A predictive model for thiol reactivity of N-heteroaryl α-methylene–γ-lactams—a medicinally relevant covalent reac-tive group

02 April 2025, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 (σHet), for their correlation with experimental reactivity (DG‡exp) as determined by 1H NMR kinetics 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 subse-quently 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.

Keywords

Covalent Inhibitor Design
Multivariate Linear Regression
Tunable
Thiol-Michael Addition
α-Methylene–γ-Lactam
Het-eroarenes
Covalent Reactive Group
Predictive Model
Density Functional Theory
Electron Affinity
Heteroaryl Hammett-type Substituent Constant
1H NMR Kinetics
Papain Inhibition

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