Systematic Study of the Glutathione (GSH) Reactivity of N-Arylacrylamides: 1. Effects of Aryl Substitution

Success in the design of targeted covalent inhibitors depends in part on a knowledge of the factors influencing electrophile reactivity. In an effort to further develop an understanding of structure–reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction ratesfor a family of N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common to inhibitor design. We find that substituent effects on reaction ratesshow a linear Hammett correlation for ortho-, meta-, and para-substitution. In addition, we note a correlation between 1H and 13C NMR chemical shiftsof the acrylamidewith GSH reaction rates, suggesting that NMR chemical shiftsmay be a convenient surrogate measure of relative acrylamidereactivity. Density functional theory calculations reveal a correlation between computed activation parameters and experimentally determined reaction rates, validating the use of such methodology for the screening of synthetic candid...