Novel tacrine-based acetylcholinesterase inhibitors as potential agents for the treatment of Alzheimer’s disease: Quinolotacrine hybrids

A new series of quinolotacrine hybrids including cyclopenta- and cyclohexa-quinolotacrine derivatives were designed, synthesized, and assessed as anti-cholinesterase (ChE) agents. The designed derivatives indicated higher inhibitory effect on the acetylcholinesterase (AChE) with IC₅₀ values of 0.285–100 µM compared to butyrylcholinesterase (BChE) with IC₅₀ values of?>?100 µM. Of these compounds, cyclohexa-quinolotacrine hybrids displayed a little better anti-AChE activity than cyclopenta-quinolotacrine hybrids. Compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c'] diquinolin-6-one (6m) including 3-hydroxyphenyl and cyclohexane ring moieties exhibited the best AChE inhibitory activity with IC₅₀ value of 0.285 µM. The kinetic and molecular docking studies indicated that compound 6m occupied both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE as a mixed inhibitor. Using neuroprotective assay against H₂O₂-induced cell death in PC12 cells, the compound 6h illustrated significant protection among the assessed compounds. In silico ADME studies estimated good drug-likeness for the designed compounds. As a result, these quinolotacrine hybrids can be very encouraging AChE inhibitors to treat Alzheimer’s disease.

Graphic abstract

A novel series of quinolotacrine hybrids were designed, synthesized, and evaluated against AChE and BChE enzymes as potential agents for the treatment of AD. The hybrids showed good to significant inhibitory activity against AChE (0.285–100 μM) compared to butyrylcholinesterase (BChE) with IC₅₀ values of?>?100 μM. Among them, compound 8-amino-7-(3-hydroxyphenyl)-5,7,9,10,11,12-hexahydro-6H-pyrano[2,3-b:5,6-c′] diquinolin-6-one (6 m) bearing 3-hydroxyphenyl moiety and cyclohexane ring exhibited the highest anti-AChE activity with IC₅₀ value of 0.285 μM. The kinetic and molecular docking studies illustrated that compound 6 m is a mixed inhibitor and binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of AChE.

     

Effects of vitrification suppression on structure morphology, conductivity and dielectric properties of vanadium phosphate glasses

Vitrification suppression in the (V₂O₅)_1−x (P₂O₅)_x glasses where x=0.10, 0.15, 0.20, and 0.25 was controlled by changing the rate of quenching glasses. The structure variations occurring in the glasses were detected by differential thermal analysis and optical microscope. The results implied the separation and growth of V₂O₅ orthorhombic microcrystal in the samples with x=0.10 and 0.15 whereas other samples did not illustrate remarkable changes in their microstructure. However, in temperature range between 300 and 473 K a semiconducting behavior for all samples appears during the study of electrical conductivity-temperature dependence. A decrease in conductivity values accompanied with some variations in activation energies by reducing quenching rate was observed. The conductivity results suggested that the conduction occurs by the phonon assisted hopping of a small polaron between V⁴⁺ and V⁵⁺ states at relatively higher temperature range above θ_D/2. Whereas at relatively low temperatures the conduction may occur by electron jumping between filled and empty states at Fermi level in the disordered matrix besides polaronic conduction. Reasonable values for the density of localized states, carrier concentration and carrier mobility were estimated and discussed. Also, dielectric constant and dielectric loss were studied as a function of frequency at different temperatures confirming the structure variations in the glass system.     

Cooperative Strategies for Solving the Bicriteria Sparse Multiple Knapsack Problem

For hard optimization problems, it is difficult to design heuristic algorithms which exhibit uniformly superior performance for all problem instances. As a result it becomes necessary to tailor the algorithms based on the problem instance. In this paper, we introduce the use of a cooperative problem solving team of heuristics that evolves algorithms for a given problem instance. The efficacy of this method is examined by solving six difficult instances of a bicriteria sparse multiple knapsack problem. Results indicate that such tailored algorithms uniformly improve solutions as compared to using predesigned heuristic algorithms.     

