anti-Alzheimer Drug Research Articles

Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data

According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques—a hallmark finding in patients with Alzheimer’s disease—and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer’s disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.

Recent Advances in the Synthesis of Tacrine Derivatives as Multifunctional Agents for Alzheimer's Disease

Alzheimer’s is a neurodegenerative pathology. The first therapeutic strategy for the treatment of AD was mainly acetylcholinesterase inhibitors (AChEIs) such as Tacrine; a linear tricyclic compound that occupies an important place in the treatment of this disease with its properties pharmacophore. In this regard, the development of tacrine-analogs more efficient and safe with new measures and investigations has drawn immense attention. Various structural modifications of Tacrine have been carried out on different parts. Mainly some modification in the ring structure of tacrine or by connecting the amino group with different hybrids based on natural or synthetic compounds and drugs already in existence. These tacrine congeners have considerable potential for the development of new drugs for the treatment of Alzheimer's disease. Therefore, this review presents an overview of the most important structural modifications in tacrine rings based on the current trends reported in recent decades towards the use of natural products and synthetic analogs as a source of new anti-Alzheimer drugs.

Comorbidity and Treatment in Older Psychiatric In-patients-A Retrospective Study in a Chinese Psychiatric Hospital.

Background: Comorbid somatic diseases increase the death risk and affect the condition, treatment, and prognosis of older psychiatric patients. We investigated the comorbidity and drug treatment in older patients with psychosis.Methods: This retrospective study used data from 3,115 older psychiatric in-patients hospitalized at the Shanghai Mental Health Center Affiliated to Shanghai Jiaotong University School of Medicine, China discharged from 2005 to 2015. Descriptive analyses of patients' age, sex, treatment drugs, diagnoses (based on ICD-10), and time trend were performed.Results: Patients' median age was 56 (range, 50-98) years; 1,824 (58.6%) were female. The top five first-level diagnoses were schizophrenia (F20) (n = 1,818, 58.3%), depressive episode (F32) (n = 457, 14.6%), bipolar affective disorder (F31) (n = 151, 4.8%), manic episode (F30), (n = 143, 4.6%), and vascular dementia (F01) (n = 136, 4.4%). Mental (99.9%), central nervous system (85.2%), digestive system (83.5%), cardiovascular system (72.5%), and anti-infective (59.6%) drugs had the highest prescription rates. The combined use of antidepressants, anti-anxiety, anti-arrhythmic, hormones and endocrine system drugs were significantly higher in female than in male patients, while mood stabilizers and genitourinary system drugs significantly more frequent in men. With increasing age, the F20-F29 patients decreased, while F00-F09 patients increased, with the corresponding changes to prescription in those patients. In comparison to that in 2005-2010, the combined prescriptions for genitourinary and cardiovascular drugs increased between 2011 and 2015, and F00-F09 and F40-F48 older patients doubled, accordingly anti-Alzheimer's disease drugs and antidepressants more than doubled. F30-F39 patients increased by 49.1%, and anti-anxiety drugs, mood stabilizers, etc. increased by ≥50%; F20-F29 older patients decreased by 26.7%, while antipsychotics only increased by 4.4%.Conclusions: This study found the combined drug treatment of somatic diseases, particularly for central nervous, digestive, cardiovascular, respiratory and genitourinary drugs were extremely common among older psychiatric in-patients in China. With increasing age, the F20-F29 patients decreased, while F00-F09 patients increased; the antipsychotics prescriptions decreased, and almost all comorbidity drugs increased. Compared with that in 2005-2010, the older patients with all diagnosis except F20-F29 increased in 2011-2015, and the prescriptions for psychotropic, genitourinary, and cardiovascular drugs increased.

