Aminoadamantane conjugates with carbazole derivatives as potential multitarget agents for the treatment of Alzheimer’s disease. Effect of the spacer structure

Russian Chemical Bulletin - The paper considers the influence of the structure of aminoadamantane–carbazole conjugates linked by five different spacers on their ability to inhibit...     

Exploring facile synthesis and cholinesterase inhibiting potential of heteroaryl substituted imidazole derivatives for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder and cholinesterase (ChE) enzymes are considered as crucial targets for the treatment of AD. Herein, a series of heteroaryl substituted imidazole derivatives (5a-5x) was prepared using amino acid catalyzed, one-pot facile synthetic approach. In this context, the catalytic potentials of different amino acids were investigated and 15 mol% of glutamic acid was identified as the most suitable catalyst to obtain the target products in good yields up to 90 %. These structurally exciting heterocyclic hybrids were screened against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. This series displayed moderate to excellent inhibitory potential against AChE with IC₅₀ values > 25 µM and the most active compound was 3-(4-(1-(3,5-dimethylphenyl)-4,5-diphenyl-1H-imidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl)–2H-chromen-2-one (5x) with IC₅₀ value of 25.83 ± 0.25 µM.This inhibitory potential was attributed to hydrophobicity as the major contributory factor. The most potent compound against BChE was 1,3-diphenyl-4-(1,4,5-triphenyl-1H-imidazol-2-yl)-1H-pyrazole (5a) with IC₅₀ value of 0.35 ± 0.02 µM followed by other potent compounds 5p, 5 m, 5x, 5b, 5c, 5e and 5f with IC₅₀ values < 10 µM. SAR studies further revealed that coumarinyl moiety at R¹ position in the imidazolylpyrazole skeleton significantly improved the overall cholinesterase inhibitory potential. However, a simple phenyl ring attached at this R¹ site was highly effective and selective for BChE inhibition (5a) over AChE. Docking data also demonstrated the interaction of 5x and AChE with a docking score of 7564 and atomic contact energy (ACE) value of –291.90 kcal/mol whereas docking score for 5a against BChE was 7096 with ACE value of –332.95 kcal/mol. The results altogether suggest further investigations of the heteroaryl substituted imidazole core skeleton in search of potential leads towards designing of new anti-cholinesterase drugs for the treatment of AD.     

Strategies for examination of Alzheimer’s disease amyloid precursor protein isoforms

We describe a proteomics procedure using bioinformatics, immunoprecipitation, two-dimensional gel electrophoresis, Western blotting, in-gel digestion, LC–MS, MALDI–MS, and MS–MS for isolation and identification of amyloid precursor protein (APP) isoforms APP₆₉₅, APP₇₅₁, and APP₇₇₀. Retinoic acid-induced Ntera 2 cell line, derived from a human teratocarcinoma cells, was the in-vitro source of APP. Initial isolation of whole APP was performed by immunoprecipitation, using AB10, a monoclonal antibody raised to amino acids 1–17 of the β-amyloid peptide sequence, which is present in all three alpha secretase-cleaved isoforms of interest. The next stage was separation of whole APP into its isoform components by two-dimensional gel electrophoresis. Because of low APP concentrations, detection by the usual staining methods, for example Sypro Ruby, able to detect low picomole concentrations, did not enable visualisation of the isoforms. Western analysis, however, enabled primary detection of APP, because of the inherent sensitivity of antibodies raised to specific isoform regions. This initial visualization acted as a template for excision of isoforms from 2D gels, which were then subjected to peptide mass mapping. Initial theoretical digestion of each isoform revealed the presence of specific peptides, which were then used as “tags” for isoform detection.     

Metal-amyloid-β peptide interactions: a preliminary investigation of molecular mechanisms for Alzheimer’s disease

Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2 and Zn2 inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.     

Molecular docking studies of coumarin hybrids as potential acetylcholinesterase,butyrylcholinesterase, monoamine oxidase A/B and β-amyloid inhibitors for Alzheimer’s disease

Coumarins are the phytochemicals, which belong to the family of benzopyrone, that display interesting pharmacological properties. Several natural, synthetic and semisynthetic coumarin derivatives have been discovered in decades for their applicability as lead structures as drugs. Coumarin based conjugates have been described as potential AChE, BuChE, MAO and β-amyloid inhibitors. Therefore, the objective of this review is to focus on the construction of these pharmacologically important coumarin analogues with anti-Alzheimer’s activities, highlight their docking studies and structure–activity relationships based on their substitution pattern with respect to the selected positions on the chromen ring by emphasising on the research reports conducted in between year 1968 to 2017.

