Tacrine-Trolox Hybrids: A Novel Class of Centrally Active, Nonhepatotoxic Multi-Target-Directed Ligands Exerting Anticholinesterase and Antioxidant Activities with Low In Vivo Toxicity
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Acetylcholinesterase chemistry MeSH
- Antioxidants chemical synthesis pharmacology toxicity MeSH
- Cholinesterase Inhibitors chemical synthesis pharmacology toxicity MeSH
- Chromans chemistry pharmacology toxicity MeSH
- Blood-Brain Barrier MeSH
- Hepatocytes drug effects MeSH
- Injections, Intramuscular MeSH
- Microsomes, Liver drug effects metabolism MeSH
- Catalysis MeSH
- Kinetics MeSH
- Rats MeSH
- Humans MeSH
- Ligands MeSH
- Models, Molecular MeSH
- Rats, Wistar MeSH
- Drug Design MeSH
- Free Radical Scavengers chemical synthesis pharmacology MeSH
- Tacrine chemistry pharmacology toxicity MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid MeSH Browser
- Acetylcholinesterase MeSH
- Antioxidants MeSH
- Cholinesterase Inhibitors MeSH
- Chromans MeSH
- Ligands MeSH
- Free Radical Scavengers MeSH
- Tacrine 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.
References provided by Crossref.org
Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease
In vitro investigating of anticancer activity of new 7-MEOTA-tacrine heterodimers
Acute Toxic Injuries of Rat's Visceral Tissues Induced by Different Oximes
Profiling donepezil template into multipotent hybrids with antioxidant properties
Development of 2-Methoxyhuprine as Novel Lead for Alzheimer's Disease Therapy
