Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT6 receptor with anti-aggregation properties against amyloid-beta and tau

2021
journal article
article
cris.lastimport.wos2024-04-10T00:09:14Z
dc.abstract.enMultifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.pl
dc.affiliationWydział Farmaceutyczny : Zakład Fizykochemicznej Analizy Lekupl
dc.affiliationWydział Farmaceutyczny : Zakład Chemii Lekówpl
dc.affiliationWydział Farmaceutyczny : Zakład Radioligandówpl
dc.affiliationWydział Farmaceutyczny : Katedra Farmakobiologiipl
dc.affiliationWydział Farmaceutyczny : Zakład Technologii i Biotechnologii Środków Leczniczychpl
dc.affiliationSzkoła Doktorska Nauk Medycznych i Nauk o Zdrowiupl
dc.affiliationWydział Farmaceutycznypl
dc.cm.id105707
dc.cm.idOmegaUJCM42162727d4ca437ca4e814f17b194096pl
dc.contributor.authorWichur, Tomasz - 175517 pl
dc.contributor.authorPasieka, Anna - 193721 pl
dc.contributor.authorGodyń, Justyna - 232820 pl
dc.contributor.authorPanek, Dawid - 148623 pl
dc.contributor.authorGóral, Izabella - 245532 pl
dc.contributor.authorLatacz, Gniewomir - 200736 pl
dc.contributor.authorHonkisz-Orzechowska, Ewelina - 366666 pl
dc.contributor.authorBucki, Adam - 140601 pl
dc.contributor.authorSiwek, Agata - 133399 pl
dc.contributor.authorGłuch-Lutwin, Monika - 186610 pl
dc.contributor.authorKnez, Damijanpl
dc.contributor.authorBrazzolotto, Xavierpl
dc.contributor.authorGobec, Stanislavpl
dc.contributor.authorKołaczkowski, Marcin - 130216 pl
dc.contributor.authorSabate, Raimonpl
dc.contributor.authorMalawska, Barbara - 130819 pl
dc.contributor.authorWięckowska, Anna - 160757 pl
dc.date.accession2022-02-01pl
dc.date.accessioned2021-10-22T09:49:33Z
dc.date.available2021-10-22T09:49:33Z
dc.date.issued2021pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.versionostateczna wersja wydawcy
dc.description.volume225pl
dc.identifier.articleid113783pl
dc.identifier.doi10.1016/j.ejmech.2021.113783pl
dc.identifier.eissn1768-3254pl
dc.identifier.issn0223-5234pl
dc.identifier.urihttps://ruj.uj.edu.pl/xmlui/handle/item/281370
dc.identifier.weblinkhttps://www.sciencedirect.com/science/article/pii/S0223523421006322?via%3Dihubpl
dc.languageengpl
dc.language.containerfrapl
dc.pbn.affiliationDziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rightsDodaję tylko opis bibliograficzny*
dc.rights.licenceCC-BY-NC-ND
dc.rights.uri*
dc.share.typeinne
dc.subject.enAlzheimer's diseasepl
dc.subject.enmultifunctional agentspl
dc.subject.enβ-amyloidpl
dc.subject.enTau proteinpl
dc.subject.encholinesterase inhibitorspl
dc.subject.en5-HT6 antagonistspl
dc.subtypeArticlepl
dc.titleDiscovery of 1-(phenylsulfonyl)-1<I>H</I>-indole-based multifunctional ligands targeting cholinesterases and 5-HT<SUB>6</SUB> receptor with anti-aggregation properties against amyloid-beta and taupl
dc.title.journalEuropean Journal of Medicinal Chemistrypl
dc.typeJournalArticlepl
dspace.entity.typePublication
cris.lastimport.wos
2024-04-10T00:09:14Z
dc.abstract.enpl
Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment of multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biological evaluation led to the discovery of two compounds with favorable pharmacological characteristics and ADMET profile. Compounds 17 and 35 are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM respectively) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound 17, a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM respectively), while compound 35 with rivastigmine-derived phenyl N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound 17 and 68% for 35 at 10 μM) moreover, compound 35 is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound 17 and 35 respectively), no or little effect on CYP3A4 and 2D6 up to a concentration of 10 μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21 μM, for 17 and 35 respectively). Based on the pharmacological characteristics and favorable pharmacokinetic properties, we propose compounds 17 and 35 as an excellent starting point for further optimization and in-depth biological studies.
