Expanding the Chemistry of Dihaloacetamides as Tunable Electrophiles for Reversible Covalent Targeting of Cysteines.

The choice of an appropriate electrophile is crucial in the design of targeted covalent inhibitors (TCIs). In this report, we systematically investigated the glutathione (GSH) reactivity of various haloacetamides and the aqueous stability of their thiol adducts. Our findings revealed that dihaloacetamides cover a broad range of GSH reactivity depending on the combination of the halogen atoms and the structure of the amine scaffold.

Selective covalent targeting of SARS-CoV-2 main protease by enantiopure chlorofluoroacetamide.

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The main protease (M) is a promising target for COVID-19 treatment. Here, we report an irreversible SARS-CoV-2 M inhibitor possessing chlorofluoroacetamide (CFA) as a warhead for the covalent modification of M.