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Current Neuropharmacology 2021The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from...
The aim of this work is to review tacrine analogues from the last three years, which were not included in the latest review work, donepezil and galantamine hybrids from 2015 and rivastigmine derivatives from 2014. In this account, we summarize the efforts toward the development and characterization of non-toxic inhibitors of cholinesterases based on mentioned drugs with various interesting additional properties such as antioxidant, decreasing β-amyloid plaque aggregation, nitric oxide production, pro-inflammatory cytokines release, monoamine oxidase-B activity, cytotoxicity and oxidative stress in vitro and in animal model that classify these hybrids as potential multifunctional therapeutic agents for Alzheimer's disease. Moreover, herein, we have described the cholinergic hypothesis, mechanisms of neurodegeneration and current pharmacotherapy of Alzheimer's disease based on the restoration of cholinergic function through blocking enzymes that break down acetylcholine.
Topics: Alzheimer Disease; Animals; Cholinesterase Inhibitors; Donepezil; Galantamine; Rivastigmine; Tacrine
PubMed: 33342413
DOI: 10.2174/1570159X19666201218103434 -
Chemphyschem : a European Journal of... Aug 2022Chemiluminescent labelling, which is one of the promising procedures of modern immunodiagnostics, is increasingly carried out using acridinium derivatives, an oxidant,...
Chemiluminescent labelling, which is one of the promising procedures of modern immunodiagnostics, is increasingly carried out using acridinium derivatives, an oxidant, and an alkaline aqueous environment. However, the efficiency of the chemiluminescence of luminol or acridinium esters is higher in non-aqueous solvents such as dimethyl sulfoxide or acetonitrile. Therefore, the search for a new environment for the chemiluminescence reaction, especially the one characterized by a higher quantum yield of chemiluminescence, is one of the aims of current research. Using computational methods (DFT and TD DFT with PCM model of solvent), we examined thermodynamic and kinetic data concerning the chemiluminescence and competitive dark pathways. Our results suggest that better characteristics of the chemiluminescence reaction of acridinium thioester are observed in nonpolar solvents, such as methylcyclohexane, n-hexane and n-pentane, than in aqueous media used so far. Further experimental verification is necessary to confirm the possible application of proposed nonpolar solvents in chemiluminescent labelling and hence in immunodiagnostics.
Topics: Acridines; Luminescence; Luminescent Measurements; Luminol; Solvents
PubMed: 35607880
DOI: 10.1002/cphc.202200166 -
Journal of Molecular Modeling Jun 2022Using TD-DFT/DFT, the ground and excited states of the acriflavine dye were studied in an aqueous medium. The mutual influence of photoexcitation and strong hydrogen...
Using TD-DFT/DFT, the ground and excited states of the acriflavine dye were studied in an aqueous medium. The mutual influence of photoexcitation and strong hydrogen bonds with the solvent was studied by comparing the purely implicit and combined modeling of the aqueous environment of the dye. The excitation of acriflavine was calculated considering the vibronic coupling. The effect of photoexcitation on dye vibrations was analyzed. The spatial structure of the acriflavine H-dimer was obtained and its absorption was estimated.
Topics: Acriflavine; Hydrogen Bonding; Quantum Theory; Solvents; Water
PubMed: 35723744
DOI: 10.1007/s00894-022-05182-z -
Langmuir : the ACS Journal of Surfaces... May 2022Quinacrine is a versatile drug that is widely recognized for its antimalarial action through its inhibition of the phospholipase enzyme. It also has antianthelmintic and...
Quinacrine is a versatile drug that is widely recognized for its antimalarial action through its inhibition of the phospholipase enzyme. It also has antianthelmintic and antiprotozoan activities and is a strong DNA binder that may be used to combat multidrug resistance in cancer. Despite extensive cell-based studies, a detailed understanding of quinacrine's influence on the cell membrane, including permeability, binding, and rearrangement at the molecular level, is lacking. Herein, we apply microcavity-suspended lipid bilayers (MSLBs) as models of the cell membrane comprising DOPC, DOPC:Chol(3:1), and DOPC:SM:Chol(2:2:1) to investigate the influence of cholesterol and intrinsic phase heterogeneity induced by mixed-lipid composition on the membrane interactions of quinacrine. Using electrochemical impedance spectroscopy (EIS) and surface-enhanced Raman spectroscopy (SERS) as label-free surface-sensitive techniques, we have studied quinacrine interaction and permeability across the different MSLBs. Our EIS data reveal that the drug is permeable through ternary DOPC:SM:Chol and DOPC-only bilayer compositions. In contrast, the binary cholesterol/DOPC membrane arrested permeation, yet the drug binds or intercalates at this membrane as reflected by an increase in membrane impedance. SERS supported the EIS data, which was utilized to gain structural insights into the drug-membrane interaction. Our SERS data also provides a simple but powerful label-free assessment of drug permeation because a significant SERS enhancement of the drug's Raman signature was observed only if the drug accessed the plasmonic interior of the pore cavity passing through the membrane. Fluorescent lifetime correlation spectroscopy (FLCS) provides further biophysical insight, revealing that quinacrine binding increases the lipid diffusivity of DOPC and the ternary membrane while remarkably decreasing the lipid diffusivity of the DOPC:Chol membrane. Overall, because of its adaptability to multimodal approaches, the MSLB platform provides rich and detailed insights into drug-membrane interactions, making it a powerful tool for drug screening.
