disease represents a relevant health problem in Central and South America. The first line of treatment is Nifurtimox and Benznidazole which have a great deal of disadvantages that demands the rapid generation of therapeutic alternatives. Based in our research on aza-thiaheterocycles as anti-Trypanosoma cruzi agents we identified pharmacophores that act through oxidative stress. Here, we describe the synthesis and the activity of new containing bioactive-heterocycles analogues of naftifine as potential T. cruzi membrane sterol biosynthesis inhibitors. Benzimidazole 1,3-dioxides (11 and 13) and quinoxaline 1,4-dioxides (22 and 23) displayed excellent parasite/mammal selectivity indexes. Analysis of the free sterols from parasite incubated with the compounds showed that any of them are able to accumulate squalene suggesting that in the anti-T. cruzi mechanism of action is not involved the inhibition of sterol biosynthesis. Some derivatives were also tested as antifungal agents. The results obtained in the present work open potential therapeutic possibilities of new compounds 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: Lucía
authors.initials: L
authors.lastname: Boiani
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: D000499:Allylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D005658:Fungi / Q000187:drug effects; D020128:Inhibitory Concentration 50; D051379:Mice; D008826:Microbial Sensitivity Tests; D013185:Squalene / Q000378:metabolism; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: D014344:Trypanocidal Agents; D000499:Allylamine; C029178:naftifine; D013185:Squalene