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Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity
E. Nepovimova, J. Korabecny, R. Dolezal, K. Babkova, A. Ondrejicek, D. Jun, V. Sepsova, A. Horova, M. Hrabinova, O. Soukup, N. Bukum, P. Jost, L. Muckova, J. Kassa, D. Malinak, M. Andrs, K. Kuca,
Journal of medicinal chemistry.
2015 ;
58 (22) :
8985-9003.
[pub] 20151110
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Perzistentní odkaz
https://www.medvik.cz/link/bmc16009922
- MeSH
- acetylcholinesterasa chemie MeSH
- antioxidancia chemická syntéza farmakologie toxicita MeSH
- cholinesterasové inhibitory chemická syntéza farmakologie toxicita MeSH
- chromany (dihydrobenzopyrany) chemie farmakologie toxicita MeSH
- hematoencefalická bariéra MeSH
- hepatocyty účinky léků MeSH
- injekce intramuskulární MeSH
- jaterní mikrozomy účinky léků metabolismus MeSH
- katalýza MeSH
- kinetika MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- ligandy MeSH
- molekulární modely MeSH
- potkani Wistar MeSH
- racionální návrh léčiv MeSH
- scavengery volných radikálů chemická syntéza farmakologie MeSH
- takrin chemie farmakologie toxicita MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Coupling of two distinct pharmacophores, tacrine and trolox, endowed with different biological properties, afforded 21 hybrid compounds as novel multifunctional candidates against Alzheimer's disease. Several of them showed improved inhibitory properties toward acetylcholinesterase (AChE) in relation to tacrine. These hybrids also scavenged free radicals. Molecular modeling studies in tandem with kinetic analysis exhibited that these hybrids target both catalytic active site as well as peripheral anionic site of AChE. In addition, incorporation of the moiety bearing antioxidant abilities displayed negligible toxicity on human hepatic cells. This striking effect was explained by formation of nontoxic metabolites after 1 h incubation in human liver microsomes system. Finally, tacrine-trolox hybrids exhibited low in vivo toxicity after im administration in rats and potential to penetrate across blood-brain barrier. All of these outstanding in vitro results in combination with promising in vivo outcomes highlighted derivative 7u as the lead structure worthy of further investigation.
Citace poskytuje Crossref.org
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