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Laser irradiated phenothiazines: New potential treatment for COVID-19 explored by molecular docking.Journal of Photochemistry and... Oct 2020The worldwide infection with the new Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) demands urgently new potent treatment(s). In this study we predict,...
The worldwide infection with the new Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) demands urgently new potent treatment(s). In this study we predict, using molecular docking, the binding affinity of 15 phenothiazines (antihistaminic and antipsychotic drugs) when interacting with the main protease (M) of SARS-CoV-2. Additionally, we tested the binding affinity of photoproducts identified after irradiation of phenothiazines with Nd:YAG laser beam at 266 nm respectively 355 nm. Our results reveal that thioridazine and its identified photoproducts (mesoridazine and sulforidazine) have high biological activity on the virus M. This shows that thioridazine and its two photoproducts might represent new potent medicines to be used for treatment in this outbreak. Such results recommend these medicines for further tests on cell cultures infected with SARS-CoV-2 or animal model. The transition to human subjects of the suggested treatment will be smooth due to the fact that the drugs are already available on the market.
Topics: Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus 3C Proteases; Coronavirus Infections; Cysteine Endopeptidases; Host Microbial Interactions; Humans; Lasers, Solid-State; Molecular Docking Simulation; Pandemics; Phenothiazines; Photochemical Processes; Pneumonia, Viral; SARS-CoV-2; Structure-Activity Relationship; Viral Nonstructural Proteins; COVID-19 Drug Treatment
PubMed: 32829256
DOI: 10.1016/j.jphotobiol.2020.111997 -
Molecules (Basel, Switzerland) May 2020This mini-review summarizes the syntheses and functionalizations of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines, both electron density-enriched congeners... (Review)
Review
This mini-review summarizes the syntheses and functionalizations of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines, both electron density-enriched congeners of phenothiazines with remarkable electronic properties. Diversity-oriented, straightforward, and efficient syntheses, including versatile one-pot processes, have been developed for the anellated 1,4-thiazines as well as various functionalization for the expansion of the π-systems. Thereby, syntheses of different regioisomers depending on the (benzo)thieno-thiazine anellation are discussed, which exert a deep impact on the electronic properties. The tunable photophysical and electrochemical properties of dithieno[1,4]thiazines and bis[1]benzothieno[1,4]thiazines outscore phenothiazines on many points and promise an enormous potential in molecular electronics and applications beyond.
Topics: Electrons; Heterocyclic Compounds; Organometallic Compounds; Phenothiazines; Protein Isoforms; Thiazines
PubMed: 32392728
DOI: 10.3390/molecules25092180 -
International Journal of Molecular... Mar 2023The paper aims to investigate the antitumor activity of a series of phenothiazine derivatives in order to establish a structure-antitumor activity relationship. To this...
The paper aims to investigate the antitumor activity of a series of phenothiazine derivatives in order to establish a structure-antitumor activity relationship. To this end, PEGylated and TEGylated phenothiazine have been functionalized with formyl units and further with sulfonamide units via dynamic imine bonds. Their antitumor activity was monitored in vitro against seven human tumors cell lines and a mouse one compared to a human normal cell line by MTS assay. In order to find the potential influence of different building blocks on antitumor activity, the antioxidant activity, the ability to inhibit farnesyltransferase and the capacity to bind amino acids relevant for tumor cell growth were investigated as well. It was established that different building blocks conferred different functionalities, inducing specific antitumor activity against the tumor cells.
Topics: Humans; Animals; Mice; Structure-Activity Relationship; Phenothiazines; Antipsychotic Agents; Neoplasms; Farnesyltranstransferase; Cell Proliferation; Polyethylene Glycols; Antineoplastic Agents; Drug Screening Assays, Antitumor; Cell Line, Tumor
PubMed: 36982524
DOI: 10.3390/ijms24065449 -
ACS Infectious Diseases Apr 2018New classes of antifungal drugs are an urgent unmet clinical need. One approach to the challenge of developing new antifungal drugs is to optimize the antifungal...
