|
Title
|
|
|
|
Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement
| |
|
Author
|
|
|
|
| |
|
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. |
| |
|
Language
|
|
|
|
English
| |
|
Source (journal)
|
|
|
|
Bioorganic and medicinal chemistry. - Oxford
| |
|
Publication
|
|
|
|
Oxford
:
2019
| |
|
ISSN
|
|
|
|
0968-0896
| |
|
DOI
|
|
|
|
10.1016/J.BMC.2019.115083
| |
|
Volume/pages
|
|
|
|
27
:22
(2019)
, 14 p.
| |
|
Article Reference
|
|
|
|
115083
| |
|
ISI
|
|
|
|
000491130200001
| |
|
Pubmed ID
|
|
|
|
31561938
| |
|
Medium
|
|
|
|
E-only publicatie
| |
|
Full text (Publisher's DOI)
|
|
|
|
| |
|