Topics: Cell Membrane; Cholesterol; Dielectric Spectroscopy; Lipid Bilayers; Phosphatidylcholines; Quinacrine
PubMed: 35561255
DOI: 10.1021/acs.langmuir.2c00524 -
Vestnik Otorinolaringologii 2021Evaluation of the effectiveness of various schemes of local immunotherapy in immunocompromised patients with allergic rhinitis was carried out.
UNLABELLED
Evaluation of the effectiveness of various schemes of local immunotherapy in immunocompromised patients with allergic rhinitis was carried out.
MATERIALS AND METHODS
A comparative analysis of the treatment of 72 patients with allergic rhinitis, divided into groups: I (main, =21), which included immunocompromised patients who received sublingual allergen-specific immunotherapy with antipollin and inhaled immunotherapy with cycloferon (every other day, a course of 10 procedures, the total dose of Cycloferon per course is 1250 mg); II (comparison, =22) - immunocompromised patients who received monotherapy with antipollinum and III (control, =29) - patients with allergic rhinitis without signs of immunocompromise, who also received antipollinum. The effectiveness of therapy was assessed by the quality of life (RQLQ questionnaire), the severity of nasal symptoms (the patient's self-observation diary) and the need for drugs after a course of intranasal immunotherapy.
RESULTS
The inclusion of cycloferon in the treatment of immunocompromised patients with allergic rhinitis increased its effectiveness - the severity of nasal symptoms decreased: in terms of sneezing, a decrease of 53.5 times versus 1.82 - in the control, «nasal congestion» - 6.3 times versus 2.6 - in the control, «itching in the nose» - 4.9 and 4.2 times, respectively (<0.05). The changes had a positive effect on the total indicator of the quality of life of patients - an increase of 6.2 times (by 83.7%) (>0.05) and significantly reduced the need for cromones (18 times, versus 10.3 - in the group comparison), inhaled corticosteroids (10.4 times versus 8 times in the comparison group, and in decongestans - 8.1 times versus 6.1 - in the comparison group (>0.05)).
CONCLUSIONS
The combined use of local immunotherapy with cycloferon and sublingual allergen-specific immunotherapy with antipollinum in immunocompromised patients with allergic rhinitis is the first-line method of choice that statistically significantly changes the quality of life of patients.
Topics: Acridines; Humans; Immunotherapy; Quality of Life; Rhinitis; Rhinitis, Allergic
PubMed: 33720657
DOI: 10.17116/otorino20218601178 -
NeuroImage Sep 2022Transitive inference (TI) is a critical capacity involving the integration of relevant information into prior knowledge structure for drawing novel inferences on... (Meta-Analysis)
Meta-Analysis
Transitive inference (TI) is a critical capacity involving the integration of relevant information into prior knowledge structure for drawing novel inferences on unobserved relationships. To date, the neural correlates of TI remain unclear due to the small sample size and heterogeneity of various experimental tasks from individual studies. Here, the meta-analysis on 32 fMRI studies was performed to detect brain activation patterns of TI and its three paradigms (spatial inference, hierarchical inference, and associative inference). We found the hippocampus, prefrontal cortex (PFC), putamen, posterior parietal cortex (PPC), retrosplenial cortex (RSC), supplementary motor area (SMA), precentral gyrus (PreCG), and median cingulate cortex (MCC) were engaged in TI. Specifically, the RSC was implicated in the associative inference, whereas PPC, SMA, PreCG, and MCC were implicated in the hierarchical inference. In addition, the hierarchical inference and associative inference both evoked activation in the hippocampus, medial PFC, and PCC. Although the meta-analysis on spatial inference did not generate a reliable result due to insufficient amount of investigations, the present work still offers a new insight for better understanding the neural basis underlying TI.
Topics: Aminoacridines; Gyrus Cinguli; Humans; Magnetic Resonance Imaging; Parietal Lobe; Prefrontal Cortex
PubMed: 35659997
DOI: 10.1016/j.neuroimage.2022.119354 -
The Journal of Organic Chemistry Aug 2022The total synthesis of marine alkaloids cystodytins A-K has been accomplished in five to six steps starting from commercially available compounds. The highlights of the...
The total synthesis of marine alkaloids cystodytins A-K has been accomplished in five to six steps starting from commercially available compounds. The highlights of the synthesis include an oxidative amination-cyclization of tryptamine and para-hydroquinones to build a tetracyclic pyridoacridinone ring with different side chains and a copper(II)-catalyzed enantioselective Henry reaction to construct an oxygenated stereogenic carbon center. For the first time, the absolute configuration of the stereogenic centers embedded in cystodytins D-I and K was established as . Moreover, the stereochemistry of the olefin unit in the side chain of cystodytins H and I was revised to the configuration from the originally assigned configuration.
