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The Cornell Veterinarian 1945
Topics: Animals; Hydrocarbons; Phenothiazines; Sheep; Sheep Diseases; Sheep, Domestic
PubMed: 21005483
DOI: No ID Found -
Antiviral Research Jan 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells using angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP-1) as the primary receptor and entry co-factor, respectively. Cell entry is the first and major step in initiation of the viral life cycle, representing an ideal target for antiviral interventions. In this study, we used a recombinant replication-deficient vesicular stomatitis virus-based pseudovirus bearing the spike protein of SARS-CoV-2 (SARS2-S) to screen a US Food and Drug Administration-approved drug library and identify inhibitors of SARS-CoV-2 cell entry. The screen identified 24 compounds as primary hits, and the largest therapeutic target group formed by these primary hits was composed of seven dopamine receptor D2 (DRD2) antagonists. Cell-based and biochemical assays revealed that the DRD2 antagonists inhibited both fusion activity and the binding of SARS2-S to NRP-1, but not its binding to ACE2. On the basis of structural similarity to the seven identified DRD2 antagonists, which included six phenothiazines, we examined the anti-SARS-CoV-2 activity of an additional 15 phenothiazines and found that all the tested phenothiazines shared an ability to inhibit SARS2-S-mediated cell entry. One of the phenothiazines, alimemazine, which had the lowest 50% effective concentration of the tested phenothiazines, exhibited a clear inhibitory effect on SARS2-S-NRP-1 binding and SARS-CoV-2 multiplication in cultured cells but not in a mouse infection model. Our findings provide a basis for the development of novel anti-SARS-CoV-2 therapeutics that interfere with SARS2-S binding to NRP-1.
Topics: Animals; Mice; Angiotensin-Converting Enzyme 2; COVID-19; Neuropilin-1; Phenothiazines; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Virus Internalization; Humans
PubMed: 36481388
DOI: 10.1016/j.antiviral.2022.105481 -
Molecules (Basel, Switzerland) May 2022The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the...
The search for new ways to obtain analogues of the well-known Methylene Blue dye is an important synthetic task. Herein, we proposed and developed an approach to the synthesis of 3-'-arylaminophenothiazines and asymmetrical 3,7-di('-arylamino)phenothiazines. This approach included the optimization of synthetic strategy by quantification analysis of the positive charge distribution in the cation of 3-'-arylaminophenothiazine derivative. The obtained experimental data are confirmed by DFT studies. Two synthetic routes for asymmetrical phenothiazine diarylamino derivatives were suggested and verified. The developed convenient and versatile synthetic approach makes it easy to obtain aromatic Methylene Blue isostructural analogues with various substituents. As a result, a series of novel 3-'-arylaminophenothiazines and asymmetrical 3,7-di('-arylamino)phenothiazines containing ester, -butoxycarbonyl, sulfonic acid, hydroxyl and amine groups were obtained in high yields.
Topics: Antipsychotic Agents; Methylene Blue; Phenothiazines
PubMed: 35566375
DOI: 10.3390/molecules27093024 -
Biosensors Feb 2024A flow-through biosensor system for the determination of uric acid was developed on the platform of flow-through electrochemical cell manufactured by 3D printing from...
A flow-through biosensor system for the determination of uric acid was developed on the platform of flow-through electrochemical cell manufactured by 3D printing from poly(lactic acid) and equipped with a modified screen-printed graphite electrode (SPE). Uricase was immobilized to the inner surface of a replaceable reactor chamber. Its working volume was reduced to 10 μL against a previously reported similar cell. SPE was modified independently of the enzyme reactor with carbon black, pillar[5]arene, poly(amidoamine) dendrimers based on the -butylthiacalix[4]arene (PAMAM-calix-dendrimers) platform and electropolymerized 3,7-bis(4-aminophenylamino) phenothiazin-5-ium chloride. Introduction of the PAMAM-calix-dendrimers into the electrode coating led to a fivefold increase in the redox currents of the electroactive polymer. It was found that higher generations of the PAMAM-calix-dendrimers led to a greater increase in the currents measured. Coatings consisted of products of the electropolymerization of the phenothiazine with implemented pillar[5]arene and PAMAM-calix-dendrimers showing high efficiency in the electrochemical reduction of hydrogen peroxide that was formed in the enzymatic oxidation of uric acid. The presence of PAMAM-calix-dendrimer G2 in the coating increased the redox signal related to the uric acid assay by more than 1.5 times. The biosensor system was successfully applied for the enzymatic determination of uric acid in chronoamperometric mode. The following optimal parameters for the chronoamperometric determination of uric acid in flow-through conditions were established: pH 8.0, flow rate 0.2 mL·min, 5 U of uricase per reactor. Under these conditions, the biosensor system made it possible to determine from 10 nM to 20 μM of uric acid with the limit of detection (LOD) of 4 nM. Glucose (up to 1 mM), dopamine (up to 0.5 mM), and ascorbic acid (up to 50 μM) did not affect the signal of the biosensor toward uric acid. The biosensor was tested on spiked artificial urine samples, and showed 101% recovery for tenfold diluted samples. The ease of assembly of the flow cell and the low cost of the replacement parts make for a promising future application of the biosensor system in routine clinical analyses.
