From tryptophan-based amides to tertiary amines: Optimization of a butyrylcholinesterase inhibitor series
A. Meden, Damijan Knez, Xavier Brazzolotto, Florian Nachon, José Dias, Jurij Svete, Jure Stojan, Uroš Grošelj, Stanislav Gobec
Abstract
-rich analogues with better synthetic accessibility and high selectivity over acetylcholinesterase (one to ten thousandfold). Taking it one step further, the introduction of a carbamate warhead on the well-explored reversible scaffold allowed conversion to pseudoirreversible inhibitors that bound covalently to BChE and prolonged the duration of inhibition (half-life of 14.8 h for compound 45a-carbamoylated enzyme). Additionally, N-hydroxyindole was discovered as a novel leaving group chemotype. The covalent mechanism of action was confirmed by time-dependency experiments, progress curve analysis, and indirectly by co-crystallization with the human recombinant enzyme. Two crystal structures of BChE-inhibitor complexes were solved and coupled with the supporting molecular dynamics simulations increased our understanding of the structure-activity relationship, while also providing the necessary structural information for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.