title: Structural investigation of anti-Trypanosoma cruzi 2-iminothiazolidin-4-ones allows the identification of agents with efficacy in infected mice.
abstract: We modified the thiazolidinic ring at positions N3, C4, and C5, yielding compounds 6-24. Compounds with a phenyl at position N3, 15-19, 22-24, exhibited better inhibitory properties for cruzain and against the parasite than 2-iminothiazolidin-4-one 5. We were able to identify one high-efficacy trypanocidal compound, 2-minothiazolidin-4-one 18, which inhibited the activity of cruzain and the proliferation of epimastigotes and was cidal for trypomastigotes but was not toxic for splenocytes. Having located some of the structural determinants of the trypanocidal properties, we subsequently wished to determine if the exchange of the thiazolidine for a thiazole ring leaves the functional properties unaffected. We therefore tested thiazoles 26-45 and observed that they did not inhibit cruzain, but they exhibited trypanocidal effects. Parasite development was severely impaired when treated with 18, thus reinforcing the notion that this class of heterocycles can lead to useful cidal agents for Chagas disease.
authors.affiliation: Departamento de Química Fundamental, Centro de Ciências Exatas and da Natureza, Universidade Federal de Pernambuco, 50670-901, Recife, PE, Brazil. diogollucio@gmail.com
authors.forename: Diogo Rodrigo Magalhaes
authors.initials: DR
authors.lastname: Moreira
authors.forename: Salvana Priscylla Manso
authors.initials: SP
authors.lastname: Costa
authors.forename: Marcelo Zaldini
authors.initials: MZ
authors.lastname: Hernandes
authors.forename: Marcelo Montenegro
authors.initials: MM
authors.lastname: Rabello
authors.forename: Gevanio Bezerra
authors.initials: GB
authors.lastname: de Oliveira Filho
authors.forename: Cristiane Moutinho Lagos
authors.initials: CM
authors.lastname: de Melo
authors.forename: Lucas Ferreira
authors.initials: LF
authors.lastname: da Rocha
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: de Simone
authors.forename: Rafaela Salgado
authors.initials: RS
authors.lastname: Ferreira
authors.forename: Jordana Rodrigues Barbosa
authors.initials: JR
authors.lastname: Fradico
authors.forename: Cássio Santana
authors.initials: CS
authors.lastname: Meira
authors.forename: Elisalva Teixeira
authors.initials: ET
authors.lastname: Guimarães
authors.forename: Rajendra Mohan
authors.initials: RM
authors.lastname: Srivastava
authors.forename: Valéria Rêgo Alves
authors.initials: VR
authors.lastname: Pereira
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D003198:Computer Simulation; D003546:Cysteine Endopeptidases / Q000378:metabolism; D005260:Female; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011485:Protein Binding; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007097:Imines; D015800:Protozoan Proteins; D053778:Thiazolidines; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi