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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
- Source :
- Journal of Medicinal Chemistry
- Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- Male
Models, Molecular
Antioxidant
medicine.medical_treatment
Ligands
01 natural sciences
Injections, Intramuscular
Antioxidants
Catalysis
03 medical and health sciences
chemistry.chemical_compound
In vivo
Drug Discovery
medicine
Animals
Humans
Chromans
Rats, Wistar
030304 developmental biology
0303 health sciences
biology
010405 organic chemistry
Active site
Free Radical Scavengers
Acetylcholinesterase
In vitro
0104 chemical sciences
Rats
Kinetics
chemistry
Biochemistry
Blood-Brain Barrier
Tacrine
Drug Design
Toxicity
biology.protein
Hepatocytes
Microsomes, Liver
Molecular Medicine
Trolox
Cholinesterase Inhibitors
medicine.drug
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 58
- Issue :
- 22
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....a6dbe6280c82dfae6c04fdac19dce6ee