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New naphthalene derivative for cost-effective AChE inhibitors for Alzheimer’s treatment: In silico identification,in vitro and in vivo validation

Neurodegenerative diseases have complex etiology and pose a challenge to scientists to develop simple and cost-effective synthetic compounds as potential drug candidates for such diseases. Here, we report an extension of our previously published in silico screening, where we selected four new compounds as AChE inhibitors. Further, based on favorable binding possess, MD simulation and MMGBSA, two most promising compounds (3a and 3b) were selected, keeping in view the ease of synthesis and cost-effectiveness. Due to the critical role of BChE, LOX and α-glucosidase in neurodegeneration, the selected compounds were also screened against these enzymes.The IC₅₀ values of 3a against AChE and BChE found to be 12.53 and 352.42 μM, respectively. Moderate to slight inhibitions of 45.26 % and 28.68 % were presented by 3a against LOX and α-glucosidase, respectively, at 0.5 mM. Insignificant inhibitions were observed with 3b against the four selected enzymes. Further, in vivo trial demonstrated that 3a could significantly diminish AChE levels in the mice brain as compared to the control. These findings were in agreement with the histopathological analysis of the brain tissues. The results corroborate that selected compounds could serve as a potential lead for further development and optimization as AChE inhibitors to achieve cost-effective anti-Alzheimer’s drugs.     

Infrared spectroscopic analysis of mononuclear leukocytes in peripheral blood from Alzheimer’s disease patients

Peripheral mononuclear leukocytes from Alzheimer’s disease (AD) patients were analyzed by infrared spectroscopy and their spectroscopic properties were compared with those from age-matched healthy controls. Two-dimensional correlation analysis of mean spectra measured at various disease stages shows that the protein secondary structure from AD patients involves β-sheet enrichment and carbonyl intensity increase relative to healthy controls. The area percentages of β-sheets, which were obtained by using a peak ratio second-derivative spectral treatment, were used for receiver operating characteristic (ROC) analysis to distinguish between patients with AD and age-matched healthy controls. The critical concentration and area under the curve (AUC) were determined by this curve analysis which showed a good performance for this quantitative assay. The results were 90% sensitivity and 90.5% specificity for determinations involving mild and moderate AD patients, and 82.1% sensitivity and 90.5% specificity for determinations involving patients at the three AD stages (mild, moderate, and severe). The AUC was greater than 0.85 in both scenarios. Taken together these results show that healthy controls are distinguished from mild and moderate AD patients better than from patients with severe disease and suggest that this infrared analysis is a promising strategy for AD diagnostics.     

Application of multilayered strategy for variable selection in QSAR modeling of PET and SPECT imaging agents as diagnostic agents for Alzheimer’s disease

Structural Chemistry - Non-invasive imaging of amyloid beta (Aβ) and tau fibrils in the brain may support an early and precise diagnosis of Alzheimer’s disease. Molecular imaging...     

Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffold-based novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin–morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin–piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys^® Discovery Studio^® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design.     

Evaluating the biochemical potential for Irbid’s food waste as a source for energy

Solid waste generated from the city of Irbid is all directed to a local unlined landfill with no gas collection system. More than half of the waste stream is made of food waste which turns the landfill to a concentrated point source of greenhouse gases. To assess the impact that the landfill has at the moment on global warming and to evaluate the future value of the city’s waste as a source of biogas, 20 trucks of municipal solid waste were sampled. In addition, food waste samples from Irbid were collected from five different sources for 12 weeks to quantify their generation rates and to measure their components and chemical composition. Irbid’s solid waste was found to have a distinctively high biodegradable content 68%, which is typical of developing countries’ solid waste. Physical assessment showed that 38%, 6%, 33% and 23% of the food waste was rice, meat, fruits and vegetables, and bread, respectively. Measured methane yields for the volatile solids (VS) in rice, meat, fruits and vegetables, and bread were 362, 499, 352 and 375 mL/g VS, respectively. A representative food waste sample was created to test the actual methane yield and compare it to calculated one. Actual methane yield (414 mL/g VS) was greater than the calculated value (370 mL/g VS) based on food type proportions and their specific methane yield. To assess the anaerobic biodegradability of food waste, a stoichiometric calculation of the methane production was made based on the elemental analysis of all food waste elements. Food waste was found to have the chemical formula C₇H₁₆O₅N and calculated methane potential of 447 mL/g VS; indicating 85% anaerobic biodegradability of food waste, which makes Irbid’s waste perceived as a valuable source of energy.     

