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Title: Synthesis and properties of heterodimeric structures as potential inhibitors of cholinesterases

Abstract:

The dissertation presents current trends in searching for inhibitors of the cholinesterases including multi-target directed ligands as potential drugs for AD. Research concerned synthesis of heterodimeric compounds with acetylcholinesterease and/or butyrylcholinesterase inhibiton properties and inhibition of β-amyloid aggregation.Seven series of heterodimeric compounds were obtained with indole, phtalimide or tetrahydoisochinoline moiety connected byalkyl or p-ksylene linker with an amine. Chromatographic parameter of lipophilicity RM0 for each compound were determined by using reverse phase chromatography and also parameter log P was determined using calculation programs.Obtained compounds were tested for ability to inhibit cholinesterases in spectrophotometric assay Ellman test. All compounds inhibit AChE and 17 compounds were active against BuChE. The most active compound is 2-(7-(pirolidinoheptylo)isoindolino-1,3-dion hydrochloride 31a (IC50 = 0,27 µM) and is selective against AChE.Two series of compounds were tested against inhibiting β-amyloid aggregation.Compound 13a 2-(7-diethylo-aminoheptylo)isoindolino-1,3-dion hydrochloride has the best procent of inhibiting β-amyloid (39,4% in 80 µM), moreover has good activity an selectivity against AChe (IC50 = 0,43 µM). The results of molecular modeling studies indicate that the ability to interact in both the catalytic and peripheral binding site of the enzyme, which confirms the dual activity of the compound 13a.

Place of publishing:

Kraków

Level of degree:

2 - studia doktoranckie

Degree discipline:

farmacja

Degree grantor:

Uniwersytet Jagielloński. Collegium Medicum. Wydział Farmaceutyczny. Katedra Chemii Farmaceutycznej. Zakład Fizykochemicznej Analizy Leku.

Promoter:

Barbara Malawska

Date issued:

2014

Format:

application/pdf

Identifier:

oai:dl.cm-uj.krakow.pl:3909

Call number:

ZB-120653

ControlNumberVIRTUA:

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Language:

pol ; eng

Access rights:

tylko w bibliotece

Location of original object:

Biblioteka Medyczna Uniwersytetu Jagiellońskiego- Collegium Medicum

Object collections:

Last modified:

Jun 26, 2019

In our library since:

May 30, 2014

Number of object content hits:

29

Number of object content views in PDF format

29

All available object's versions:

http://dl.cm-uj.krakow.pl:8080/publication/3909

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ZB-120653 Jun 26, 2019
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