Acetylcholinesterase inhibitors: Modeling potential candidates

Alzheimer's disease is the leading cause of dementia for elderly people. The main active therapeutic is supported on the increased levels of acetylcholine in the synaptic cleft, based on reversible inhibition of the acetylcholinesterase (AChE) enzyme. This article aims to propose possible inhibitor candidates for AChE, designed from nonisoprenoid lipids of cashew (Anacardium occidentale), and based on several electronic properties. These electronic properties were obtained through B3LYP/6‐311+G(2d,p) calculation level. Principal component analysis reveals that from the set of studied molecular structures a small group is correlated with donepezil, a drug with known biological activity. © 2012 Wiley Periodicals, Inc.     

Efficient and Industrially Viable Synthesis of Donepezil

An efficient, economically viable process has been developed for large‐scale preparation of donepezil HCl (1), an anti‐Alzheimer's agent. The process involves the condensation of 5,6‐dimethoxy‐1‐indanone (3) and 1‐benzyl‐4‐piperidinecarboxaldehyde (4) in the presence of alkalimetal carbonates at elevated temperature to yield 1‐benzyl‐4‐[(5,6‐dimethoxy‐1‐indanone)‐2‐yidenyl] methyl piperidine (2), the key intermediate in the synthesis of donepezil. Hydrogenation of 2 yields donepezil.     

Simple determination of some antidementia drugs in wastewater and human plasma samples by tandem dispersive liquid–liquid microextraction followed by high‐performance liquid chromatography

In this work, a simple method, namely, tandem dispersive liquid–liquid microextraction, with a high sample clean‐up is applied for the rapid determination of the antidementia drugs rivastigmine and donepezil in wastewater and human plasma samples. This method, which is based on two consecutive dispersive microextractions, is performed in 7 min. In the method, using a fast back‐extraction step, the applicability of the dispersive microextraction methods in complicated matrixes is conveniently improved. This step can be performed in less than 2 min, and very simple tools are required for this purpose. To achieve the best extraction efficiency, optimization of the variables affecting the method was carried out. Under the optimized experimental conditions, the relative standard deviations for the method were in the range of 6.9–8.7%. The calibration curves were obtained in the range of 2–1100 ng/mL with good correlation coefficients, higher than 0.995, and the limits of detection ranged between 0.5 and 1.0 ng/mL.     

Application of dispersive liquid–liquid microextraction for the determination of donepezil in urine by HPLC using a core–shell column

A rapid and novel method combining dispersive liquid–liquid microextraction and high-performance liquid chromatography coupled with fluorescence detection was developed for the determination of donepezil in human urine. Parameters affecting extraction efficiency and chromatographic determination, such as the type and volume of the extraction and disperser solvent, pH of sample for dispersive liquid–liquid microextraction, mobile-phase composition, pH, column oven temperature, and flow rate for chromatographic determination, were evaluated and optimized. Using a C₁₈ core–shell column (7.5 × 4.6?mm, 2.7?μm), the determination of donepezil was accomplished within 5?min. Under optimum conditions, developed method was linear in the range of 0.5–25?ng?mL^?1 with the correlation coefficient >0.99. Limit of detection was 0.15?ng?mL^?1. The relative standard deviation at three concentration levels (2, 12.5, and 20?ng?mL^?1) was less than 11% with accuracy in the range of 96.9–102.8%. The results of this study demonstrate that the use of dispersive liquid–liquid microextraction and core–shell column can be considered as a powerful tool for the analysis of donepezil in human urine.     

ESI-MS/MS stability-indicating bioanalytical method development and validation for simultaneous estimation of donepezil, 5-desmethyl donepezil and 6-desmethyl donepezil in human plasma

A bioanalytical method was developed and validated to estimate donepezil, 6‐desmethyl donepezil and 5‐desmethyl donepezil simultaneously in human plasma using galantamine as an internal standard (IS). The chromatographic separation was achieved on a reverse‐phase XTerra RP (150 × 4.6 mm, 5 µm) column without affecting recovery (mean recovery > 60% with CV < 10%) for all analytes. ESI‐MS/MS multiple reaction monitoring in positive polarity was used to detect mass pairs for donepezil (m/z 380.3 → 91.3), 6‐desmethyl donepezil (m/z 366.4 → 91.3), 5‐desmethyl donepezil (m/z 366.4 → 91.3) and galantamine m/z (288.1 → 213.0). The linearity was established over a dynamic range of 0.339–51.870, 0.100–15.380 and 0.103–15.763 ng/mL for donepezil, 6‐desmethyl donepezil and 5‐desmethyl donepezil, respectively. The current method shows that minimal conversion of labile metabolites to parent donepezil in plasma as stability was successfully achieved for 211 days at ?15 °C storage temperature. The method was successfully applied to a clinical study after administration of 10 mg donepezil tablets to healthy male Indian volunteers. Copyright © 2011 John Wiley & Sons, Ltd.     

