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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds

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Author(s):
Lameiro, Rafael da Fonseca [1] ; Shamim, Anwar [1] ; Rosini, Fabiana [1] ; Cendron, Rodrigo [1] ; Jatai Batista, Pedro Henrique [1] ; Montanari, Carlos Alberto [1]
Total Authors: 6
Affiliation:
[1] Univ Sao Paulo, Sao Carlos Inst Chem, Grp Quim Med & Biol IQSC USP, Sao Carlos, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Future Medicinal Chemistry; v. 13, n. 1, p. 25-44, JAN 2021.
Web of Science Citations: 0
Abstract

Aim: Compounds that block enzyme activity can kill pathogens and help develop effective and safe drugs for Chagas disease and leishmaniasis. Materials \& methods: A library of nonpeptidic nitrile-based compounds was synthesized and had their inhibitory affinity tested against cruzain, Leishmania mexicana cysteine protease B and cathepsin L. Isothermal titration calorimetry experiments and molecular simulations were performed for selected compounds to obtain thermodynamic fingerprints and identify main interactions and putative modes of binding with cruzain. Results: The derivatives provided increased affinity against all enzymes compared with the lead, and thermodynamic and computational studies showed improved thermodynamic properties and a possible different mode of binding. Conclusion: Our studies culminated in 1b, a compound 60-fold more potent in cruzain than its lead that also showed entropic and enthalpic contributions favorable to Gibbs binding energy. (AU)

FAPESP's process: 18/03279-0 - Anti-Trypanosoma cruzi activity of non-Peptidic agents as inhibitors of cysteine protease cruzain
Grantee:Rafael da Fonseca Lameiro
Support Opportunities: Scholarships in Brazil - Master
FAPESP's process: 18/03985-1 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme
Grantee:Anwar Shamim
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Projects - Thematic Grants