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From tryptophan-based amides to tertiary amines : optimization of a butyrylcholinesterase inhibitor series
ID
Meden, Anže
(
Author
),
ID
Knez, Damijan
(
Author
),
ID
Brazzolotto, Xavier
(
Author
),
ID
Nachon, Florian
(
Author
),
ID
Dias, Jose
(
Author
),
ID
Svete, Jurij
(
Author
),
ID
Stojan, Jure
(
Author
),
ID
Grošelj, Uroš
(
Author
),
ID
Gobec, Stanislav
(
Author
)
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MD5: F0C505D447C6B4AFA34CF53A546EC73A
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https://www.sciencedirect.com/science/article/pii/S0223523422001507
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Abstract
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
Views:
978
Downloads:
105
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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
Projects
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0208
Name:
Farmacevtska kemija: načrtovanje, sinteza in vrednotenje učinkovin
Funder:
ARRS - Slovenian Research Agency
Project number:
P1-0179
Name:
Napredna organska sinteza in kataliza
Funder:
ARRS - Slovenian Research Agency
Funding programme:
Young Researchers
Funder:
Other - Other funder or multiple funders
Funding programme:
France, Ministry of Armed Forces
Project number:
NBC-5-C-4210
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