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Diaminomaleonitrile derivatives as new potential antichagasic compounds: a study of structure-activity relationships.
de Oliveira, Aldo S; S Mello, Lucas Dos; H Ogihara, Camila; H Döring, Thiago; L Palomino-Salcedo, David; Michelan-Duarte, Simone; Lg Ferreira, Leonardo; M Souza, Julia; Dávila-Rodríguez, María José; Cruz Júnior, José W da; R Dockal, Edward; D Andricopulo, Adriano.
Affiliation
  • de Oliveira AS; Federal University of Santa Catarina, Campus of Blumenau, Department of Exact Sciences & Education, Rua João Pessoa, 2750, Velha, Blumenau - SC, 89036-256, Brazil.
  • S Mello LD; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • H Ogihara C; Federal University of São Carlos - UFSCar, Department of Chemistry, Laboratory of Inorganic Synthesis, Catalysis & Kinetics, Rodovia Washington Luis s/n Km 235, São Carlos, SP, Brazil.
  • H Döring T; University of Campinas- UNICAMP, Chemistry institute, R. Josué de Castro, 126 - Cidade Universitária, Campinas, SP, Brazil.
  • L Palomino-Salcedo D; Federal University of Santa Catarina, Campus of Blumenau, Department of Exact Sciences & Education, Rua João Pessoa, 2750, Velha, Blumenau - SC, 89036-256, Brazil.
  • Michelan-Duarte S; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • Lg Ferreira L; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • M Souza J; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • Dávila-Rodríguez MJ; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • Cruz Júnior JWD; University of Sao Paulo, Laboratory of Medicinal & Computational Chemistry, Center for Research & Innovation in Biodiversity & Drug Discovery, Institute of Physics of São Carlos, Av. João Dagnone, 1100 - Santa Angelina, São Carlos, SP, 13563-120- Brazil.
  • R Dockal E; Federal University of Santa Catarina, Campus of Blumenau, Department of Exact Sciences & Education, Rua João Pessoa, 2750, Velha, Blumenau - SC, 89036-256, Brazil.
  • D Andricopulo A; Federal University of São Carlos - UFSCar, Department of Chemistry, Laboratory of Inorganic Synthesis, Catalysis & Kinetics, Rodovia Washington Luis s/n Km 235, São Carlos, SP, Brazil.
Future Med Chem ; 13(24): 2167-2183, 2021 12.
Article in En | MEDLINE | ID: mdl-34708659
ABSTRACT

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 (R2 = 0.844; Q2 = 0.719).

Conclusion:

These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.
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Full text: 1 Database: MEDLINE Main subject: Trypanocidal Agents / Trypanosoma cruzi / Chagas Disease / Diamines / Nitriles Type of study: Prognostic_studies Language: En Year: 2021 Type: Article
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Full text: 1 Database: MEDLINE Main subject: Trypanocidal Agents / Trypanosoma cruzi / Chagas Disease / Diamines / Nitriles Type of study: Prognostic_studies Language: En Year: 2021 Type: Article