Synthesis, structure, and properties of a new phosphorus-containing Schiff’s base, a derivative of pyrazole-5-one

A new Schiff’s base and its salt have been prepared from 2-aminophenyl(triphenyl)phosphonium chloride and 5-hydroxy-3-methyl-1-phenyl-4-formylpyrazole. The products structures have been proved by IR, ¹H NMR, and UV spectroscopy, mass spectrometry, X-ray diffraction analysis, and quantum-chemical modeling. Possible tautomerism and some properties of the products have been studied.     

Molecular interpretation of Trouton’s and Hildebrand’s rules for the entropy of vaporization of a liquid

The entropy of vaporization at a liquid’s boiling point is well approximated by Trouton’s rule and even more accurately by Hildebrand’s rule. A cell method is used here to calculate the entropy of vaporization for a range of liquids by subtracting the entropy of the gas from that of the liquid. The liquid’s entropy is calculated from the force magnitudes measured in a molecular dynamics simulation based on the harmonic approximation. The change in rotational entropy is not accounted for except in the case of liquid water. The predicted entropies of vaporization agree well with experiment and Trouton’s and Hildebrand’s rules for most liquids and for water except other liquids with hydrogen bonds. This supports the idea that molecular rotation is close to ideal at a liquid’s boiling point if hydrogen bonds are absent; if they are present, then the rotational entropy gain must be included. The method provides a molecular interpretation of those rules by providing an equation in terms of a molecule’s free volume in a liquid which depends on the force magnitudes. Free volumes at each liquid’s boiling point are calculated to be ～1 Å³ for liquids lacking hydrogen bonds, lower at ～0.3 Å³ for those with hydrogen bonds, and they decrease weakly with increasing molecular size.     

Characterization of a new epoxy-hydroxycarvotanacetone derivative from the leaf essential oil of Laggera pterodonta from Côte d’Ivoire

The leaf essential oil of Laggera pterodonta (DC.) Sch. Bip. ex Oliv. (Asteraceae) collected in the Eastern Côte d’Ivoire was investigated using a combination of chromatographic (GC-RI, CC, pc-GC) and spectroscopic (GC-MS, ¹³C NMR) techniques. Eighty-three components accounting for 98.0% of the whole composition were identified with 2,5-dimethoxy-p-cymene (43.3%), sabinene (14.1%), α-humulene (9.8%), (E)-β-caryophyllene (7.2%) and germacrene D (5.2%) as major compounds. This study led to the structural elucidation of a new natural compound, (3αH,4βH,6αH,1αMe)-1,6-epoxy-3-hydroxycarvotanacetone, angelic acid ester from the leaf oil by 1D and 2D NMR spectroscopy.     

A label-free MALDI TOF MS-based method for studying the kinetics and inhibitor screening of the Alzheimer’s disease drug target β-secretase

Analytical and Bioanalytical Chemistry - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) is a well-established method with a unique set of qualities...     

Synthesis of N-substituted ε-hexonolactams as pharmacological chaperones for the treatment of N370S mutant Gaucher disease

A series of N-substituted ε-hexonolactams have been designed and prepared by a concise route with a tandem ring-expansion reaction as the key step. Some of the N-substituted ε-hexonolactams show better enhancements to N370S mutant β-glucocerebrosidase activity than NB-DNJ and NN-DNJ. Both the experimental results and computational studies highlight the importance of the carbonyl group for stabilizing protein folds in the mutant enzyme. The structure-activity relationships are also discussed. These novel N-alkylated iminosugars are promising pharmacological chaperones for the treatment of N370S mutant Gaucher disease.     

Nano-HPLC–MS analysis of phospholipids in cerebrospinal fluid of Alzheimer’s disease patients—a pilot study

There is emerging evidence that lipids play an important role in many neurodegenerative processes, for example in Alzheimer's disease (AD). Although different lipid alterations in the AD brain have been reported, there have only been very few investigations of lipid changes in the cerebrospinal fluid (CSF). Recent developments in mass spectrometry (MS) have enabled fast and sensitive detection of lipid species in different biological matrixes. In this study we developed an on-line HPLC-MS method for phospholipid profiling in the CSF based on nano-HPLC separation using an Amide column and detection with electrospray (ESI) quadrupole-time of flight (QTOF) MS. We achieved good separation, reproducibility, and sensitivity in monitoring of the major phospholipid classes, phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylinositol (PI), and sphingomyelin (SM) in CSF. To emphasize the applicability of the method, a pilot study was performed on a group of CSF samples (N = 16) from individuals with probable AD and non-demented controls. We observed a statistically significant increase of SM levels (24.3 ± 2.4%) in CSF from probable AD individuals vs. controls. Our findings indicate that SM levels in the CSF could potentially provide a new lead in AD biomarker research, and show the potential of the method for disease-associated CSF phospholipid screening.