Sinteza i biološka evaluacija heterocikličkih karbamata kao inhibitora humanih kolinesteraza

master's thesis

• Title (english): Synthesis and biological evaluation of heterocyclic carbamates as human cholinesterases inhibitors
• Author: Aleksandrina Vodolšak
• Mentor: Anita Bosak (mentor)
• Committee member: Iva Juranović Cindrić (predsjednik povjerenstva)
• Committee member: Ines Primožič (član povjerenstva)
• Committee member: Jana Pisk (član povjerenstva)
• Committee member: Adriana Kenđel (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Chemistry); Zagreb
• Defense date and country: 2023-10-18, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Chemistry

Abstract

Acetilkolinesteraza (AChE) i butirilkolinesteraza (BChE) su enzimi koji u ljudskom organizmu
hidroliziraju acetilkolin te se stoga istražuju kao terapijska meta u tretmanu
neurodegenerativnih bolesti povezanih s promjenom u koncentraciji tog prijenosnika živčanih
impulsa, naročito Alzheimerovom bolešću. U okviru ovog diplomskog rada sintetizirano je
osam karbamata s piperidinskim ili pirolidinskim supstituentom na dušiku karbamatne skupine.
Struktura spojeva potvrđena je snimanjem spektara 1H i 13C NMR. Za četiri karbamata čija je
čistoća bila veća od 85% određena je sposobnost inhibicije AChE i BChE te je in silico
procijenjena sposobnost prolaska kroz krvno-moždanu barijeru. Svi spojevi pokazali su se
brzim ili jako brzim inhibitorima obiju kolinesteraza s konstantama brzine inhibicije u rasponu
od 103 - 106 mol-1 dm3 min-1 Najbržim inhibitorima AChE pokazali su se spojevi 8 i 5,
piperidinski karbamati s feniletilnim, odnosno piperidinskim, supstituentom na 1-hidroksi-2-
aminoetilnom lancu, redom, dok su najbrži inhibitori BChE bili spojevi 3 (pirolidinski
piperidinski monokarbamat s cikličkim pirolidinskim supstituentom na 1-hidroksi-2-
aminoetilnom lancu na dušiku karbamatne skupine) i 5. Svi ispitivani karbamati pokazali su se
selektivnim inhibitorima BChE u odnosu na AChE. Za ispitivane karbamate je procijenjeno da
mogu proći kroz krvno-moždanu barijeru.

Abstract (english)

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that, in humans,
are responsible for the hydrolysis of acetylcholine and are therefore investigated as therapeutic
targets in the treatment of neurodegenerative diseases associated with a change in the
concentration of that neurotransmitter, especially Alzheimer's disease. In this study, eight
carbamates with piperidine and pyrrolidine substituents on the nitrogen of the carbamate group
were synthesized. The structure of the compounds was characterized by 1H and 13C NMR
spectra. For four carbamates whose purity was higher than 85% the ability to inhibit AChE and
BChE was determined, and ability to pass the blood-brain barrier evaluated in silico. All
compounds proved to be fast or very fast inhibitors of both cholinesterases with inhibition rate
constants in the range of 103 -106 mol-1 dm3 min-1. The fastest AChE inhibitors were compounds
8 and 5, piperidine carbamates with a phenylethyl or piperidine substituent at 1- hydroxy-2-
aminoethyl chain, respectively, while the fastest BChE inhibitors were compounds 3
(pyrrolidine piperidine monocarbamate with a cyclic pyrrolidine substituent on the 1-hydroxy-
2-aminoethyl chain nitrogen of the carbamate group) and 5. All of the tested carbamates were
selective inhibitors of BChE compared to AChE. For the tested carbamates, it was estimated
that they can pass through the blood-brain barrier.

• Keywords: karbamati; kolinesteraze; brzina inhibicije; Alzheimerova bolest
• Keywords (english): Alzheimer's disease; cholinesterase; inhibition rate; monocarbamates
• Language: croatian
• URN:NBN: urn:nbn:hr:217:338165
• Project: Number: IP-2020-02-9343; Title: Razvoj bioaktivnih molekula za tretman neurodegenerativnih bolesti; Title: Development of Bioactive Molecules for Neurodegenerative Diseases Treatment; Acronym: BioMol4ND; Leader: Dejan Opsenica; Jurisdiction: Croatia; Funder: HRZZ; Funding stream: IP
• Study programme: Title: Graduate university studies in chemistry; specializations in: Research programme; Course: Research programme; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra kemije (magistar/magistra kemije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-10-18
• Created on: 2023-10-20 09:04:11