New classes of antifungal drugs are an urgent unmet clinical need. One approach to the challenge of developing new antifungal drugs is to optimize the antifungal properties of currently used drugs with favorable pharmacologic properties, so-called drug or scaffold repurposing. New therapies for cryptococcal meningitis are particularly important given its worldwide burden of disease and limited therapeutic options. We report the first systematic structure-activity study of the anticryptococcal properties of the phenothiazines. We also show that the antifungal activity of the phenothiazine scaffold correlates well with its calmodulin antagonism properties and, thereby, provides the first insights into the mechanism of its antifungal properties. Guided by this mechanism, we have generated improved trifluoperazine derivatives with increased anticryptococcal activity and, importantly, reduced affinity for receptors that modulate undesired neurological effects. Taken together, these data suggest that phenothiazines represent a potentially useful scaffold for further optimization in the search for new antifungal drugs.
Topics: Antifungal Agents; Antipsychotic Agents; Candida albicans; Cryptococcus neoformans; Drug Repositioning; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Structure; Phenothiazines; Sensory Receptor Cells; Structure-Activity Relationship
PubMed: 29058407
DOI: 10.1021/acsinfecdis.7b00157 -
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 -
European Journal of Pharmaceutical... Oct 2016The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride,...
The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37°C. The pKa values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37°C and methanol/water at 25°C). The log S-pH profiles were measured at 24h incubation time in 0.15M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pKa values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S0) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25°C were 0.5, 1.1, and 2.7μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152kJ·mol(-1)). Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25°C. The effects persisted at 37°C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.
Topics: Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Micelles; Phenothiazines; Solubility; Spectrophotometry, Ultraviolet; Temperature
PubMed: 27449396
DOI: 10.1016/j.ejps.2016.07.013 -
International Journal of Molecular... Mar 2021We report here the synthesis and structural characterization of novel cationic (phenothiazinyl)vinyl-pyridinium (PVP) dyes, together with optical (absorption/emission)...
We report here the synthesis and structural characterization of novel cationic (phenothiazinyl)vinyl-pyridinium (PVP) dyes, together with optical (absorption/emission) properties and their potential applicability as fluorescent labels. Convective heating, ultrasound irradiation and mechanochemical synthesis were considered as alternative synthetic methodologies proficient for overcoming drawbacks such as long reaction time, nonsatisfactory yields or solvent requirements in the synthesis of novel dye (E)-1-(3-chloropropyl)-4-(2-(10-methyl-10H-phenothiazin-3-yl)vinyl)pyridin-1-ium bromide and its -alkyl-2-methylpyridinium precursor . The geometry of the newly synthesized (E)-4-(2-(7-bromo-10-ethyl-10H-phenothiazin-3-yl)vinyl)-1-methylpyridin-1-ium iodide and (E)-1-methyl-4-(2-(10-methyl-10H-phenothiazin-3-yl)vinyl)pyridin-1-ium tetrafluoroborate was confirmed by single crystal X-ray diffraction. A negative solvatochromism of the dyes in polar solvents was highlighted by UV-Vis spectroscopy and explanatory insights were supported by molecular modeling which suggested a better stabilization of the lowest unoccupied molecular orbitals (LUMO). The photostability of the dye was investigated by irradiation at 365 nm in different solvents, while the steady-state and time-resolved fluorescence properties of dye and in solid state were evaluated under one-photon excitation at 485 nm. The in vitro cytotoxicity of the new PVP dyes on B16-F10 melanoma cells was evaluated by WST-1 assay, while their intracellular localization was assessed by epi-fluorescence conventional microscopy imaging as well as one- and two-photon excited confocal fluorescence lifetime imaging microscopy (FLIM). PVP dyes displayed low cytotoxicity, good internalization inside melanoma cells and intense fluorescence emission inside the B16-F10 murine melanoma cells, making them suitable staining agents for imaging applications.
Topics: Animals; Fluorescent Dyes; Mice; Microscopy, Fluorescence; Phenothiazines; Photons; Pyridinium Compounds; Solvents; Spectrometry, Fluorescence; Staining and Labeling
PubMed: 33804193
DOI: 10.3390/ijms22062985 -
British Journal of Pharmacology and... Apr 1964Chlorpromazine and phenoxybenzamine have been shown to potentiate the actions of bradykinin in vivo. To test whether this phenomenon could be due to inhibition of the...
