Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.
Chem Biodivers
; 21(7): e202400557, 2024 Jul.
Article
en En
| MEDLINE
| ID: mdl-38701359
ABSTRACT
In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50 1.52±0.19â
µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56â
ng/g) after dosing 30â
min. Its half-life in the serum is 331â
min (5.52â
h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean 2.76) within 24â
hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Barrera Hematoencefálica
/
Inhibidores de la Colinesterasa
/
Cinamatos
Límite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Chem Biodivers
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China