Synthesis, Characterization, Crystal Structure, Molecular Docking Analysis and Other Physico-Chemical Properties of (E)-2-(3,4-Dimethoxystyryl)Quinoline

A biologically active heterocyclic compound (E)-2-(3,4-dimethoxystyryl)quinoline has been synthesized. Detailed 1H NMR, 13C NMR spectra and elemental mass analysis has been carried out. The single crystal X-ray studies revealed that the asymmetric unit of the compound contains two crystallographically independent molecules with almost similar geometries and the compound crystallizes in a monoclinic space group P 21/c, Z = 8. The crystal structure is stabilized with elaborate network of intermolecular C–H…O hydrogen bonds, C–H…π, π–π and van der-Waal’s forces to form supramolecular structures. 3D Hirshfeld surfaces and allied 2D fingerprint plots were analyzed for non-covalent interactions. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H…H (41.8%) and C···H/H···C (39.9%) interactions. Theoretical (DFT) studies on the molecular structure, vibrational spectra, Mulliken charges, HOMO, LUMO, MESP surfaces have been performed at B3LYP/6-311++G (d,p) level of theory. The geometrical parameters of the optimized compound are in good agreement with the XRD experimental data. Molecular docking studies supported by in silico drug likeness screening explored the promising anti-Alzheimer's activity of this N-containing bioactive styryl-quinoline, which could be considered as a lead compound for anti-Alzheimer's drug design.

Donepezil, an anti-Alzheimer's disease drug, promotes differentiation and regeneration in injured skeletal muscle through the elevation of the expression of myogenic regulatory factors

We previously demonstrated that donepezil, an anti-Alzheimer's disease drug, improved skeletal muscle atrophy by enhancing the angiogenesis of endothelial cells and activating the proliferation of satellite cells in a mouse model of peripheral arterial disease. However, the effect of donepezil on muscle differentiation during regeneration remains unclear. Therefore, we measured the expressions of myogenic regulatory factors and late muscle differentiation markers in donepezil-treated C2C12 myoblast cells before and after the induction of cell differentiation. The results indicate that the expressions of myogenin, troponin T (TnT) and myosin heavy chain (MyHC) were significantly increased and myotube formation was accelerated in donepezil-treated cells under the differentiation condition. However, the promotive effect of donepezil on muscle differentiation could not be reproduced by the addition of acetylcholine (ACh) and was not disrupted after treatment with ACh receptor blockers. Moreover, other kinds of acetylcholinesterase inhibitors failed to promote muscle differentiation in C2C12 cells. These results indicate that the specific characteristics of donepezil in the promotion of muscle differentiation are independent of its acetylcholinesterase-inhibitory action. We further found that donepezil induced an incremental shift of the cross-sectional area of myofibers and elevated the expressions of myogenin, TnT and MyHC in a mouse model of cardiotoxin injury. These results suggest that donepezil promotes the differentiation of muscle regeneration upon injury via the elevation of the expressions of myogenic regulatory factors and late muscle differentiation markers. Our findings suggest that donepezil can be a useful therapeutic agent for injured skeletal muscle treatment.

Prevalence and incidence of young onset dementia and associations with comorbidities: A study of data from the French national health data system.

Dementia onset in those aged <65 years (young onset dementia, YOD) has dramatic individual and societal consequences. In the context of population aging, data on YOD are of major importance to anticipate needs for planning and allocation of health and social resources. Few studies have provided precise frequency estimates of YOD. The aim of this study is to provide YOD prevalence and incidence estimates in France and to study the contribution of comorbidities to YOD incidence. Using data from the French national health data system (Système National des Données de Santé, SNDS) for 76% of the French population aged 40 to 64 years in 2016 (n = 16,665,795), we identified all persons with dementia based on at least 1 of 3 criteria: anti-Alzheimer drugs claims, hospitalization with the International Classification of Diseases-10th Revision (ICD-10) dementia codes (F00 to F03, G30, G31.0, G31.1, or F05.1), or registration for free healthcare for dementia. We estimated prevalence rate (PR) and incidence rate (IR) and estimated the association of comorbidities with incident YOD. Sex differences were investigated. We identified 18,466 (PRstandardized = 109.7/100,000) and 4,074 incident (IRstandardized = 24.4/100,000 person-years) persons with prevalent and incident YOD, respectively. PR and IR sharply increased with age. Age-adjusted PR and IR were 33% (95% confidence interval (CI) = 29 to 37) and 39% (95% CI = 31 to 48) higher in men than women (p < 0.001 both for PR and IR). Cardio- and cerebrovascular, neurological, psychiatric diseases, and traumatic brain injury prevalence were associated with incident YOD (age- and sex-adjusted p-values <0.001 for all comorbidities examined, except p = 0.109 for antihypertensive drug therapy). Adjustment for all comorbidities explained more than 55% of the sex difference in YOD incidence. The lack of information regarding dementia subtypes is the main limitation of this study. We estimated that there were approximately 24,000 and approximately 5,300 persons with prevalent and incident YOD, respectively, in France in 2016. The higher YOD frequency in men may be partly explained by higher prevalence of cardiovascular and neurovascular diseases, substance abuse disorders, and traumatic brain injury and warrants further investigation.