Chlorpromazine and phenoxybenzamine have been shown to potentiate the actions of bradykinin in vivo. To test whether this phenomenon could be due to inhibition of the enzymatic destruction of bradykinin, bradykinin was incubated with either tissue extracts or with carboxypeptidase B. Bradykinin was rapidly destroyed by acetonedried powders of brain and serum of various animals as well as by purified carboxypeptidase B. The rate of disappearance of bradykinin activity was decreased in the presence of phenothiazine derivatives, phenoxybenzamine and hydroxyzine, but not by compounds of a larger group including other psychotropic drugs, tranquillizers and ganglionic and adrenergic blocking agents. Spectrophotometric studies of the hydrolysis of hippuryl-L-arginine confirmed the presence of a carboxypeptidase B-like activity in brain. The substances that acted as inhibitors of bradykinin destruction were also enzyme inhibitors as measured by this technique. Previous incubation of carboxypeptidase B with phenothiazines and zinc ions greatly reduced the enzymatic inhibition by the phenothiazines, which indicated a possible chelating action by these inhibitors on the metalo-enzyme carboxypeptidase B.
Topics: Animals; Antipsychotic Agents; Arginine; Birds; Bradykinin; Brain Chemistry; Carboxypeptidases; Cats; Cattle; Chlorpromazine; Chymotrypsin; Dogs; Enzyme Inhibitors; Ganglionic Blockers; Hallucinogens; Imipramine; In Vitro Techniques; Indoles; Pharmacology; Phenothiazines; Phenoxybenzamine; Psilocybin; Rabbits; Rats; Research; Swine; Sympatholytics; Tranquilizing Agents
PubMed: 14190467
DOI: 10.1111/j.1476-5381.1964.tb02037.x -
ChemMedChem Dec 2021The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density...
The reactivity of phenothiazine (PS), phenoselenazine (PSE), and phenotellurazine (PTE) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM-ORSA (Quantum Mechanics-based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculation. Four radical scavenging mechanisms have been screened, namely hydrogen atom transfer (HAT), radical adduct formation (RAF), single electron transfer (SET), and the direct oxidation of the chalcogen atom. The chosen ROS are HO , HOO , and CH OO . PS, PSE, and PTE exhibit an excellent antioxidant activity in water regardless of the ROS due to their characteristic diffusion-controlled regime processes. For the HO radical, the primary active reaction mechanism is, for all antioxidants, RAF. But, for HOO and CH OO , the dominant mechanism strongly depends on the antioxidant: HAT for PS and PSE, and SET for PTE. The scavenging efficiency decreases dramatically in lipid environment and remains only significant (via RAF) for the most reactive radical (HO ). Therefore, PS, PSE, and PTE are excellent antioxidant molecules, especially in aqueous, physiological environments where they are active against a broad spectrum of harmful radicals. There is no advantage or significant difference in the scavenging efficiency when changing the chalcogen since the reactivity mainly derives from the amino hydrogen and the aromatic sites.
Topics: Density Functional Theory; Dose-Response Relationship, Drug; Free Radical Scavengers; Hydrogen Peroxide; Molecular Structure; Phenothiazines; Structure-Activity Relationship
PubMed: 34536069
DOI: 10.1002/cmdc.202100546 -
Molecules (Basel, Switzerland) Jan 2019New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized...
New 10-substituted derivatives of 3,6-diazaphenothiazine, containing the triple bond linker terminated with tertiary cyclic and acyclic amine groups, were synthesized and screened for their anticancer action. The compounds exhibited varied anticancer activities against human glioblastoma SNB-19, melanoma C-32, and breast cancer MDA-MB231 cell lines, depending on the nature of the substituents. The most active 3,6-diazaphenothiazine, , was the derivative with the ,-diethylamino-2-butynyl substituent against glioblastoma SNB-19, and was ten times more potent than cisplatin. For this compound, the expression of and genes was detected by the RT-qPCR method. The gene expression ratio indicated the induction of mitochondrial apoptosis in cancer cell lines. The transformation of the propynyl substituent into amino-2-butynyl can be a method applicable to the search for more anticancer-active azaphenothiazines.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; Phenothiazines
PubMed: 30642021
DOI: 10.3390/molecules24020267