A Predictive Model for Thiol Reactivity of N-Heteroaryl α-Methylene-γ-Lactams─A Medicinally Relevant Covalent Reactive Group.

Herein, we present a systematic study on the effects of electronically diverse heteroarenes on the rate of glutathione (GSH) addition to novel N-heteroaryl α-methylene-γ-lactam covalent reactive groups (CRGs). Despite their unique electronic and drug-like properties, heteroarenes have not been extensively studied as handles for systematically tuning the reactivity of CRGs. Informed by mechanistic insights, we evaluated 16 substrate parameters, including a new heteroaryl Hammett-type substituent constant (σ(Het)), for their correlation with experimental reactivity (ΔG(‡)(exp)) as determined by (1)H NMR kinetic studies. Of these parameters, electron affinity represents a robust single-parameter predictive model of CRG reactivity with thiols, as demonstrated by test sets of additional N-heteroaryl lactams (MUE = 0.4 kcal/mol) and other α,β-unsaturated amide CRGs (MUE = 0.3 kcal/mol). These N-heteroaryl lactams were subsequently shown to inhibit cysteine protease activity (i.e., papain enzyme) to varying degrees that correlate with both the experimentally observed and predicted reactivity with GSH.