Topics: Dendrimers; Uric Acid; Urate Oxidase; Electrodes; Phenothiazines; Biosensing Techniques
PubMed: 38534227
DOI: 10.3390/bios14030120 -
International Journal of Molecular... May 2021The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new...
The synthesis of new phenothiazine derivatives, analogs of Methylene Blue, is of particular interest in the design of new drugs, as well as in the development of a new generation of agents for photodynamic therapy. In this study, two new derivatives of phenothiazine, i.e., 3,7-bis(4-aminophenylamino)phenothiazin-5-ium chloride dihydrochloride () and 3,7-bis(4-sulfophenylamino)phenothiazin-5-ium chloride (), are synthesized for the first time and characterized by NMR, IR spectroscopy, HRMS and elemental analysis. The interaction of the obtained compounds and with salmon sperm DNA is investigated. It is shown by UV-Vis spectroscopy and DFT calculations that substituents in arylamine fragments play a crucial role in dimer formation and interaction with DNA. In the case of , two amine groups promote H-aggregate formation and DNA interactions through groove binding and intercalation. In the case of , sulfanilic acid fragments prevent any dimer formation and DNA binding due to electrostatic repulsion. DNA interaction mechanisms are studied and confirmed by UV-vis and fluorescence spectroscopy in comparison with Methylene Blue. The obtained results open significant opportunities for the development of new drugs and photodynamic agents.
Topics: Amines; DNA; Dimerization; Intercalating Agents; Magnetic Resonance Spectroscopy; Methylene Blue; Models, Molecular; Molecular Conformation; Molecular Structure; Spectrometry, Fluorescence; Structure-Activity Relationship
PubMed: 34072560
DOI: 10.3390/ijms22115847 -
Molecules (Basel, Switzerland) Aug 2022The phenothiazine derivatives, tricyclic 10-3,6-diazaphenothiazine () and pentacyclic 7-(3'-dimethylaminopropyl)diquinothiazine (), have recently been shown to exhibit...
The phenothiazine derivatives, tricyclic 10-3,6-diazaphenothiazine () and pentacyclic 7-(3'-dimethylaminopropyl)diquinothiazine (), have recently been shown to exhibit promising anticancer activities in vitro. In this report, we demonstrated that and could be pro-apoptotic agents in lung carcinoma, the human lung carcinoma A549 and non-small lung carcinoma H1299, in the range of IC = 1.52-12.89 µM, with a protective potential to healthy cell lines BEAS-2B and NHDF. The compounds showed higher activity in the range of the tested concentrations and low cytotoxicity in relation to normal healthy cells than doxorubicin, used as the reference drug. The cytostatic potential of and was demonstrated with the use of MTT assay. Cell cycle analysis via flow cytometry using Annexin-V assay showed the pro-apoptotic and pro-necrotic role of the studied diazaphenothiazines in the cell cycle. and initiated a biological response in the investigated cancer models with a different mechanism and at a different rate. Based on these findings, it can be concluded that and have potential as chemotherapeutic agents.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma; Cell Line; Cell Line, Tumor; Cell Proliferation; Humans; Lung; Lung Neoplasms; Phenothiazines
PubMed: 36014495
DOI: 10.3390/molecules27165255 -
British Journal of Clinical Pharmacology Jun 1985Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and... (Clinical Trial)
Clinical Trial
Previous work has left unresolved questions on whether promethazine reduces the sensation of breathlessness. This study was designed to provide a definitive answer and to determine the contributions from promethazine's major pharmacological actions. Twelve healthy subjects participated in a double-blind, within-subject comparison of promethazine and placebo each given acutely by mouth. Breathlessness was assessed with visual analogue scales during a progressive exercise test and was related to minute ventilation. Promethazine had no significant effect on breathlessness nor on the relationship between breathlessness and ventilation. The role of histamine-antagonism was investigated in a subgroup of the subjects by administration of mebhydrolin. No effect on breathlessness was detected. In contrast, the standard phenothiazine, chlorpromazine, caused a marked and statistically significant reduction in breathlessness without affecting ventilation and without causing detectable sedation. This unexpected finding merits further study in patients and is discussed with reference to the role of chlorpromazine as a constituent of Brompton's Mixture.
Topics: Adult; Carbolines; Chlorpromazine; Humans; Physical Exertion; Promethazine; Respiration
PubMed: 4027121
DOI: 10.1111/j.1365-2125.1985.tb02716.x -
Cell Transplantation Mar 2019In vitro liver conservation is an issue of ongoing critical importance in graft transplantation. In this study, we investigated the possibility of augmenting the...
