Načrtovanje, sinteza in vrednotenje novih N-benzilpiperidinov kot zaviralcev holin-esteraz

Sraka, Tina (author), Gobec, Stanislav (mentor), Košak, Urban (co-mentor)

Encim butirilholin-esteraza (BChE) postaja vse bolj pomembna tarča za lajšanje simptomov Alzheimerjeve bolezni. S selektivnim zaviranjem BChE lahko pomembno zvišamo koncentracijo acetilholina v možganih in tako vplivamo na potek bolezni. Na podlagi kemijske strukture spojine 2, ki je prvi nekovalentni selektivni zaviralec BChE s farmakološkim delovanjem in vivo, smo načrtovali in sintetizirali deset novih spojin z namenom poglobitve razumevanja odnosa med kemijsko strukturo in biološko učinkovitostjo. Sledilo je in vitro določanje jakosti zaviranja s pomočjo Ellmanove metode. Osem od desetih sintetiziranih spojin je bilo in vitro aktivnih, najmočnejši zaviralec BChE pa je bila spojina 10 (IC50 = 0,21 μM). V magistrski nalogi smo tako ugotovili, da je naftalen ključen za močnejše zaviranje BChE in obenem poglobili znanje o odnosu med strukturo in delovanjem selektivnih zaviralcev BChE.

• Language: Slovenian
• Keywords: butirilholin-esteraza, zaviralci butirilholin-esteraze, Alzheimerjeva bolezen, N-benzilpiperidini
• Work type: Master's thesis/paper
• Organization: FFA - Faculty of Pharmacy
• Year: 2022
• PID: 20.500.12556/RUL-135919
• Publication date in RUL: 01.04.2022

Secondary language

• Language: English
• Title: Design, synthesis and evaluation of novel N-benzylpiperidines as cholinesterase inhibitors

Abstract

Butyrylcholinesterase (BChE) is becoming an increasingly important drug target for alleviating the symptoms of Alzheimer's disease. Selective inhibition of BChE can successfully increase levels of acetylcholine in central nervous system and consequently improve the course of the disease. Based on the chemical structure of the compound 2, which is the first noncovalent selective BChE inhibitor with in vivo activity, we designed and synthesized ten new compounds to better understand the structure-activity relationship. Inhibitory potency was determined in vitro with the use of the method of Ellman. Eight out of ten synthesized compounds showed in vitro inhibitory activity against BChE. The most potent BChE inhibitor is compound 10 (IC50 = 0,21 μM). We determined that the naphthalene of compound 2 is essential for potent inhibition of BChE. At the same time, we were able to deepen the knowledge and further expand the structure-activity relationship of N-benzylpiperidines as selective BChE inhibitors.

• Keywords: butyrylcholinesterase, butryrylcholinesterase inhibitors, Alzheimer's disease, N-benzylpiperidines