Adapting the plant defense systems’ toolbox of Michael acceptors to electrophilic drug development

Plant metabolites are an invaluable source of bioactive molecules, and a high percentage of them can react covalently with their targets. Lipid-derived α,β-unsaturated systems (Michael acceptors), which are present in all plants, regulate signaling pathways in cells. In addition, they potentially represent novel molecular targets and mechanisms of action in drug development. The irreversible covalent binding of the majority of these electrophilic molecules to their corresponding molecular targets, combined with, in certain cases, unfavorable pharmacokinetic properties, i.e., absorption, distribution, metabolism, and excretion (ADME), has shifted their use predominantly to that of molecular probes for target identification. In this review, we present examples of structural modification of the original naturally occurring Michael acceptor-containing compounds, as well as examples of incorporating naturally occurring functionalities in the design of reversible covalent probes and drug candidates in order to improve ADME and increase target selectivity.