Formulation and Evaluationation of Anti-Alzheimer Drug MEM HCL Nanogel

The object of present study was to formulate and evaluate MEM HCl loaded thermo sensitive in situ nanogel for 08 nasal delivery formulations. In present project a novel drug delivery system i.e. in situ polymeric gel was designed in the manner that the gel load MEM HCl in better concentration and it also incorporates penetration enhancer as a way to enhance the absorption of release drug from gel to the systemic circulation. In this research work Different Nanoparticles were (NP) prepared, using ionotropic gelation method with slight medication in which chitosan (0.4% w/v) was dissolved in aqueous acetic acid solutions (1 % v/v) (pH 6.1), while TPP (0.1% w/v) was dissolved in deionized water. Dried nanoparticles are incorporated with in situ gel. In situ gel was prepared by cold method using the solutions of Poloxamer-188 and Carbopol-934. From this study, it is concluded that, among all formulations prepared, NG8 was the best optimized formulation. Prepared gel can be used as promising nasal drug delivery system for the anti-Alzheimer drug MEM HCl, which enhance nasal residence time owing to increased viscosity and mucoadhesive characteristics; furthermore, it also exhibited a permeation enhancing effect.

Bioproduction of Prodigiosin from Fishery Processing Waste Shrimp Heads and Evaluation of Its Potential Bioactivities

The aim of this work was to reuse a fish processing waste, shrimp head powder (SHP), for the production of prodigiosin (PG) via microbial technology and to assess its potential bioactivities. PG was produced in a 12 L-bioreactor system, and the highest PG productivity of 6310 mg L−1 was achieved when Serratia marcescens CC17 was used for fermentation in a novel designed medium (6.75 L) containing 1.5% C/N source (SHP/casein = 9/1), 0.02% K2SO4, ans 0.025% Ca3(PO4)2, with initial pH 7.0, and fermentation was performed at 28 °C for 8 h. The purified PG showed moderate antioxidants, efficient anti-NO (anti-nitric oxide), and acetylcholinesterase (AChE) inhibitory activities. In a docking study, PG showed better binding energy scores (−12.3 kcal/mol) and more interactions (6 linkages) with several prominent amino acids in the biding sites on AChE that were superior to those of Berberine chloride (−10.8 kcal/mol and one linkage). Notably, this is the first investigation using shrimp heads for the mass bioproduction of PG with high productivity, and Ca3(PO4)2 salt was also newly found to significantly enhance PG production by S. marcescens. This study also provided available data on the anti-NO and anti-AChE effects of PG, especially from the docking simulation PG towards AChE that was described for the first time in this study. The above results suggest that SHP is a good material for the cost-effective bioproduction of PG, which is a potential candidate for anti-NO and anti-Alzheimer drugs.

