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

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Autor(es):
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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]
Número total de Autores: 14
Afiliação do(s) autor(es):
[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
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Fonte: Bioorganic & Medicinal Chemistry; v. 27, n. 22 NOV 15 2019.
Citações Web of Science: 0
Resumo

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)

Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
Beneficiário:Carlos Alberto Montanari
Modalidade de apoio: Auxílio à Pesquisa - Temático
Processo FAPESP: 16/07946-5 - Síntese e atividade tripanossomicida de potenciais inibidores covalentes reversíveis da enzima cruzaína
Beneficiário:Lorenzo Cianni
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto