title: Design, synthesis and cruzain docking of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents.
abstract: Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target, since inhibitors of this protease affect the pathology appropriately. By exploring the N-acylhydrazones (NAH) as privileged structures usually present in antiparasitic agents, we investigated a library of 16 NAH bearing the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold (NAH 3a-h, 4a-h). The in vitro bioactivity against epimastigote and trypomastigote forms of T. cruzi was evaluated, and some NAH under study exhibited antitrypanosomal activity at concentrations that are not toxic to mammalian cells. The series of compounds based on the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold revealed the remarkable importance of each substituent at the phenyl's 4-position for the inhibitory activity. Non-nitrated compounds 3a and 4e were found to be as potent as the reference drug, Benznidazole. In addition, the molecular origin of the antitrypanosomal properties for these series was investigated using docking studies of the TCC structure.
authors.affiliation: Departamento de Engenharia Química, Centro de Tecnologia e Geociências, Universidade Federal de Pernambuco, Rua Prof. Artur Sá S/N, Cidade Universitária, 50740-521 Recife, PE, Brazil. mauricio_santosfilho@yahoo.com.br
authors.forename: José Mauricio
authors.initials: JM
authors.lastname: dos Santos Filho
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
authors.forename: Boaz Galdino
authors.initials: BG
authors.lastname: de Oliveira
authors.forename: Diogo Rodrigo Magalhães
authors.initials: DR
authors.lastname: Moreira
authors.forename: Milena S
authors.initials: MS
authors.lastname: Lima
authors.forename: Milena Botelho Pereira
authors.initials: MB
authors.lastname: Soares
authors.forename: Lucia Fernanda C C
authors.initials: LF
authors.lastname: Leite
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D014355:Chagas Disease / Q000188:drug therapy*; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006835:Hydrazones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010069:Oxadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D021261:Parasitic Sensitivity Tests; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D013154:Spleen / Q000166:cytology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism
chemical_list: D006835:Hydrazones; D010069:Oxadiazoles; D015800:Protozoan Proteins; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C074032:cruzain, Trypanosoma cruzi