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Fizykochemicznej Analizy Leku
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Chemii Leków
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Radioligandów
dc.affiliationpl
Wydział Farmaceutyczny : Katedra Farmakobiologii
dc.affiliationpl
Wydział Farmaceutyczny : Zakład Technologii i Biotechnologii Środków Leczniczych
dc.affiliationpl
Szkoła Doktorska Nauk Medycznych i Nauk o Zdrowiu
dc.affiliationpl
Wydział Farmaceutyczny
dc.cm.id
105707
dc.cm.idOmegapl
UJCM42162727d4ca437ca4e814f17b194096
dc.contributor.authorpl
Wichur, Tomasz - 175517
dc.contributor.authorpl
Pasieka, Anna - 193721
dc.contributor.authorpl
Godyń, Justyna - 232820
dc.contributor.authorpl
Panek, Dawid - 148623
dc.contributor.authorpl
Góral, Izabella - 245532
dc.contributor.authorpl
Latacz, Gniewomir - 200736
dc.contributor.authorpl
Honkisz-Orzechowska, Ewelina - 366666
dc.contributor.authorpl
Bucki, Adam - 140601
dc.contributor.authorpl
Siwek, Agata - 133399
dc.contributor.authorpl
Głuch-Lutwin, Monika - 186610
dc.contributor.authorpl
Knez, Damijan
dc.contributor.authorpl
Brazzolotto, Xavier
dc.contributor.authorpl
Gobec, Stanislav
dc.contributor.authorpl
Kołaczkowski, Marcin - 130216
dc.contributor.authorpl
Sabate, Raimon
dc.contributor.authorpl
Malawska, Barbara - 130819
dc.contributor.authorpl
Więckowska, Anna - 160757
dc.date.accessionpl
2022-02-01
dc.date.accessioned
2021-10-22T09:49:33Z
dc.date.available
2021-10-22T09:49:33Z
dc.date.issuedpl
2021
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
225
dc.identifier.articleidpl
113783
dc.identifier.doipl
10.1016/j.ejmech.2021.113783
dc.identifier.eissnpl
1768-3254
dc.identifier.issnpl
0223-5234
dc.identifier.uri
https://ruj.uj.edu.pl/xmlui/handle/item/281370
dc.identifier.weblinkpl
https://www.sciencedirect.com/science/article/pii/S0223523421006322?via%3Dihub
dc.languagepl
eng
dc.language.containerpl
fra
dc.pbn.affiliation
Dziedzina nauk medycznych i nauk o zdrowiu : nauki farmaceutyczne
dc.rights*
Dodaję tylko opis bibliograficzny
dc.rights.licence
CC-BY-NC-ND
dc.rights.uri*
dc.share.type
inne
dc.subject.enpl
Alzheimer's disease
dc.subject.enpl
multifunctional agents
dc.subject.enpl
β-amyloid
dc.subject.enpl
Tau protein
dc.subject.enpl
cholinesterase inhibitors
dc.subject.enpl
5-HT6 antagonists
dc.subtypepl
Article
dc.titlepl
Discovery of 1-(phenylsulfonyl)-1<I>H</I>-indole-based multifunctional ligands targeting cholinesterases and 5-HT<SUB>6</SUB> receptor with anti-aggregation properties against amyloid-beta and tau
dc.title.journalpl
European Journal of Medicinal Chemistry
dc.typepl
JournalArticle
dspace.entity.type
Publication

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