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STUDIES TOWARD THE STRUCTURAL OPTIMIZATION OF NOVEL THIAZOLYLHYDRAZONE-BASED POTENT ANTITRYPANOSOMAL AGENTS
Hernandes, Marcelo Zaldini et al. | Date Issued: 2010
Author
Hernandes, Marcelo Zaldini
Rabello, Marcelo Montenegro
Leite, Ana Cristina Lima
Cardoso, Marcos Veríssimo Oliveira
Moreira, Diogo Rodrigo Magalhaes
Brondani, Dalci José
Simone, Carlos Alberto
Reis, Luiza Campos
Souza, Marina Assis
Pereira, Valéria Rego Alves
Ferreira, Rafaela Salgado
McKerrow, James Hobson
Affilliation
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
Federal University of Pernambuco. Centre for Health Science. Department of Pharmaceutical Sciences. Recife, PE, Brazil.
University of São Paulo. Institute of Physics. Department of Physics and Informatics. São Carlos, SP, Brazil.
Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Recife, PE, Brasil.
Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Recife, PE, Brasil.
Fundação Oswaldo Cruz. Instituto Aggeu Magalhães. Departamento de Imunologia. Recife, PE, Brasil.
University of California. Sandler Center for Drug Discovery in Parasitic Diseases. San Francisco, CA, USA.
University of California. Sandler Center for Drug Discovery in Parasitic Diseases. San Francisco, CA, USA.
Abstract
In previous studies, we identified promising anti-Trypanosoma cruzi cruzain inhibitors based on thiazolylhydrazones. To optimize this series, a number of medicinal chemistry directions were explored and new thiazolylhydrazones and thiosemicarbazones were thus synthesized. Potent cruzain inhibitors were identified, such as thiazolylhydrazones 3b and 3j, which exhibited IC(50) of 200-400nM. Furthermore, molecular docking studies showed concordance with experimentally derived structure-activity relationships (SAR) data. In the course of this work, lead compounds exhibiting in vitro activity against both the epimastigote and trypomastigote forms of T. cruzi were identified and in vivo general toxicity analysis was subsequently performed. Novel SAR were documented, including the importance of the thiocarbonyl carbon attached to the thiazolyl ring and the direct comparison between thiosemicarbazones and thiazolylhydrazones.
Keywords in Portuguese
Bioisosterismo
Cisteína protease cruzain
Hidrazonas
Ancoragem Molecular
Tiazoles
Tiossemicarbazonas
Trypanosoma cruzi
 
Keywords
Bioisosterism
Cysteine protease cruzain
Hydrazones
Molecular docking
Thiazoles
Thiosemicarbazones
Trypanosoma cruzi
 
DeCS
Animais
Encadernação
Células Cultivadas
Simulação de computador
Cisteína Proteases / química
Proteases de cisteína / metabolismo
Inibidores da Proteína Cisteína / síntese química
Inibidores da Proteína Cisteína / química
Inibidores da Proteína Cisteína / toxicidade
Fêmea
Hidrazonas / síntese química
Hidrazonas / química
Hidrazonas / toxicidade
Ratos
Estrutura proteica, terciária
Estereoisomerismo
Relação Estrutura-Atividade
Triazoles / química
Agentes Tripanocidas / síntese química
Agentes Tripanocidas / Química
Agentes Tripanocidas / toxicidade
Trypanosoma cruzi / efeitos de drogas
 
Publisher
Elsevier
Citation
HERNANDES, M. Z. et al. Studies toward the structural optimization of novel thiazolylhydrazone-based potent antitrypanosomal agents. Bioorganic & Medicinal Chemistry, v. 18, n. 22, p. 7826–7835, 15 nov. 2010.
DOI
10.1016/j.bmc.2010.09.056
ISSN
1464-3391