Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

Autor: Shi Q; College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China., Yang ZY; College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China., Wang YH; College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China., Yi BX; Hunan Drug Inspection center, Changsha, 410001, China., Gao XH; College of Pharmacy, Changsha health Vocational College, Changsha, 410600, China., Ding YJ; College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China., Peng D; College of Pharmacy, Changsha health Vocational College, Changsha, 410600, China., Chen YL; Department of Pharmacy, Changsha Hospital of Traditional Chinese Medicine (Changsha Eighth Hospital), Changsha, 410199, China., Liu HR; College of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, China.
Jazyk: angličtina
Zdroj: Chemistry & biodiversity [Chem Biodivers] 2024 Jul; Vol. 21 (7), pp. e202400557. Date of Electronic Publication: 2024 Jun 08.
DOI: 10.1002/cbdv.202400557
Abstrakt: 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 (IC 50 : 1.52±0.19 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±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the C Brain /C Serum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 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.
(© 2024 Wiley-VHCA AG, Zurich, Switzerland.)
Databáze: MEDLINE
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