Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement.
Basic Information
ID: ALA4304821
Journal: Bioorg Med Chem
Title: Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement.
Authors: Gomes JC, Cianni L, Ribeiro J, Dos Reis Rocho F, da Costa Martins Silva S, Batista PHJ, Moraes CB, Franco CH, Freitas-Junior LHG, Kenny PW, Leitão A, Burtoloso ACB, de Vita D, Montanari CA.
Abstract: 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.
CiteXplore: 31561938
DOI: 10.1016/j.bmc.2019.115083
Patent ID: ┄