Cinchonines and cinchonidines as selective human butyrylcholinesterase inhibitors (CROSBI ID 628071)
Prilog sa skupa u zborniku | sažetak izlaganja sa skupa
Podaci o odgovornosti
Bosak, Anita ; Ramić, Alma ; Šmidlehner, Tamara ; Kovarik, Zrinka ; Primožič, Ines
engleski
Cinchonines and cinchonidines as selective human butyrylcholinesterase inhibitors
Quinine and quinidine derivatives have been identified as selective butyrylcholinesterase (BChE) inhibitors with respect to acetylcholinesterase (AChE). Regarding to importance of selective targeting BChE in treatment of AD with cholinesterase inhibitors, further investigation of these compounds might result in leads for the development of enhanced anti‐AD drugs. In this work we present the synthesis of ten quaternary derivatives of cinchonines and their corresponding pseudo‐ enantiomeric cinchonidines and interactions of prepared compounds with cholinesterases. Quaternization of quinuclidine moiety was carried out with groups diverse in their size: methyl and differently meta and para substituted benzyl groups. All tested compounds reversibly inhibited both cholinesterases. To define the inhibition potency of the compounds the dissociation constants of the enzyme−inhibitor complex (Ki) were determined. Compounds inhibited BChE with Ki constants in the range of 0.04‐30 μM, while AChE in the range of 2.5‐70 μM. Five cinchonidines displayed 95‐510 times higher inhibition selectivity to BChE compared to AChE. Four cinchonidines proved to be potent inhibitors of BChE with Ki constants up to 100 nM, while cinchonidines with methyl or nitro group in metaposition on benzene ring are the best AChE inhibitors with inhibition constants around 3 μM. Stereoselectivity of both enzymes was poor. Based on the results presented here, para‐ substituted quaternary cinchonidine derivatives could be considered for further investigations. Supported by HrZZ4307.
human cholinesterases ; stereoselectivity ; selectivity
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Podaci o prilogu
95-96.
2015.
objavljeno
Podaci o matičnoj publikaciji
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference, Elche, Španjolska, Program
Podaci o skupu
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference
poster
27.09.2015-02.10.2015
Elche, Španjolska