Design, synthesis and cruzain docking of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents
| Autor: | Ana Cristina Lima Leite, Lúcia Fernanda C. da Costa Leite, Milena S. Lima, Diogo Rodrigo Magalhães Moreira, Milena Botelho Pereira Soares, Boaz G. Oliveira, José Maurício dos Santos Filho |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Cell Survival Stereochemistry Trypanosoma cruzi medicine.medical_treatment Clinical Biochemistry Protozoan Proteins Pharmaceutical Science Biochemistry Chemical synthesis Mice Structure-Activity Relationship Parasitic Sensitivity Tests Drug Discovery medicine Animals Structure–activity relationship Chagas Disease Molecular Biology Mice Inbred BALB C Oxadiazoles Protease biology Chemistry Organic Chemistry Hydrazones biology.organism_classification Trypanocidal Agents Antiparasitic agent Cysteine protease Cysteine Endopeptidases Docking (molecular) Benznidazole Molecular Medicine Spleen Protein Binding medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 17:6682-6691 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2009.07.068 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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