In vitro liver conservation is an issue of ongoing critical importance in graft transplantation. In this study, we investigated the possibility of augmenting the standard pre-transplant liver conservation protocol (University of Wisconsin (UW) cold solution) with the phenothiazines chlorpromazine and promethazine. Livers from male Sprague-Dawley rats were preserved either in UW solution alone, or in UW solution plus either 2.4, 3.6, or 4.8 mg chlorpromazine and promethazine (C+P, 1:1). The extent of liver injury following preservation was determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, the ratio of AST/ALT, morphological changes as assessed by hematoxylin-eosin staining, apoptotic cell death as determined by ELISA, and by expression of the apoptotic regulatory proteins BAX and Bcl-2. Levels of glucose (GLU) and lactate dehydrogenase (LDH) in the preservation liquid were determined at 3, 12, and 24 h after incubation to assess glucose metabolism. Oxidative stress was assessed by levels of superoxide dismutase (SOD), reactive oxygen species (ROS), and malondialdehyde (MDA), and inflammatory cytokine expression was evaluated with Western blotting. C+P augmentation induced significant reductions in ALT and AST activities; the AST/ALT ratio; as well as in cellular swelling, vacuolar degeneration, apoptosis, and BAX expression. These changes were associated with lowered levels of GLU and LDH; decreased expression of SOD, MDA, ROS, TNF-α, and IL-1β; and increased expression of Bcl-2. We conclude that C+P augments hypothermic preservation of liver tissue by protecting hepatocytes from ischemia-induced oxidative stress and metabolic dysfunction. This result provides a basis for improvement of the current preservation strategy, and thus for the development of a more effective graft conservation method.
Topics: Animals; Cell Hypoxia; Cold Temperature; Gene Expression Regulation; Hepatocytes; Liver; Male; Organ Preservation; Organ Preservation Solutions; Oxidative Stress; Phenothiazines; Pilot Projects; Rats; Rats, Sprague-Dawley
PubMed: 30666889
DOI: 10.1177/0963689718824559 -
Acta Pharmacologica Sinica Oct 2003To investigate the risk factors and clinical significance of blood-lipid metabolic disorder in schizophrenic patients caused by phenothiazine treatment for long term... (Comparative Study)
Comparative Study
AIM
To investigate the risk factors and clinical significance of blood-lipid metabolic disorder in schizophrenic patients caused by phenothiazine treatment for long term (from 1 month to 25 years).
METHODS
Serum levels of apolipoprotein AI (apoAI), apolipoprotein B (apoB), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC) were measured in 120 chronic schizophrenia patients, 50 vascular dementia, and 100 normal controls by the enzyme method and immune fluoroscopy turbidimetric method.
RESULTS
The patients with schizophrenia and vascular dementia had significantly lower content of apoAI, HDL-C, and apoAI/apoB than those in normal control (P<0.01). Their apoB and TG levels were higher than the healthy control group (P<0.01). The TG contents in the negative group and the vascular dementia group were obviously higher than the positive group (P<0.01) while there was no marked difference between the TC levels in the three groups and the normal control group (P>0.05).
CONCLUSION
The chronic schizophrenic patients have a blood-lipid metabolic disorder by long-term intake of phenothiazine drugs. It is suggested that the traditional treatment with antipsychotic should reformed, and that drugs of degrading lipid and coagulation should be used to prevent and reduce the risk factors causing the onset of cardiovascular and cerebrovascular diseases and delay the development of the disturbance of intelligence and dementia.
Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Apolipoprotein A-I; Apolipoproteins B; Cholesterol; Cholesterol, HDL; Dementia, Vascular; Female; Humans; Male; Middle Aged; Phenothiazines; Schizophrenia; Triglycerides
PubMed: 14531942
DOI: No ID Found -
Biomolecules Aug 2019A comparative study of melanin and ommochrome-containing samples, isolated from the black soldier fly (BSF) by enzymatic hydrolysis, alkaline and acid alcohol extraction...
A comparative study of melanin and ommochrome-containing samples, isolated from the black soldier fly (BSF) by enzymatic hydrolysis, alkaline and acid alcohol extraction or by acid hydrolysis, was carried out. Melanin was isolated both as a melanin-chitin complex and as a water-soluble melanin. Acid hydrolysis followed by delipidization yielded a more concentrated melanin sample, the electron spin resonance (ESR) signal of which was 2.6 × 10 spin/g. The ommochromes were extracted from the BSF eyes with acid methanol. The antiradical activity of BSF melanins and ommochromes was determined by the method of quenching of luminol chemiluminescence. It has been shown that delipidization of water-soluble melanin increases its antioxidant properties. A comparison of the antioxidant activity of BSF melanins and ommochromes in relation to photoinduced lipid peroxidation was carried out. The ESR characteristics of native and oxidized melanins and ommochromes were studied. It is assumed that adult flies can be a useful source of natural pigments with antioxidant properties.
Topics: Adsorption; Animals; Antioxidants; Electron Spin Resonance Spectroscopy; Hydrogen Peroxide; Light; Lipid Peroxidation; Melanins; Phenothiazines; Simuliidae
PubMed: 31450873
DOI: 10.3390/biom9090408