Thiol-Michael addition reaction (TMA)

Thiol-Michael chemistry refers to a versatile class of chemical reactions involving the nucleophilic addition of a thiol to an electron-deficient alkene, typically an alpha, beta-unsaturated carbonyl compound. While not a biological target itself (such as a receptor or enzyme), this reaction mechanism is a cornerstone of drug discovery and bioconjugation, particularly in the design of covalent inhibitors (Nair et al., 2014). In a therapeutic context, drug molecules are engineered with 'Michael acceptor' warheads to form irreversible covalent bonds with specific nucleophilic cysteine residues on a target protein, such as Bruton's tyrosine kinase (BTK) or the epidermal growth factor receptor (EGFR) (Ghosh et al., 2019). This approach allows for high potency and a prolonged duration of action that is independent of the drug's systemic half-life. Beyond small molecules, thiol-Michael addition is widely utilized in biotech for the synthesis of site-specific antibody-drug conjugates (ADCs) and the formation of biocompatible hydrogels for controlled drug delivery (Mather et al., 2006). However, the reactivity of these motifs must be carefully tuned to avoid excessive off-target interactions with abundant cellular thiols like glutathione, which can lead to toxicity (Nair et al., 2014).

Other names

Thiol-Michael reactionMichael addition of thiolsSulfhydryl-Michael additionThiol-ene Michael addition

The reaction involves the nucleophilic attack of a thiolate anion on the beta-carbon of an electron-deficient alkene (Michael acceptor), resulting in the formation of a stable carbon-sulfur (thioether) covalent bond.