Topics: Acridines; Alkaloids; Amination; Cyclization; Stereoisomerism
PubMed: 35947782
DOI: 10.1021/acs.joc.2c01317 -
Bioorganic & Medicinal Chemistry Jan 2021Unlike other DNA topoisomerase II (topo II) inhibitors, our recently identified acridone derivative E17 exerted strong cytotoxic activity by inhibiting topo II without...
Unlike other DNA topoisomerase II (topo II) inhibitors, our recently identified acridone derivative E17 exerted strong cytotoxic activity by inhibiting topo II without causing topo II degradation and DNA damage, which promoted us to explore more analogues of E17 by expanding its chemical diversification and enrich the structure-activity relationship (SAR) outcomes of acridone-oriented chemotypes. To achieve this goal, 42 novel acridone derivatives were synthesized and evaluated for their antiproliferative efficacies. SAR investigations revealed that orientation and spatial topology of R substituents make greater contributions to the bioactivity, exemplified by compounds E24, E25 and E27, which has provided valuable information for guiding further development of acridone derivatives as promising drug candidates.
Topics: Acridones; Antineoplastic Agents; Cell Proliferation; DNA Topoisomerases, Type II; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Topoisomerase II Inhibitors; Tumor Cells, Cultured
PubMed: 33191085
DOI: 10.1016/j.bmc.2020.115868 -
International Journal of Pharmaceutics Aug 2020Manufacturing of liposomal nanomedicines (e.g. Doxil®/Caelyx®) is a challenging and slow process based on multiple-vessel and batch processing techniques. As a result,... (Comparative Study)
Comparative Study
Manufacturing of liposomal nanomedicines (e.g. Doxil®/Caelyx®) is a challenging and slow process based on multiple-vessel and batch processing techniques. As a result, the translation of these nanomedicines from bench to bedside has been limited. Microfluidic-based manufacturing offers the opportunity to address this issue, and de-risk the wider adoption of nanomedicines. Here we demonstrate the applicability of microfluidics for continuous manufacturing of PEGylated liposomes encapsulating ammonium sulfate (250 mM). Doxorubicin was subsequently active-loaded into these pre-formed liposomes. Critical process parameters and material considerations demonstrated to influence the liposomal product attributes included solvent selection and lipid concentration, flow rate ratio, and temperature and duration used for drug loading. However, the total flow rate did not affect the liposome product characteristics, allowing high production speeds to be adopted. The final liposomal product comprised of 80-100 nm vesicles (PDI < 0.2) encapsulating ≥ 90% doxorubicin, with matching release profiles to the innovator product and is stable for at least 6 months. Additionally, vincristine and acridine orange were active-loaded into these PEGylated liposomes (≥ 90% and ~100 nm in size) using the same process. These results demonstrate the ability to produce active-loaded PEGylated liposomes with high encapsulation efficiencies and particle sizes which support tumour targeting.
Topics: Acridine Orange; Ammonium Sulfate; Antibiotics, Antineoplastic; Doxorubicin; Drug Liberation; Drug Stability; Drug Storage; Lipids; Liposomes; Microfluidics; Nanoparticles; Particle Size; Polyethylene Glycols; Solvents; Vincristine
PubMed: 32622812
DOI: 10.1016/j.ijpharm.2020.119566 -
Analytical Chemistry Aug 20221,4-Dithiothreitol (DTT), a highly water-soluble and well-known reducing agent for preservation and regeneration of sulfhydryl groups in biomedical applications, has...
1,4-Dithiothreitol (DTT), a highly water-soluble and well-known reducing agent for preservation and regeneration of sulfhydryl groups in biomedical applications, has been developed as an efficient and stable coreactant of lucigenin for the first time. DTT efficiently reacts with lucigenin to generate intense chemiluminescence (CL), eliminating the need for external catalysts to facilitate the lucigenin CL. The DTT-lucigenin CL is approximately 15-fold more intense when compared with the lucigenin-HO classical system. Superoxide dismutase (SOD) remarkably quenches the DTT-lucigenin CL. Based on this phenomenon, a newly developed CL approach for the determination of SOD was proposed with a linear range of 0.01-1.5 μg/mL and a limit of detection of 2.2 ng/mL. Various factors affecting the CL emission of the DTT-lucigenin probe were studied and optimized. Plausible mechanistic pathways for the CL coreaction of lucigenin with DTT were proposed and fully discussed. Our proposed method not only has the merit of being selective toward the target analytes but also eliminates the need for the complex synthesis of luminescent probes and facilitates the sensitive detection of SOD in human serum and cosmetics SOD raw material with satisfactory recoveries.
Topics: Acridines; Dithiothreitol; Humans; Hydrogen Peroxide; Luminescent Agents; Luminescent Measurements; Superoxide Dismutase
PubMed: 35878317
DOI: 10.1021/acs.analchem.2c01690