Novel trypanocidal thiophen-chalcone cruzain inhibitors: structure- and ligand-based studies

Author(s):Show less -

de Oliveira, Aldo S. ; Valli, Marilia ; Ferreira, Leonardo L. G. ; Souza, Julia M. ; Krogh, Renata ; Meier, Lidiane ; Abreu, Heitor R. ; Voltolini, Bruna G. ; Llanes, Luana C. ; Nunes, Ricardo J. ; Braga, Antonio L. ; Andricopulo, Adriano D.

• Document type: Journal article
• Source: Future Medicinal Chemistry; v. 14, n. 11, p. 14-pg., 2022-05-11.

Abstract

Background: Chagas disease is a neglected tropical disease that affects millions of people worldwide and for which no effective treatment is available. Materials & methods: 17 chalcones were synthesized, for which the inhibition of cruzain and trypanocidal activity were investigated. Results: Chalcone C8 showed the highest cruzain inhibitory (IC50 = 0.536 mu M) and trypanocidal activity (IC50 = 0.990 mu M). Molecular docking studies showed interactions involving Asp161 and the thiophen group interacting with the S2 subsite. Furthermore, quantitative structure-activity relationship (q(2) = 0.786; r(2) = 0.953) and density functional theory studies were carried out, and a correlation between the lowest unoccupied molecular orbital surface and trypanocidal activity was observed. Conclusion: These results demonstrate that these chalcones are worthwhile hits to be further optimized in Chagas disease drug discovery programs. (AU)

• FAPESP's process: 13/07600-3 - CIBFar - Center for Innovation in Biodiversity and Drug Discovery
• Grantee: Glaucius Oliva
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/06392-3 - Cu(II)/Co(III), Cu(II)/Fe(III) and Cu(II)/Ni(II) bimetallic complexes containing Schiff bases: potential catalyzers on the oxidation of catechols
• Grantee: Edward Ralph Dockal
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/05967-3 - Understanding the biological function of Natural Products' scaffolds from Databases for the design of active compounds for the treatment of infectious diseases
• Grantee: Marilia Valli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral