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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 and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement

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Gomes, Juliana C. [1] ; Cianni, Lorenzo [2] ; Ribeiro, Jean [2] ; Rocho, Fernanda dos Reis [2] ; Martins Silva, Samelyn da Costa [2] ; Jatai Batista, Pedro Henrique [2] ; Moraes, Carolina Borsoi [3] ; Franco, Caio Haddad [3] ; Freitas-Junior, Lucio H. G. [3] ; Kenny, Peter W. [2] ; Leitao, Andrei [2] ; Burtoloso, Antonio C. B. [1] ; de Vita, Daniela [2] ; Montanari, Carlos A. [2]
Total Authors: 14
[1] Univ Sao Paulo, Inst Quim Sao Carlos, Sao Carlos, SP - Brazil
[2] Univ Sao Paulo, IQSC, Grp Quim Med, Sao Carlos, SP - Brazil
[3] Univ Sao Paulo, Inst Ciencias Biomed, Dept Microbiol, Sao Paulo - Brazil
Total Affiliations: 3
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 27, n. 22 NOV 15 2019.
Web of Science Citations: 0

The structure-activity relationship for nitrile-based cruzain inhibitors incorporating a P2 amide replacement based on trifluoroethylamine was explored by deconstruction of a published series of inhibitors. It was demonstrated that the P3 biphenyl substituent present in the published inhibitor structures could be truncated to phenyl with only a small loss of affinity. The effects of inverting the configuration of the P2 amide replacement and linking a benzyl substituent at P1 were observed to be strongly nonadditive. We show that plotting affinity against molecular size provides a means to visualize both the molecular size efficiency of structural transformations and the nonadditivity in the structure-activity relationship. We also show how the relationship between affinity and lipophilicity, measured by high-performance liquid chromatography with an immobilized artificial membrane stationary phase, may be used to normalize affinity with respect to lipophilicity. (AU)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support type: Research Projects - Thematic Grants
FAPESP's process: 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme
Grantee:Lorenzo Cianni
Support type: Scholarships in Brazil - Doctorate (Direct)