From tryptophan-based amides to tertiary amines : optimization of a butyrylcholinesterase inhibitor series

Meden, Anže (author), Knez, Damijan (author), Brazzolotto, Xavier (author), Nachon, Florian (author), Dias, Jose (author), Svete, Jurij (author), Stojan, Jure (author), Grošelj, Uroš (author), Gobec, Stanislav (author)

Lead optimization of a series of tryptophan-based nanomolar butyrylcholinesterase (BChE) inhibitors led to tertiary amines as highly potent, achiral, sp$^3$-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 neccessary structural infromation for future optimization of this series. Overall, this research demonstates the high versatility and potential of this series of BChE inhibitors.

• Language: English
• Keywords: cholinesterase inhibitors, Alzheimer's disease, butyrylcholinesterase, carbamate, pseudoirreversible inhibition
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy; FKKT - Faculty of Chemistry and Chemical Technology; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 39 str.
• Numbering: Vol. 234, art. 114248
• PID: 20.500.12556/RUL-140000
• UDC: 615.4:54:616.894
• ISSN on article: 0223-5234
• DOI: 10.1016/j.ejmech.2022.114248
• COBISS.SI-ID: 100613379
• Publication date in RUL: 09.09.2022

Record is a part of a journal

• Title: European journal of medicinal chemistry
• Shortened title: Eur. j. med. chem.
• Publisher: Elsevier
• ISSN: 0223-5234
• COBISS.SI-ID: 25429760

Licences

• License: CC BY-NC-ND 4.0, Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
• Link: http://creativecommons.org/licenses/by-nc-nd/4.0/
• Description: The most restrictive Creative Commons license. This only allows people to download and share the work for no commercial gain and for no other purposes.

Secondary language

• Language: Slovenian
• Keywords: zaviralci holinesteraze, butirilholinesteraza, karbamat, psevdoireverzibilna inhibicija, Alzheimerjeva bolezen, farmacevtska kemija