1. Synthesis and structure–activity relationship study of a new series of antiparasitic aryloxyl thiosemicarbazones inhibiting Trypanosoma cruzi cruzain
- Author
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Ana Cristina Lima Leite, Rafaela Salgado Ferreira, José Wanderlan Pontes Espíndola, Dayane Albuquerque Oliveira e Silva, Valéria Rêgo Alves Pereira, Carlos A. de Simone, Maria Carolina Accioly Brelaz de Castro, Tanira Matutino Bastos, Diogo Rodrigo Magalhães Moreira, Marcos Veríssimo de Oliveira Cardoso, Policarpo Ademar Sales Junior, Gevanio Bezerra de Oliveira Filho, Alvaro J. Romanha, Milena Botelho Pereira Soares, Silvane M. F. Murta, and Filipe Silva Villela
- Subjects
Models, Molecular ,Thiosemicarbazones ,Chagas disease ,Stereochemistry ,Antiparasitic ,medicine.drug_class ,Trypanosoma cruzi ,medicine.medical_treatment ,Relationship analysis ,Protozoan Proteins ,Crystallography, X-Ray ,Structure-Activity Relationship ,chemistry.chemical_compound ,Parasitic Sensitivity Tests ,Drug Discovery ,medicine ,Structure–activity relationship ,Enzyme Inhibitors ,Semicarbazone ,Pharmacology ,Protease ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Chemistry ,Aryl ,Organic Chemistry ,General Medicine ,medicine.disease ,biology.organism_classification ,Trypanocidal Agents ,Cysteine Endopeptidases - Abstract
The discovery of new antiparasitic compounds against Trypanosoma cruzi, the etiological agent of Chagas disease, is necessary. Novel aryloxy/aryl thiosemicarbazone-based conformationally constrained analogs of thiosemicarbazones (1) and (2) were developed as potential inhibitors of the T. cruzi protease cruzain, using a rigidification strategy of the iminic bond of (1) and (2). A structure-activity relationship analysis was performed in substituents attached in both aryl and aryloxy rings. This study indicated that apolar substituents or halogen atom substitution at the aryl position improved cruzain inhibition and antiparasitic activity in comparison to unsubstituted thiosemicarbazone. Two of these compounds displayed potent inhibitory antiparasitic activity by inhibiting cruzain and consequently were able to reduce the parasite burden in infected cells and cause parasite cell death through necrosis. In conclusion, we demonstrated that conformational restriction is a valuable strategy in the development of antiparasitic thiosemicarbazones.
- Published
- 2015
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