Optimization of Release Conditions of Alzheimer's Drug Donepezil Hydrochloride from Sodium Alginate/Sodium Carboxymethyl Cellulose Blend Microspheres

Microspheres of blends of sodium alginate (NaAlg) and sodium carboxymethyl cellulose (NaCMC) were prepared by a water-in-oil (w/o) emulsion crosslinking method and used for the release of donepezil hydrochloride (DP), which is an Alzheimer's drug. The microspheres were characterized with Fourier transform infrared spectroscopy (FTIR), differantial scanning calorimetry (DSC), and scanning electron microscopy (SEM). The microsphere characteristics, including DP entrapment efficiency, particle size, equilibrium swelling degree (ESD), and DP release kinetics, were determined. The effects of the preparation conditions, including the NaAlg/NaCMC (w/w) ratio, drug/polymer (w/w) ratio, cross-linker concentration and time of exposure to the cross-linker, on the release of DP were investigated for successive gastrointestinal tract pH values of 1.2, 6.8, and 7.4 at 37°C. The release of DP increased with the increase in NaAlg/NaCMC (w/w) ratio and drug/polymer (d/p) ratio, while it decreased with increasing extent of cross-linking. The optimum DP release was obtained as 99.13% for a NaAlg/NaCMC (w/w) ratio of 2/1, d/p ratio of 1/4, CaCl₂ concentration of 5% and crosslinking time of 30 min. It was also observed from release results that DP release from the microspheres through the external medium was higher at low pH (1.2) values than that at high pH (6.8 and 7.4) values. The DP release of the microspheres followed either Fickian transport below a value of n < 0.5 or anomalous transport (n = 0.5–1.0).     

Development of a green stability-indicating HPLC–DAD method for the determination of donepezil hydrochloride in the presence of its related substance and degradation products

A simple, eco-friendly, stability-indicating HPLC method was developed for the determination of donepezil hydrochloride (DH) in tablet dosage form in the presence of its pharmacopoeia-related compound (donepezil-related compound A) and its different degradation products. The chromatographic conditions were optimized to achieve the highest performance parameters using Zorbax Eclipse Plus C18 rapid resolution column (4.6?×?100?mm, 3.5?µm), with a mobile phase composed of 72.5% acetate buffer pH 5.5 and 27.5% ethanol, flowing at 1?mL?min^?1. The diode array detector (DAD) was set at 315?nm and the column oven was adjusted at 45°C. Linear response (r?=?0.9999) was observed over the range of 2–28?µg?mL^?1 of donepezil, with detection and quantitation limits of 0.031 and 0.103?µg?mL^?1, respectively. Forced degradation studies were performed on standard DH and test Demepezil® 5-mg tablets under various conditions and the method was found to be stability indicating. The purity of DH peak was confirmed using the DAD. In the developed method, two principles of green chromatography were adopted (reduce and replace) by reducing solvent consumption through the utilization of a short column (10?cm) with a smaller particle size (3.5?µm) instead of a normal 25?cm with a 5?µm particle size and by replacing hazardous solvents of the official United States Pharmacopoeia method as acetonitrile with ethanol. Furthermore, the greenness of the method was assessed using three assessment tools.     

Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC₅₀ 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.     

Interaction study of aspirin or clopidogrel on pharmacokinetics of donepezil hydrochloride in rats by HPLC-fluorescence detection

The present study aims to investigate the possibility of interaction of aspirin (Asp) or clopidogrel (CG) on donepezil (DP) hydrochloride in rats by HPLC-fluorescence detection. The separation of DP was achieved in ca. 13 min without interference of Asp and CG on the chromatogram. DP levels in rat plasma with a single administration of DP (5 mg/kg, i.p., group I) and those with a co-administration of Asp (200 mg/kg, p.o., group II or 200 mg/kg, i.p., group III) or CG (5 mg/kg, p.o., group IV) were monitored. The DP concentrations determined in rat plasma ranged from 25.0 to 336.1 ng/mL. Pharmacokinetic parameters for these groups were calculated and compared with one another. No significant difference was observed on the comparison of group I with other groups except for the mean resident time of group IV (p = 0.012). These basic findings may help clinical inference when DP is co-administered with Asp and CG to human.     

The Impact of Dextran Sodium Sulfate-Induced Gastrointestinal Injury on the Pharmacokinetic Parameters of Donepezil and Its Active Metabolite 6-O-desmethyldonepezil,and Gastric Myoelectric Activity in Experimental Pigs

Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20–30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans.