First enzymatic hydrolysis/thio-Michael addition cascade route to synthesis of AChE inhibitors.

The irreversible Michael addition of thiols to acrylamides is reported as a new tool for the kinetic target-guided synthesis. In an unprecedented enzymatic hydrolysis/thio-Michael addition procedure, potent and selective acetylcholinesterase inhibitors are assembled by the enzyme using both its esterasic and templating ability.