title: Heteroallyl-containing 5-nitrofuranes as new anti-Trypanosoma cruzi agents with a dual mechanism of action.
abstract: New heteroallyl-containing 5-nitrofuranes were synthesized as potential anti-Trypanosoma cruzi agents with a dual mechanism of action, oxidative stress and inhibition of membrane sterol biosynthesis. Some of the derivatives were found to have high and selective activity against the proliferative stages of the parasite, with IC(50) values against the clinically relevant intracellular amastigote forms in the low micromolar to sub-micromolar range. Oxidative stress was verified measuring cyanide dependent respiration. Inhibition of the de novo sterol biosynthesis at the level of squalene epoxidase was confirmed, using high-resolution gas-liquid chromatography coupled to mass spectrometry, by the disappearance of the parasite's mature sterols and the concomitant accumulation of squalene. The in vitro activities of these novel compounds were superior to that of nifurtimox, a nitrofuran currently used in the treatment of human Chagas' disease, and terbinafine, a commercially available allylamine-based squalene epoxidase inhibitor. The results support further in vivo studies of some of these nitrofuran derivatives.
authors.affiliation: Laboratorio de Química Orgánica, Facultad de Química/Facultad de Ciencias, Iguá 4225, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gerpe
authors.forename: Imeria
authors.initials: I
authors.lastname: Odreman-Nuñez
authors.forename: Patricia
authors.initials: P
authors.lastname: Draper
authors.forename: Lucía
authors.initials: L
authors.lastname: Boiani
authors.forename: Julio A
authors.initials: JA
authors.lastname: Urbina
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D020128:Inhibitory Concentration 50; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D018384:Oxidative Stress; D013185:Squalene / Q000032:analysis; D050603:Squalene Monooxygenase / Q000037:antagonists & inhibitors; D013261:Sterols / Q000032:analysis / Q000096:biosynthesis; D053719:Tandem Mass Spectrometry; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D009581:Nitrofurans; D013261:Sterols; D013185:Squalene; D050603:Squalene Monooxygenase