Bioactive potential and RP-HPLC detection of phenolics and alkaloids (lycorine and galanthamine) from ultrasonic-assisted extracts of Crinum roots

In this study, ultrasonic-assisted root extracts (methanolic and aqueous) of 16 Crinum genotypes were investigated for their antioxidants, phytochemicals and alkaloids (lycorine and galanthamine). The maximum TPC was recorded in methanolic extract of CAF1 (10.871 ± 0.2 mg TAE/g DW) and the least in CA (5.291 ± 0.1 mg TAE/g DW). TFC ranged from 0.446 ± 0.03 (CA) to 1.051 ± 0.07 mg CE/g DW (CMOR) for methanolic extracts whereas for aqueous extracts the range was 0.258 ± 0.01 (CAF2) to 1.312 ± 0.05 mg CE/g DW (COME). TTC values were recorded higher from aqueous extracts whereas TAC was on the higher side in methanolic extracts. TTC was the highest in COME (6.960 ± 0.16 mg CE/g DW) and TAC in CMOR (2.510 ± 0.21 mg BE/g DW). The highest DPPH and ABTS radical scavenging were noted in CMOR (1.886 ± 0.07 mg AAE/g DW) and CP (18.251 ± 1.32 mg TE/g DW), respectively. Similarly, the highest FRAP and PMA activities were found from methanolic extracts of CAF1 (6.751 ± 0.06 mg Fe(II)E/g DW) and CAF2 (6.093 ± 0.16 mg AAE/g DW). Water extract of CM (4.788 ± 0.03 mg EDTA/g DW) had the highest metal chelation potential. Maximum inhibition of α-amylase and α-glucosidase was noticed in the methanolic extracts of CV (43.51%) and CM (85.58%), respectively. Similarly, the maximum inhibition (95.99%) of acetylcholinesterase activity was noted in the methanolic extract of CA. RP-HPLC revealed that GA and COA were the most common phenolics in the roots. The alkaloid, lycorine was detected in all the genotypes and galanthamine in only 14 genotypes. The highest lycorine content was detected in CW (6.28 ± 0.54 mg/g DW) and the lowest in CXA (0.45 ± 0.01 mg/g DW). Galanthamine content ranged from 0.10 ± 0.00 μg/g DW (CP) to 348.98 ± 0.01 μg/g DW (CXA). Ultrasonic-assisted extraction can be one of the sustainable approaches for the enhanced recovery of phytochemicals from Crinum species. Present study inferred that Crinum is a magnificent source of antioxidants, natural inhibitors of α-glucosidase as well as anti-Alzheimer and anticancer drugs.

Probing the acetylcholinesterase inhibitory activity of a novel Ru(II) polypyridyl complex and the supramolecular interaction by (STD)-NMR

Currently, acetylcholinesterase (AChE) inhibitors are the only anti-Alzheimer drugs commercially available. Despite their wide use those drugs are all dose dependent and their effect last for no longer than two years, with several side effects. The search of novel acetylcholinesterase (AChE) inhibitors remains as the main scientific route. Here we describe the synthesis, characterization, biological activity and an NMR binding-target study of a novel cis-[Ru(Bpy)2(EtPy)2]2+, (RuEtPy), Bpy = 2,2′-bipyridine and EtPy = 4,2-Ethylamino-pyridine) as a potential AChE inhibitor. The classic Ellman's colorimetric assay suggests that the RuEtPy exhibits a high inhibitory activity, following a competitive mechanism, with a remarkable low inhibition constant (Ki ≈ 16.8 μM), together with a IC50 = 39 μM. Hence, we have studied the spatial interactions for this novel candidate towards the human acetylcholinesterase (hAChE) using saturation transfer difference (STD)-NMR, in order to describe the mechanism of the interaction. NMR binding-target results shows that the 4,2-Ethylamino-Pyridine group is spatially closer to hAChE surface chemical arrangement than 2,2′ bipyridine counterpart, exerting an efficient intermolecular interaction, with a low dissociation constant (KD ≈ 55 μM), probing that 4,2-Ethylamino-pyridine motif plays a key role in the inhibitory action.

