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Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity
- Source :
- Bioorganicmedicinal chemistry letters. 27(11)
- Publication Year :
- 2017
-
Abstract
- The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC50=33.0µM; 2, IC50=8.5µM) compared to tacrine (CYP1A2 IC50=1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species.
- Subjects :
- 0301 basic medicine
Risk
Cytochrome
Stereochemistry
Cytochrome P-450 CYP1A2 Inhibitors
Clinical Biochemistry
Pharmaceutical Science
Pharmacology
Biochemistry
03 medical and health sciences
0302 clinical medicine
Cytochrome P-450 CYP1A2
Drug Discovery
Cytochrome P-450 CYP3A
medicine
Humans
Molecular Biology
Cholinesterase
Benzoflavones
Cytochrome P-450 CYP3A Inhibitors
Binding Sites
biology
CYP3A4
Chemistry
Organic Chemistry
CYP1A2
Cytochrome P450
Molecular Docking Simulation
030104 developmental biology
Ketoconazole
Tacrine
biology.protein
Molecular Medicine
Chemical and Drug Induced Liver Injury
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 14643405
- Volume :
- 27
- Issue :
- 11
- Database :
- OpenAIRE
- Journal :
- Bioorganicmedicinal chemistry letters
- Accession number :
- edsair.doi.dedup.....a85805a9d25f5cad4f02f7e5a8a4f68b