title: Development of bis-thiazoles as inhibitors of triosephosphate isomerase from Trypanosoma cruzi. Identification of new non-mutagenic agents that are active in vivo.
abstract: The neglected disease American trypanosomiasis is one of the major health problems in Latin America. Triosephosphate isomerase from Trypanosoma cruzi (TcTIM), the etiologic agent of this disease, has been proposed as a druggable target. Some bis-benzothiazoles have been described as irreversible inhibitors of this enzyme. On the other hand, new bioactive furane-containing thiazoles have been described as excellent in vivo anti-T. cruzi agents. This encouraged us to design and develop new bis-thiazoles with potential use as drugs for American trypanosomiasis. The bis-thiazol 5, 3,3'-allyl-2,2'-bis[3-(2-furyl)-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, showed the best in vitro anti-T. cruzi profile with a higher selectivity index than the reference drugs Nifurtimox and Benznidazole against amastigote form of the parasite. This derivative displayed marginal activity against TcTIM however the bis-thiazol 14, 3-allyl-2-[3-(2-furyl)-2-propenylidenehydrazono]-3'-phenyl-2'-(3-phenyl-2-propenylidenehydrazono]-2,2',3,3'-tetrahydro-4,4'-bisthiazole, was an excellent inhibitor of the enzyme of the parasite. The absence of both in vitro mutagenic and in vivo toxicity effects, together with the activity of bis-thiazol 5in vivo, suggests that this compound is a promising anti-T. cruzi agent surpassing the "hit-to-lead" stage in the drug development process.
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Guzmán
authors.initials: G
authors.lastname: Álvarez
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Jennyfer
authors.initials: J
authors.lastname: Martínez
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Javier
authors.initials: J
authors.lastname: Varela
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Estefania
authors.initials: E
authors.lastname: Birriel
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cruces
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay.
authors.forename: Martín
authors.initials: M
authors.lastname: Gabay
authors.affiliation: Centro de Investigaciones de Enfermedades Tropicales, Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Centro de Investigaciones de Enfermedades Tropicales, Departamento de Ciencias Básicas, Universidad Industrial de Santander, Bucaramanga, Colombia.
authors.forename: Patricia
authors.initials: P
authors.lastname: Escobar
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aguirre-López
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Nallely
authors.initials: N
authors.lastname: Cabrera
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Marietta
authors.initials: M
authors.lastname: Tuena de Gómez-Puyou
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Armando
authors.initials: A
authors.lastname: Gómez Puyou
authors.affiliation: Departamento de Bioquímica y Biología Estructural, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
authors.forename: Ruy
authors.initials: R
authors.lastname: Pérez-Montfort
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Gloria
authors.initials: G
authors.lastname: Yaluff
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Susana
authors.initials: S
authors.lastname: Torres
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Elva
authors.initials: E
authors.lastname: Serna
authors.affiliation: Departamento de Medicina Tropical, Instituto de Investigaciones en Ciencias de la Salud, Universidad Nacional de Asunción, Paraguay.
authors.forename: Ninfa
authors.initials: N
authors.lastname: Vera de Bilbao
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay. Electronic address: megonzal@fq.edu.uy.
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.affiliation: Grupo de Química Medicinal, Laboratorio de Química Orgánica, Facultad de Ciencias, Universidad de la República, 11400 Montevideo, Uruguay; Área de Radiofarmacia, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay. Electronic address: hcerecet@cin.edu.uy.
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
mesh_terms: D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008264:Macrophages; D051379:Mice; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D013844:Thiazoles; D014344:Trypanocidal Agents; D014305:Triose-Phosphate Isomerase
keywords: Anti-T. cruzi; Bis-thiazoles; Triosephosphate isomerase