Publication Type:

Journal Article

Source:

Natural Product Communications, Natural Product Incorporation, Volume 9, Number 4, p.455-458 (2014)

URL:

https://www.scopus.com/inward/record.url?eid=2-s2.0-84898779080&partnerID=40&md5=dd5279660cddc195ef7882b0fb970597

Keywords:

10, 11 dibromo 10, 11 dihydrocinchonidine, alkaloid derivative, article, Butyrylcholinesterase, Cell Line, cell strain CACO 2, cell strain HepG2, chemical modification, cholinesterase, Cholinesterase Inhibitors, Cinchona, Cinchona alkaloid, Cinchona Alkaloids, cinchonidine, cinchonine, competitive inhibition, controlled study, cytotoxicity, drug selectivity, drug synthesis, enzyme inhibition, galantamine, human, human cell, Humans, hydroxyl group, IC 50, in vitro study, liver cell, molecular docking, Molecular Structure, nerve cell, o (trimethylsilyl)cinchonine, physostigmine, Plant Bark, Plant Stems, Structure-Activity Relationship, trimethylsilyl derivative, unclassified drug

Abstract:

Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10≡)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with Ki = 3.45±0.39 μM, and IC 50 BChE = 9.83±0.30 μM / human (h)BChE = 34.47±4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with Kiuc = 1.73±0.46 μM and Kic = 0.85±0.26 μM, and IC 50 BChE = 0.56±0.14 μM / hBChE = 0.24±0.04. In cytotoxicity experiments, ≥80% of the cells remained viable when exposed to concentrations of up to 80 μM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE.

Cite this Research Publication

D. Karlsson, Fallarero, A., Shinde, P., Anju, C. P., Busygin, I., Leino, R., Dr. Gopi Mohan C., and Vuorela, P., “Chemical modifications of cinchona alkaloids lead to enhanced inhibition of human butyrylcholinesterase”, Natural Product Communications, vol. 9, pp. 455-458, 2014.

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