Association between statin use and Alzheimer\u2019s disease with dose response relationship

This study aimed to determine the dose–response relationship between the levels of statin exposure and the incidence of Alzheimer’s disease (AD). We included 119,013 Korean adults (≥ 60 years old) using a database from the Korean National Health Insurance Service (2002–2013). Statin exposure was treated as a time-varying variable. Incidence of AD was defined by the first claim code for AD with anti-Alzheimer drugs. AD occurred in 9467 cases during a median 7.2 years of follow-up. Overall, statin use was not associated with an increased risk of AD incidence [adjusted hazard ratio (aHR) = 1.04; 95% confidence interval (CI) = 0.99–1.10]. When examined by level of statin exposure, statin prescription < 540 days during a 2-year window time was associated with a higher risk for incidence of AD compared to statin non-use. However, days of prescription ≥ 540 and cumulative defined daily dose ≥ 540 of statin were associated with decreased risk of AD [aHR (95% CI) = 0.87 (0.80–0.95) and 0.79 (0.68–0.92), respectively]. Our findings indicate that less persistent statin use is associated with increased risk of AD, whereas persistent and adherent statin use is associated with decreased risk of AD.

Bio-Guided Fractionation of Stem Bark Extracts from Phyllanthus muellarianus: Identification of Phytocomponents with Anti-Cholinesterase Activity.

A combination of flash chromatography, solid phase extraction, high-performance liquid chromatography, and in vitro bioassays was used to isolate phytocomponents endowed with anticholinesterase activity in extract from Phyllanthus muellarianus. Phytocomponents responsible for the anti-cholinesterase activity of subfractions PMF1 and PMF4 were identified and re-assayed to confirm their activity. Magnoflorine was identified as an active phytocomponent from PMF1 while nitidine was isolated from PMF4. Magnoflorine was shown to be a selective inhibitor of human butyrylcholinesterase—hBChE (IC50 = 131 ± 9 μM and IC50 = 1120 ± 83 μM, for hBuChE and human acetylcholinesterase—hAChE, respectively), while nitidine showed comparable inhibitory potencies against both enzymes (IC50 = 6.68 ± 0.13 μM and IC50 = 5.31 ± 0.50 μM, for hBChE and hAChE, respectively). When compared with the commercial anti-Alzheimer drug galanthamine, nitidine was as potent as galanthamine against hAChE and one order of magnitude more potent against hBuChE. Furthermore, nitidine also showed significant, although weak, antiaggregating activity towards amyloid-β self-aggregation.

The structural simplification of lysergic acid as a natural lead for synthesizing novel anti-Alzheimer agents

Alzheimer’s disease (AD) is a neurodegenerative disorder, projected to be the second leading cause of mortality by 2040. AD is characterized by a progressive impairment of memory leading to dementia and loss of ability to carry out daily functions. In addition to the deficiency of acetylcholine release in synapse, there are other mechanisms explaining the etiology of the disease. The most disputing ones are associated with the accumulation of damaged proteins β-amyloid (Aβ) and hyperphosphorylated tau outside and inside neurons, respectively. Lysergic acid derivatives have been shown to possess promising anti-Alzheimer effect. Moreover, lysergic acid structure encompasses the general structural requirements for acetylcholinesterase inhibition. In this study, sixteen analogues, derived from lysergic acid structure, were synthesized. Heck and Mannich reactions were carried out to 4-bromo indole nucleus to generate potentially active analogues. Some of them were subsequently cyclized by nitromethane and zinc reduction procedures. Some of these compounds showed neuroprotective and anti-inflammatory effects stronger than the currently used anti-Alzheimer drug; donepezil. Some of the synthesized com-pounds showed a noticeable acetylcholinesterase inhibition. Twelve molecular targets attributed with AD etiology were tested versus the synthesized compounds by in silico modeling. Docking scores of modeling were plotted against in vitro activity of the compounds. The one afforded the strongest positive correlation was ULK-1 which has a significant role in autophagy.

