Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties

2015
journal article
article
68
dc.abstract.enThe presented study describes the synthesis, pharmacological evaluation (AChE and BuChE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 μM). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 μM) possesses additional properties, such as the ability to inhibit Aβ aggregation (65.96% at 10 μM) and a neuroprotective effect against Aβ toxicity at 1 and 3 μM. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders.pl
dc.affiliationWydział Farmaceutyczny : Zakład Fizykochemicznej Analizy Lekupl
dc.affiliationWydział Chemii : Zakład Krystalochemii i Krystalofizykipl
dc.cm.id70304
dc.contributor.authorSzałaj, Natalia - 140437 pl
dc.contributor.authorBajda, Marek - 165281 pl
dc.contributor.authorSkrok, Mirosławpl
dc.contributor.authorKurpiewska, Katarzyna - 142859 pl
dc.contributor.authorLewiński, Krzysztof - 129948 pl
dc.contributor.authorBrus, Borispl
dc.contributor.authorPišlar, Anjapl
dc.contributor.authorKos, Jankopl
dc.contributor.authorGobec, Stanislavpl
dc.contributor.authorMalawska, Barbara - 130819 pl
dc.date.accessioned2015-07-02T10:15:22Z
dc.date.available2015-07-02T10:15:22Z
dc.date.issued2015pl
dc.description.additionalNa publikacji autorka Szałaj Natalia podpisana jako Guzior Natalia.pl
dc.description.physical738-749pl
dc.description.volume92pl
dc.identifier.doi10.1016/j.ejmech.2015.01.027pl
dc.identifier.eissn1768-3254pl
dc.identifier.issn0223-5234pl
dc.identifier.urihttp://ruj.uj.edu.pl/xmlui/handle/item/11196
dc.languageengpl
dc.language.containerengpl
dc.rights.licenceBez licencji otwartego dostępu
dc.subtypeArticlepl
dc.titleDevelopment of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective propertiespl
dc.title.journalEuropean Journal of Medicinal Chemistrypl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
The presented study describes the synthesis, pharmacological evaluation (AChE and BuChE inhibition, beta amyloid anti-aggregation effect and neuroprotective effect), molecular modeling and crystallographic studies of a novel series of isoindoline-1,3-dione derivatives. The target compounds were designed as dual binding site acetylcholinesterase inhibitors with an arylalkylamine moiety binding at the catalytic site of the enzyme and connected via an alkyl chain to a heterocyclic fragment, capable of binding at the peripheral anionic site of AChE. Among these molecules, compound 15b was found to be the most potent and selective AChE inhibitor (IC50EeAChE = 0.034 μM). Moreover, compound 13b in addition to AChE inhibition (IC50 EeAChE = 0.219 μM) possesses additional properties, such as the ability to inhibit Aβ aggregation (65.96% at 10 μM) and a neuroprotective effect against Aβ toxicity at 1 and 3 μM. Compound 13b emerges as a promising multi-target ligand for the further development of the therapy for age-related neurodegenerative disorders.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Fizykochemicznej Analizy Leku
dc.affiliationpl
Wydział Chemii : Zakład Krystalochemii i Krystalofizyki
dc.cm.id
70304
dc.contributor.authorpl
Szałaj, Natalia - 140437
dc.contributor.authorpl
Bajda, Marek - 165281
dc.contributor.authorpl
Skrok, Mirosław
dc.contributor.authorpl
Kurpiewska, Katarzyna - 142859
dc.contributor.authorpl
Lewiński, Krzysztof - 129948
dc.contributor.authorpl
Brus, Boris
dc.contributor.authorpl
Pišlar, Anja
dc.contributor.authorpl
Kos, Janko
dc.contributor.authorpl
Gobec, Stanislav
dc.contributor.authorpl
Malawska, Barbara - 130819
dc.date.accessioned
2015-07-02T10:15:22Z
dc.date.available
2015-07-02T10:15:22Z
dc.date.issuedpl
2015
dc.description.additionalpl
Na publikacji autorka Szałaj Natalia podpisana jako Guzior Natalia.
dc.description.physicalpl
738-749
dc.description.volumepl
92
dc.identifier.doipl
10.1016/j.ejmech.2015.01.027
dc.identifier.eissnpl
1768-3254
dc.identifier.issnpl
0223-5234
dc.identifier.uri
http://ruj.uj.edu.pl/xmlui/handle/item/11196
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights.licence
Bez licencji otwartego dostępu
dc.subtypepl
Article
dc.titlepl
Development of multifunctional, heterodimeric isoindoline-1,3-dione derivatives as cholinesterase and β-amyloid aggregation inhibitors with neuroprotective properties
dc.title.journalpl
European Journal of Medicinal Chemistry
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

* The migration of download and view statistics prior to the date of April 8, 2024 is in progress.

Views
16
Views per month
Views per city
Des Moines
6
Ashburn
2
Wroclaw
2
Dublin
1
Krakow
1

No access

No Thumbnail Available