title: Design, synthesis and biological evaluation of new potent 5-nitrofuryl derivatives as anti-Trypanosoma cruzi agents. Studies of trypanothione binding site of trypanothione reductase as target for rational design.
abstract: Design, using force-field calculations on the catalytic site of trypanothione reductase from Trypanosoma cruzi, has led to the development of new 5-nitrofuryl derivatives as potential anti-trypanosomal agents. The synthesized compounds were tested in vitro against T. cruzi and more than 75% of the prepared derivatives showed higher activity than nifurtimox. Compounds 5 and 11, hexyl 4-(5-nitrofurfurylidene)carbazate and N-hexyl 3-(5-nitrofuryl)propenamide, showed the highest in vitro trypanocidal effect reported to date for members of the nitrofuran family. Partition coefficients and energies for the single-electron reduction of compounds were theoretically determined. These properties could be not the major cause of the activities' differences. The physicochemical environment around E19, W22, C53 and Y111 residues within the trypanothione binding site of trypanothione reductase resulted a valuable target for the rational design of anti-trypanosomal drugs.
authors.affiliation: Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Iguá 4225, 11400 Montevideo, Uruguay.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Aguirre
authors.forename: Eliana
authors.initials: E
authors.lastname: Cabrera
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Rossanna
authors.initials: R
authors.lastname: Di Maio
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Gustavo
authors.initials: G
authors.lastname: Seoane
authors.forename: Adelina
authors.initials: A
authors.lastname: Duffaut
authors.forename: Ana
authors.initials: A
authors.lastname: Denicola
authors.forename: María J
authors.initials: MJ
authors.lastname: Gil
authors.forename: Victor
authors.initials: V
authors.lastname: Martínez-Merino
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009581:Nitrofurans / Q000138:chemical synthesis* / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D013095:Spermidine / Q000031:analogs & derivatives* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D009581:Nitrofurans; D014344:Trypanocidal Agents; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005978:Glutathione; D013095:Spermidine