Pharmacokinetics, distribution, and excretion of sodium oligomannate, a recently approved anti-Alzheimer's disease drug in China

The National Medical Products Administration has authorized sodium oligomannate for treating mild-to-moderate Alzheimer's disease. In this study, an LC-MS/MS method was developed and validated to quantitate sodium oligomannate in different biomatrices. The plasma pharmacokinetics, tissue distribution, and excretion of sodium oligomannate in Sprague-Dawley rats and beagle dogs were systematically investigated. Despite its complicated structural composition, the absorption, distribution, metabolism, and excretion profiles of the oligosaccharides in sodium oligomannate of different sizes and terminal derivatives were indiscriminate. Sodium oligomannate mainly crossed the gastrointestinal epithelium through paracellular transport following oral administration, with very low oral bioavailability in rats (0.6%–1.6%) and dogs (4.5%–9.3%). Absorbed sodium oligomannate mainly resided in circulating body fluids in free form with minimal distribution into erythrocytes and major tissues. Sodium oligomannate could penetrate the blood-cerebrospinal fluid (CSF) barrier of rats, showing a constant area under the concentration-time curve ratio (CSF/plasma) of approximately 5%. The cumulative urinary excretion of sodium oligomannate was commensurate with its oral bioavailability, supporting that excretion was predominantly renal, whereas no obvious biliary secretion was observed following a single oral dose to bile duct-cannulated rats. Moreover, only 33.7% (male) and 26.3% (female) of the oral dose were recovered in the rat excreta within 96 h following a single oral administration, suggesting that the intestinal flora may have ingested a portion of unabsorbed sodium oligomannate as a nutrient.

Butyrylcholinesterase-inhibiting natural coumarin molecules as potential leads

Seventeen natural coumarin derivatives; badrakemin (1), 14′-acetoxybadrakemin (2), badrakemone (3), 14′-acetoxybadrakemone (4), colladonin (5), colladonin acetate (6), 14′-acetoxycolladonin (7), karatavicinol (8), deltoin (9), smyrnioridin (10), marmesin (11), osthol (12), oxypeucedanin (13), oxypeucedanin hydrate (14), isoimperatorin (15), scopoletin (16), and umbelliprenin (17), were tested against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the sister enzymes that play a critical role in the pathology of Alzheimer’s disease as well as tyrosinase (TYR) as the target for Parkinson’s disease. The tested coumarins were more selective against BChE, where the coumarins 2, 5, 8, and 15 (IC50 = 30.3 μM, 29.2 μM, 37.2 μM, and 50.1 μM, respectively) displayed higher BChE inhibition than the reference (galanthamine, IC50 = 60.2 μM) at 100 μg/mL. Only four coumarins (2, 5, 9, and 15) showed inhibition against AChE. Binding conformations of the coumarins (2, 5, 8, 9, and 15) within the active sites of AChE and BChE were explored via molecular docking experiments. The docked compounds were oriented by the interactions with the oxyanion hole and the peripheral anionic site residues of AChE/BChE. The coumarin derivatives 1–17 was found to have no or low inhibition (2.03 ± 0.92 %–12.91 ± 0.40 %) against TYR at 100 μg/mL. Our findings revealed that coumarins could be promising lead compounds for designing novel anti-Alzheimer drug candidates.

Design and synthesis of novel diosgenin-triazole hybrids targeting inflammation as potential neuroprotective agents

Alzheimer's disease is a progressive neurodegenerative disease, and its incidence is expected to increase as the global population ages. Recent studies provide increasing evidence that inflammation plays a key role in the pathogenesis and progression of AD. Diosgenin, an active ingredient in Dioscorea nipponica Makino, is a promising bioactive lead compound in the treatment of Alzheimer’s disease, which exhibited anti-inflammatory activity. To search for more efficient anti-Alzheimer agents, a series of novel diosgenin-triazolyl hybrids were designed, synthesized, and their neuroprotective effects against oxygen-glucose deprivation-induced neurotoxicity and LPS-induced NO production were evaluated. Most of these new hybrids displayed better activities than DIO. In particular, the promising compound L6 not only demonstrated an excellent neuroprotective effect but also showed the best anti-inflammatory activity. The structure-activity relationship study illustrated that the introduction of benzyl or phenyl triazole did improve the activity, and the introduction of benzyl triazole was better than that of phenyl triazole. The results we obtained showed that the diosgenin skeleton could be a promising structural template for the development of new anti-Alzheimer drug candidates, and compound L6 has the potential to be an important lead compound for further research.

