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

2019; Elsevier BV; Volume: 27; Issue: 22 Linguagem: Inglês

10.1016/j.bmc.2019.115083

1464-3391

Juliana C. Gomes, Lorenzo Cianni, Jean F. R. Ribeiro, Fernanda dos Reis Rocho, Samelyn da Costa Martins Silva, Pedro Henrique Jataí Batista, Carolina Borsoi Moraes, Caio Haddad Franco, Lúcio H. Freitas-Júnior, Peter W. Kenny, Andrei Leitão, Antonio C. B. Burtoloso, Daniela De Vita, Carlos A. Montanari,

HIV/AIDS drug development and treatment

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.