Bioorganic and Medicinal Chemistry (2019)
Update date:2022-09-26
Topics:
Gomes, Juliana C.
Cianni, Lorenzo
Ribeiro, Jean
dos Reis Rocho, Fernanda
da Costa Martins Silva, Samelyn
Batista, Pedro Henrique Jatai
Moraes, Carolina Borsoi
Franco, Caio Haddad
Freitas-Junior, Lucio H.G.
Kenny, Peter W.
Leit?o, Andrei
Burtoloso, Antonio C.B.
de Vita, Daniela
Montanari, Carlos A.
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.
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