Object

Title: Synthesis and properties of novel multifunctional ligands, inhibiting cholinesterases and Β-secretase as potential treatment of Alzheimer's disease

Abstract:

The aim of this thesis was to search for new, multifunctional ligands targeting two enzymatic systems: cholinesterases and β˗secretase, along with two processes: aggregation of neurotoxic β-amyloid and of tau proteins, both related to the underlying mechanisms of Alzheimer’s disease.We have designed compounds with a three-part molecular structure, consisting of pharmacophores which mediate activity towards selected biological targets. The first pharmacophore we have chosen was benzylamine, a fragment which appears in many inhibitors of cholinesterase, β˗secretase and β-amyloid aggregation. In the central part, which interacts with the catalytic dyad of β-secretase, we placed two alternative scaffolds: various heterocyclic amines and hydroxyalkylamine. As the terminal fragment we incorporated a phthalimide or a saccharine moiety, as well as various amines selected in virtual screening. All compounds were synthesized and subsequently evaluated for biological activity in an in vitro assay. Results confirmed their variable activity towards the presented biological targets. Based on these results, we performed structure-activity relationship analyses.Our work resulted in identification of compound 98 as a lead structure, which selectively inhibits butyrylcholinesterase activity (eqBuChE IC50 = 2.92 µM, hBuChE IC50 = 5.74 µM) in preference to acetylcholinesterase. Its activity profile also involves inhibition of disease-modifying targets and mechanisms: β-secretase (IC50 = 41.60 µM), aggregation of β-amyloid (IC50 = 3.09 µM) and aggregation of the tau protein (53.8% at 10 µM).

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmacja

Degree grantor:

Jagiellonian University. Medical College. Faculty of Pharmacy. Chair of Pharmaceutical Chemistry. Department of Physicochemical Drug Analysis.

Promoter:

Barbara Malawska ; Anna Więckowska

Date issued:

2018

Identifier:

oai:dl.cm-uj.krakow.pl:4299

Call number:

ZB-128496

ControlNumberVIRTUA:

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Access rights:

nieograniczony

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Object collections:

Last modified:

May 24, 2021

In our library since:

Jul 9, 2019

Number of object content hits:

54

All available object's versions:

http://dl.cm-uj.krakow.pl:8080/publication/4300

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ZB-128496 May 24, 2021
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