De novo synthesis of 4'-ethoxy nucleoside analogues

Butenolides 5a and 13 were used as optically active templates in the de novo synthesis of 4'-disubstituted nucleoside analogues. The butenolides were reduced and acylated in situ to give acetates 10 and 14. Vorbrüggen coupling gave the protected nucleoside analogues 11 and 15. Reduction of 11 gave 4'-ethoxy-2',3'-dideoxythymidine (6) and deprotection of 15 gave 4'-ethoxy-2',3'-dideoxydidehydrothymidine (7). The cis-dihydroxylation of a variety of butenolides occurred with the major product formed from oxidation of the beta-face.     

Characterization of oligosaccharide moieties of intact glycoproteins by microwave-assisted partial acid hydrolysis and mass spectrometry

A method, which utilizes microwave-assisted partial acid hydrolysis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS), to elucidate oligosaccharide composition of intact glycoproteins is presented here. Glycoproteins, such as ribonuclease B, avidin, alpha1-acid glycoprotein, and fetuin, are used as model systems to demonstrate this technique. Partial cleavage of oligosaccharides from whole intact glycoproteins with trifluoroacetic acid was observed after a short exposure to microwaves. Due to the high-resolution mass spectra obtained by MALDI-TOFMS from glycoproteins with molecular weights less than 20 kDa, the compositions of oligosaccharides are readily derived for ribonuclease B and avidin. The data agree with the proposed oligosaccharide structures of ribonuclease B (five glycoforms) and avidin (eight glycoforms). Larger glycoproteins such as alpha1-acid glycoprotein (many glycoforms) and fetuin (many glycoforms) exhibited only broad peaks with no glycoform resolution. Nevertheless, this method can be used successfully for analysis of glycoproteins with molecular weights greater than 20 kDa to determine the presence or absence of glycosylation.     

Long Duration Persistent Photocurrent in 3 nm Thin Doped Indium Oxide for Integrated Light Sensing and In-Sensor Neuromorphic Computation

Miniaturization and energy consumption by computational systems remain major challenges to address. Optoelectronics based synaptic and light sensing provide an exciting platform for neuromorphic processing and vision applications offering several advantages. It is highly desirable to achieve single-element image sensors that allow reception of information and execution of in-memory computing processes while maintaining memory for much longer durations without the need for frequent electrical or optical rehearsals. In this work, ultra-thin (<3 nm) doped indium oxide (In₂O₃) layers are engineered to demonstrate a monolithic two-terminal ultraviolet (UV) sensing and processing system with long optical state retention operating at 50 mV. This endows features of several conductance states within the persistent photocurrent window that are harnessed to show learning capabilities and significantly reduce the number of rehearsals. The atomically thin sheets are implemented as a focal plane array (FPA) for UV spectrum based proof-of-concept vision system capable of pattern recognition and memorization required for imaging and detection applications. This integrated light sensing and memory system is deployed to illustrate capabilities for real-time, in-sensor memorization, and recognition tasks. This study provides an important template to engineer miniaturized and low operating voltage neuromorphic platforms across the light spectrum based on application demand.     

Isotope‐Coded Affinity Tagging Technique Using Avidin Functional Affinity Electrophoresis: An Alternative to an Avidin Affinity Column

Avidin functional affinity electrophoresis (AFAEP) is substituted for an avidin affinity column (AAC) to capture biotinylated peptides in the Isotope‐Coded Affinity Tagging (ICAT) technique which is a valuable tool in quantitative proteomics. In this new technique, the AFAEP‐captured ICAT‐labeled biotinylated peptides are extracted with the biotin tag intact from the polyacrylamide gel piece with aqueous 95% formamide (pH 8.2) at 65 °C for 20 min, and then detected by a matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometer. Bovine serum albumin (BSA) and the ¹²C‐ and ¹³C‐ICAT reagents are used to test this AFAEP‐ICAT technique. The results show that both AFAEP and AAC methods provide quantitative information of the relative amounts of ¹²C‐ and ¹³C‐ICAT‐labeled biotinylated tryptic peptides of BSA in a sample. Compared with AAC, the AFAEP is cheaper to perform, more stringent in capturing the biotinylated peptides, and capable of simultaneously processing multiple samples.