Diaminomaleonitrile derivatives as new potential antichagasic compounds: a study of structure-activity relationships

Autor(es):Mostrar menos -

de Oliveira, Aldo S. ^{[1, 2]} ; Mello, Lucas dos S. ^[3] ; Ogihara, Camila H. ^[4] ; Doring, Thiago H. ^[1] ; Palomino-Salcedo, David L. ^[2] ; Michelan-Duarte, Simone ^[2] ; Ferreira, Leonardo L. G. ^[2] ; Souza, Julia M. ^[2] ; Davila-Rodriguez, Maria Jose ^[2] ; da Cruz Junior, Jose W. ^[1] ; Dockal, Edward R. ^[3] ; Andricopulo, Adriano D. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Fed Santa Catarina, Dept Exact Sci & Educ, Campus Blumenau, Rua Joao Pessoa 2750, BR-89036256 Blumenau - Brazil

^[2] Univ Sao Paulo, Ctr Res & Innovat Biodivers & Drug Discovery, Inst Phys Sao Carlos, Lab Med & Computat Chem, Av Joao Dagnone 1100, BR-13563120 Sao Carlos, SP - Brazil

^[3] Fed Univ Sao Carlos UFSCar, Dept Chem, Lab Inorgan Synth Catalysis & Kinet, Rodovia Washington Luis S-N Km 235, Sao Carlos, SP - Brazil

^[4] Univ Campinas UNICAMP, Chem Inst, R Josue de Castro 126, Cidade Univ, Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Future Medicinal Chemistry; v. 13, n. 24 OCT 2021.
• Citações Web of Science: 0

Resumo

Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods \& results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC50 = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R-2 = 0.844; Q(2) = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs. (AU)

• Processo FAPESP: 15/06392-3 - Complexos bimetálicos de Cu(II)/Co(III), Cu(II)/Fe(III) e Cu(II)/Ni(II) contendo Bases de Schiff: catalisadores potenciais na oxidação de catecóis
• Beneficiário: Edward Ralph Dockal
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs