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ACS Applied Bio Materials Oct 2023A formate (HCOO) bioanode was developed by utilizing a phenothiazine-based electropolymerized layer deposited on sucrose-derived carbon. The electrode modified with...
A formate (HCOO) bioanode was developed by utilizing a phenothiazine-based electropolymerized layer deposited on sucrose-derived carbon. The electrode modified with NAD-dependent formate dehydrogenase and the electropolymerized layer synergistically catalyzed the oxidation of the coenzyme (NADH) and fuel (HCOO) to achieve efficient electron transfer. Further, the replacement of carbon nanotubes with water-dispersible sucrose-derived carbon used as the electrode base allowed the fabrication of a surfactant-free bioanode delivering a maximum current density of 1.96 mA cm in the fuel solution. Finally, a separator- and surfactant-free HCOO/O biofuel cell featuring the above bioanode and a gas-diffusion biocathode modified with bilirubin oxidase and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) was fabricated, delivering a maximum power density of 70 μW cm (at 0.24 V) and an open-circuit voltage of 0.59 V. Thus, this study demonstrates the potential of formic acid as a fuel and possibilities for the application of carbon materials in bioanodes.
Topics: Surface-Active Agents; Bioelectric Energy Sources; Nanotubes, Carbon; Formates; Phenothiazines; Sucrose
PubMed: 37750824
DOI: 10.1021/acsabm.3c00502 -
Photodiagnosis and Photodynamic Therapy Jun 2021The aim of the present study was to compare the effects of the phenothiazine photosensitizers methylene blue (MB), toluidine blue-O (TBO) and butyl toluidine blue (BuTB)...
AIM
The aim of the present study was to compare the effects of the phenothiazine photosensitizers methylene blue (MB), toluidine blue-O (TBO) and butyl toluidine blue (BuTB) in antimicrobial photodynamic therapy (aPDT), as adjuvant therapy to scaling and root planing (SRP) in the treatment of experimental periodontitis (EP) in rats.
MATERIAL AND METHODS
120 Wistar rats underwent ligation around the lower left molar. After seven days, the ligature was removed. The animals were separated into the following groups (n = 15): EP, no treatment; SRP, SRP and irrigation with saline solution; MB, SRP and deposition of MB; TBO, SRP and deposition of TBO; BuTB, SRP and deposition of BuTB; MB-aPDT, SRP and aPDT with MB; TBO-aPDT, SRP and aPDT with TBO and; BuTB-aPDT, SRP and aPDT with BuTB. The aPDT session was performed after SRP, with deposition of the photosensitizer and irradiation with a diode laser (DL; InGaAlP, 660 nm, 40 mW, 60 s, 2.4 J). Histological and histometric analysis was performed.
RESULTS
BuTB-aPDT group had a lesser extent of the inflammatory process compared to the EP, SRP, MB and TBO at all experimental periods (p < 0.05). At 15 days, the aPDT treated groups had a greater bone tissue structure than groups EP and SRP (p < 0.05) The BuTB showed lower Alveolar Bone Loss (ABL) compared to the TBO-aPDT group at 30 days (p < 0.05).
CONCLUSION
aPDT using the photosensitizer BuTB proved to be the adjuvant therapy that most favored the reduction of inflammatory infiltrate in the furcation area and ABL.
Topics: Animals; Dental Scaling; Periodontitis; Phenothiazines; Photochemotherapy; Photosensitizing Agents; Rats; Rats, Wistar; Root Planing
PubMed: 33578028
DOI: 10.1016/j.pdpdt.2021.102198 -
Analytical Chemistry Oct 2023The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of...
The uncontrollable distribution of antitumor agents remains a large obstacle for specific and efficient cancer theranostics; thus, efficient construction of tumor-specific systems is highly desirable. In this work, a general design of tumor stimulus-activatable pretheranostic agents was put forward via a series of structures-tunable triphenylamine derivatives (, , and ) with phenothiazine, benzothiazine, and thiomorpholine as identifying groups of hypochlorite (HClO), respectively. Notably, the sulfur atom in phenothiazine of was more easily oxidized to sulfoxide groups by HClO, transforming into an electron acceptor to form an excellent push-pull electronic system, which was beneficial to a large redshift of absorbance and emission wavelengths. Based on this, resorted to a key of overexpressed HClO in the tumor to open "three locks", viz, NIR fluorescence, photothermal, and photoacoustic signals for multimodal diagnostic and treatment of the tumor. This study provided an elegant design to adopt tumor stimulus-triggerable pretheranostic for improving theranostic accuracy and efficiency, which was regarded as a promising candidate for precision medicine.
Topics: Humans; Neoplasms; Antineoplastic Agents; Phenothiazines; Theranostic Nanomedicine; Phototherapy; Nanoparticles
PubMed: 37824749
DOI: 10.1021/acs.analchem.3c02777 -
European Journal of Medicinal Chemistry Sep 2020Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a...
Targeting energy metabolism in Mycobacterium tuberculosis (Mtb) is a new paradigm in the search for innovative anti-TB drugs. NADH:menaquinone oxidoreductase is a non-proton translocating type II NADH dehydrogenase (NDH-2) that is an essential enzyme in the respiratory chain of Mtb and is not found in mammalian mitochondria. Phenothiazines (PTZs) represent one of the most known class of NDH-2 inhibitors, but their use as anti-TB drugs is currently limited by the wide range of potentially serious off-target effects. In this work, we designed and synthesized a series of new PTZs by decorating the scaffold in an unconventional way, introducing various halogen atoms. By replacing the sulfur atom with selenium, a dibromophenoselenazine 20 was also synthesized. Among the synthesized poly-halogenated PTZs (HPTZs), dibromo and tetrachloro derivatives 9 and 11, along with the phenoselenazine 20, emerged with a better anti-TB profile than the therapeutic thioridazine (TZ). They targeted non-replicating Mtb, were bactericidal, and synergized with rifampin and bedaquiline. Moreover, their anti-TB activity was found to be related to the NDH-2 inhibition. Most important, they showed a markedly reduced affinity to dopaminergic and serotonergic receptors respect to the TZ. From this work emerged, for the first time, as the poly-halogenation of the PTZ core, while permitting to maintain good anti-TB profile could conceivably lead to fewer CNS side-effects risk, making more tangible the use of PTZs for this alternative therapeutic application.
Topics: Animals; Antitubercular Agents; Chlorocebus aethiops; Drug Synergism; Enzyme Inhibitors; HEK293 Cells; Humans; Microsomes, Liver; Molecular Structure; Mycobacterium smegmatis; Mycobacterium tuberculosis; NADH Dehydrogenase; Organoselenium Compounds; Parasitic Sensitivity Tests; Phenothiazines; Protein Binding; Receptors, Dopamine D2; Receptors, Serotonin; Structure-Activity Relationship; Vero Cells
PubMed: 32526553
DOI: 10.1016/j.ejmech.2020.112420 -
Chemico-biological Interactions Aug 2019Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic... (Review)
Review
Overview of novel multifunctional agents based on conjugates of γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes for treatment of Alzheimer's disease.
Alzheimer's disease (AD) is a multifactorial neurodegenerative process whose effective treatment will require drugs that can act simultaneously on multiple pathogenic targets. Here, we present an overview of our previous multitarget studies of five groups of novel hybrid structures that combine, through spacers, five pharmacophores that have been found promising for AD treatment: γ-carbolines, carbazoles, tetrahydrocarbazoles, phenothiazines, and aminoadamantanes. Biological activity of the compounds was assessed by a battery of assays. These included inhibitory potency against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) as indicators of potential for cognition enhancement and against carboxylesterase (CaE) to exclude unwanted inhibition of this biotransformation pathway. Displacement of propidium from the peripheral anionic site of AChE was determined as a predictor of anti-aggregation activity. Binding to the two sites of the NMDA subtype of the glutamate receptor was conducted as an additional indicator of potential cognition enhancement and neuroprotection. Propensity to protect against mitochondrial triggers of cell death was evaluated by tests of mitochondrial potential and calcium-induced swelling as indicators of mitochondrial permeability transition. Antioxidant potential was measured to evaluate the tendency to prevent oxidative stress. Potential for disease modification was gauged by the ability to stimulate microtubule assembly. Finally, binding modes of conjugates to AChE and BChE were studied using quantum mechanical-assisted molecular docking. We found selective BChE inhibitors (conjugates of γ-carbolines and phenothiazine I, γ-carbolines and carbazoles II, and aminoadamantanes and carbazoles III) as well as inhibitors of both cholinesterases (conjugates of γ-carbolines and methylene blue IV and bis-γ-carbolines with ditriazole-containing spacers V). These compounds combined potentials for cognition enhancement, neuroprotection, and disease modification. None of the conjugates exhibited high potency against CaE, thereby precluding potential drug-drug interactions from CaE inhibition. Thus, the studied compounds exhibited positive characteristics of multitarget drugs, indicating their potential for the next generation of AD therapeutics.
Topics: Adamantane; Alzheimer Disease; Binding Sites; Carbazoles; Carbolines; Cholinesterase Inhibitors; Cholinesterases; Humans; Molecular Docking Simulation; Phenothiazines
PubMed: 31100279
DOI: 10.1016/j.cbi.2019.05.020 -
Journal of Photochemistry and... Sep 2015Photodynamic antimicrobial chemotherapy (PACT) is a very promising alternative to conventional antibiotics for the efficient inactivation of pathogenic microorganisms;... (Review)
Review
Photodynamic antimicrobial chemotherapy (PACT) is a very promising alternative to conventional antibiotics for the efficient inactivation of pathogenic microorganisms; this is due to the fact that it is virtually impossible for resistant strains to develop due to the mode of action employed. PACT employs a photosensitizer, which preferentially associates with the microorganism, and is then activated with non-thermal visible light of appropriate wavelength(s) to generate high localized concentrations of reactive oxygen species (ROS), inactivating the microorganism. The concept of using photosensitizers immobilized on a surface for this purpose is intended to address a range of economic, ecological and public health issues. Photosensitising molecules that have been immobilized on solid support for PACT applications are described herein. Different supports have been analyzed as well as the target microorganism and the effectiveness of particular combinations of support and photosensitizer.
Topics: Animals; Anti-Infective Agents; Humans; Indoles; Light; Phenothiazines; Photochemotherapy; Photosensitizing Agents; Porphyrins; Rose Bengal; Ruthenium
PubMed: 25982328
DOI: 10.1016/j.jphotobiol.2015.04.021 -
European Journal of Pharmacology Nov 2020In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not... (Review)
Review
In 2020 the whole world focused on antivirus drugs towards SARS-CoV-2. Most of the researchers focused on drugs used in other viral infections or malaria. We have not seen such mobilization towards one topic in this century. The whole situation makes clear that progress needs to be made in antiviral drug development. The first step to do it is to characterize the potential antiviral activity of new or already existed drugs on the market. Phenothiazines are antipsychotic agents used previously as antiseptics, anthelminthics, and antimalarials. Up to date, they are tested for a number of other disorders including the broad spectrum of viruses. The goal of this paper was to summarize the current literature on activity toward RNA-viruses of such drugs like chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine. We identified 49 papers, where the use of the phenothiazines for 23 viruses from different families were tested. Chlorpromazine, fluphenazine, perphenazine, prochlorperazine, and thioridazine possess anti-viral activity towards different types of viruses. These drugs inhibit clathrin-dependent endocytosis, cell-cell fusion, infection, replication of the virus, decrease viral invasion as well as suppress entry into the host cells. Additionally, since the drugs display activity at nontoxic concentrations they have therapeutic potential for some viruses, still, further research on animal and human subjects are needed in this field to verify cell base research.
Topics: Animals; Antipsychotic Agents; Antiviral Agents; Betacoronavirus; COVID-19; Chlorpromazine; Coronavirus Infections; Fluphenazine; Humans; Pandemics; Perphenazine; Phenothiazines; Pneumonia, Viral; Prochlorperazine; RNA Viruses; SARS-CoV-2; Thioridazine; COVID-19 Drug Treatment
PubMed: 32949606
DOI: 10.1016/j.ejphar.2020.173553 -
Organic & Biomolecular Chemistry Jul 2022A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of...
A two-step synthesis of phenothiazines has been developed using a dual-catalytic -thioarylation reaction of anilines as the key step. Activation of -(2-bromophenylthio)succinimide was achieved using the super Lewis acid, iron(III) triflimide and the Lewis base, diphenyl selenide, resulting in an accelerated and efficient -thioarylation reaction of various protected aniline derivatives and less reactive, unprotected analogues. The thioarylated adducts were then cyclised to the desired phenothiazines using either an Ullmann-Goldberg or Buchwald-Hartwig coupling reaction. The dual catalytic thioarylation and copper(I)-catalysed cyclisation approach was used for the four-step synthesis of methopromazine, a neuroleptic agent with antipsychotic activity.
Topics: Aniline Compounds; Catalysis; Copper; Ferric Compounds; Phenothiazines
PubMed: 35796590
DOI: 10.1039/d2ob01082h -
Journal of Experimental & Clinical... Jan 2020Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical...
BACKGROUND
Glioblastoma multiforme is a CNS cancer characterized by diffuse infiltrative growth, aggressive clinical behavior and very poor prognosis. The state-of-art clinical approach to this disease consists of surgical resection followed by radiotherapy plus concurrent and adjuvant chemotherapy with temozolomide. Tumor recurrence occurs in virtually all cases, therefore, despite any treatment, the median survival is very low (14.6 months), which makes the approach to these patients a challenging clinical issue.
MAIN BODY
The escalating costs and times required for new medications to reach the bedside make repurposing or repositioning of old drugs, when scientific bases allow their use in other pathologies, an appealing strategy. Here, we analyze a number of literature data concerning the antipsychotic chlorpromazine, the founder of the phenothiazines class of drugs, a medication widely used in the clinics for approximately 60 years. The drug exerts its effects on psychiatric patients by interfering with the dopamine receptor D, although more recent pharmacodynamics studies ascribe chlorpromazine a series of biological effects on cancer cells, all converging in hindering also glioblastoma survival capabilities.
SHORT CONCLUSIONS
On these bases, and assisted by the information on the well-established chlorpromazine toxicity and dosage in humans, we designed a Phase II clinical trial involving the combination of chlorpromazine with the standard treatment, temozolomide, in the adjuvant phase of the therapeutic protocol. Patients displaying hypo-methylation of the MGMT gene, and thus intrinsically resistant to temozolomide, will be enrolled. The endpoints of this study are the analysis of toxicity and clinical activity, as evaluated in terms of Progression-Free Survival, of the association of chlorpromazine with the first-line treatment for this very serious form of cancer.
Topics: Brain Neoplasms; Chlorpromazine; Drug Repositioning; Female; Glioblastoma; Humans; Male
PubMed: 32005270
DOI: 10.1186/s13046-020-1534-z -
European Journal of Drug Metabolism and... Apr 2019Aldehyde oxidase (AOX) is an important molybdenum-containing enzyme with high similarity with xanthine oxidase (XO). AOX involved in the metabolism of a large array of...
BACKGROUND
Aldehyde oxidase (AOX) is an important molybdenum-containing enzyme with high similarity with xanthine oxidase (XO). AOX involved in the metabolism of a large array of aldehydes and N-heterocyclic compounds and its activity is highly substrate-dependent.
OBJECTIVES
The aim of this work was to study the effect of five important phenothiazine drugs on AOX activity using benzaldehyde and phenanthridine as aldehyde and N-heterocyclic substrates, respectively.
METHODS
The effect of trifluperazine, chlorpromazine, perphenazine, thioridazine and promethazine on rat liver AOX was measured spectrophotometrically. To predict the mode of interactions between the studied compounds and AOX, a combination of homology modeling and a molecular docking study was performed.
RESULTS
All phenothiazines could inhibit AOX activity measured either by phenanthridine or benzaldehyde with almost no effect on XO activity. In the case of benzaldehyde oxidation, the lowest and highest half-maximal inhibitory concentration (IC) values were obtained for promethazine (IC = 0.9 µM), and trifluoperazine (IC = 3.9 µM), respectively; whereas perphenazine (IC = 4.3 µM), and trifluoperazine (IC = 49.6 µM) showed the strongest and weakest inhibitory activity against AOX-catalyzed phenanthridine oxidation, respectively. The in silico findings revealed that the binding site of thioridazine is near the dimer interference, and that hydrophobic interactions are of great importance in all the tested phenothiazines.
CONCLUSION
The five studied phenothiazine drugs showed dual inhibitory effects on AOX activity towards aldehydes and N-heterocycles as two major classes of enzyme substrates. Most of the interactions between the phenothiazine-related drugs and AOX in the binding pocket showed a hydrophobic nature.
Topics: Aldehyde Oxidase; Aldehydes; Amino Acid Sequence; Animals; Binding Sites; Computer Simulation; Enzyme Activation; Enzyme Inhibitors; Heterocyclic Compounds; Male; Molecular Docking Simulation; Phenothiazines; Protein Structure, Secondary; Rats; Rats, Wistar
PubMed: 30382490
DOI: 10.1007/s13318-018-0514-6