Xanthone: Potential Acetylcholinesterase Inhibitor for Alzheimer's Disease Treatment.

Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer's treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission. This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine, and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.

A comparison of the location in membranes of curcumin and curcumin-derived bivalent compounds with potential neuroprotective capacity for Alzheimer’s disease

Curcumin and two bivalent compounds, namely 17MD and 21MO, both obtained by conjugation of curcumin with a steroid molecule that acts as a membrane anchor, were comparatively studied. When incorporated into 1,2-dipalmitoyl-sn-glycero-3-phosphocholine the compounds showed a very limited solubility in the model membranes. Curcumin and the two bivalent compounds were also incorporated in membranes of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and quenching the fluorescence of pure curcumin or of the curcumin moiety in the bivalent compounds by acrylamide it was seen that curcumin was accessible to this water soluble quencher but the molecule was somehow located in a hydrophobic environment. This was confirmed by quenching with doxyl-phosphatidylcholines, indicating that the curcumin moieties of 17MD and 21MO were in a more polar environment than pure curcumin itself. 1H NOESY MAS-NMR analysis supports this notion by showing that the orientation of curcumin was parallel to the plane of the membrane surface close to C2 and C3 of the fatty acyl chains, while the curcumin moiety of 17MD and 21MO positioned close to the polar part of the membrane with the steroid moiety in the centre of the membrane. Molecular dynamics studies were in close agreement with the experimental results with respect to the likely proximity of the protons studied by NMR and show that 17MD and 21MO have a clear tendency to aggregate in a fluid membrane. The anchorage of the bivalent compounds to the membrane leaving the curcumin moiety near the polar part may be very important to facilitate the bioactivity of the curcumin moiety when used as anti-Alzheimer drugs.

Acetylcholinesterase as a target of halogenated marine natural products from Laurencia dendroidea

The use of chemogenomics techniques applied to a marine natural products database has pointed out halogenated sesquiterpenes present in red alga Laurencia dendroidea as potential acetylcholinesterase inhibitors. Therefore, in this work five metabolites were studied using molecular docking and enzymatic inhibition assays. According to the results the most promising metabolite in relation to acetylcholinesterase inhibition capacity was (−)-elatol 1. Molecular docking of (−)-elatol 1 showed interactions with important specific residues of the enzyme gorge involved in the activity of drugs used to treat Alzheimer's disease. In this respect, interactions between halogens bromine and chlorine with the center of the benzene ring of Tryptophan 86 and Tryptophan 286 may be contributing to the observed activity. Enzyme kinetics was investigated to find out the type of enzyme inhibition involved in the observed activities. Results have also shown stereochemical preferences related to the inhibition by halogenated compounds. (−)-Elatol 1 was able to inhibit acetylcholinesterase, thus becoming a suitable skeleton in the search for new anti-Alzheimer drugs of natural and semi-synthetic origin.

Mathematical modeling of a continuous-flow packed-bed reactor with immobilized lipase for kinetic resolution of (R,S)-2-pentanol.

In this study, the kinetic resolution of (R,S)-2-pentanol via transesterification to achieve S-2-pentanol, a key intermediate required in the synthesis of anti-Alzheimer drugs, was investigated in continuous-flow packed-bed reactors. The effects of residence time, substrate concentration, and operation time of the enzyme were investigated. Under steady state conditions, 50% conversion and enantiomeric excess of the substrate (ee S >99% were achieved at a residence time of 0.04 min. Productivity of the continuous-flow process (1.341 mmol/min/g)was about 4 times higher than that of the corresponding batch process (0.363 mmol/min/g). In addition, the mathematical modeling of the packed-bed reactor was conductedusing an axial dispersion model. Ping Pong Bi Bi kinetics was used in this model. Design parameters were determined and the developed equations were solved using an algorithm for solving boundary value problems for ordinary differential equations by collocation (bvp4c) using MATLAB. The results, obtained from the model, fitted the experimental data very well.).