Naslov
Cinchonines and cinchonidines as selective human butyrylcholinesterase inhibitors

Autori
Bosak, Anita ; Ramić, Alma ; Šmidlehner, Tamara ; Kovarik, Zrinka ; Primožič, Ines

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference, Elche, Španjolska, Program / - , 2015, 95-96

Skup
12th International Meeting on Cholinesterases and 6th Paraoxonase Conference

Mjesto i datum
Elche, Španjolska, 27.09.2015. - 02.10.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
human cholinesterases ; stereoselectivity ; selectivity

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

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