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Pharmacological Research Aug 2020Phenothiazines inhibit major antioxidant defense mechanisms in trypanosomatids and exhibit potent cytotoxic effects in vitro. However, the relevance of these drugs in...
Phenothiazines inhibit major antioxidant defense mechanisms in trypanosomatids and exhibit potent cytotoxic effects in vitro. However, the relevance of these drugs in the treatment of Trypanosoma cruzi-induced acute myocarditis is poorly explored, especially in combination with reference trypanocidal drugs. Thus, we compared the antiparasitic and cardioprotective potential of thioridazine (TDZ) and benznidazole (Bz) administered in monotherapy and combined in a murine model of T. cruzi-induced acute myocarditis. Female mice were randomized into six groups: (i) uninfected untreated, (ii) infected untreated, or infected treated with (iii) Bz (100 mg/kg), (iv) TDZ (80 mg/kg), (v) Bz (100 mg/kg) + TDZ (80 mg/kg), or (vi) Bz (50 mg/kg) + TDZ (80 mg/kg). Infected animals were inoculated with 2000 T. cruzi trypomastigotes and treated by gavage for 20 days. Animals that received TDZ alone presented the highest levels of parasitemia, parasitic load and anti-T. cruzi immunoglobulin G titers; cardiac upregulation of N-acetyl-β-D-glucosaminidase activity, nitric oxide, malondialdehyde and cytokines (IFN-γ, TNF-α, IL-10 and IL-17); as well as microstructural damage compared to the other groups (p < 0.05). These parameters were reduced in groups receiving Bz monotherapy compared to the other groups (p < 0.05). The combination of TDZ and Bz attenuated the response to treatment, worsening parasitological control, oxidative heart damage and myocarditis compared to the group treated with Bz alone (p < 0.05). Our results indicate that when administered alone, TDZ potentiated the pathological outcomes in animals infected with T. cruzi. Moreover, TDZ attenuated the antiparasitic effect of Bz when administered together, impairing parasitological control, potentiating inflammation, molecular oxidation and pathological microstructural remodeling of the heart. Thus, our findings indicate that TDZ acts as a pharmacological risk factor and Bz-based monotherapy remains a better cardioprotective drug against Trypanosoma cruzi-induced acute myocarditis.
Topics: Animals; Antiprotozoal Agents; Chagas Cardiomyopathy; Chagas Disease; Drug Therapy, Combination; Female; Mice; Myocarditis; Nitroimidazoles; Phenothiazines; Trypanocidal Agents; Trypanosoma cruzi
PubMed: 32416214
DOI: 10.1016/j.phrs.2020.104907 -
Dermatology Online Journal Feb 2013A 50-year-old man presented with a scaly erythema of the face, upper chest, forearms, and dorsum of the hands. He has been treated with cyamemazine for 6 months....
A 50-year-old man presented with a scaly erythema of the face, upper chest, forearms, and dorsum of the hands. He has been treated with cyamemazine for 6 months. Photopatch tests were performed and the patient was diagnosed with photoallergic reaction to cyamemazine. The drug was discontinued and a course of oral steroids was prescribed. The patient was advised to avoid light exposure. There has been no evidence of recurrence during a six-month follow-up period. Photoallergic reactions are much less frequent than phototoxic disorders. It is well known that several drugs including neuroleptics of the phenothiazine family may produce a skin eruption on light-exposed areas by dose-dependent (phototoxic) or photoallergic mechanisms. It is believed that photopatch testing, which is the clinical investigation of choice for suspected photoallergic reactions, is significantly underused in Europe and probably world-wide.
Topics: Anti-Anxiety Agents; Dermatitis, Photoallergic; Dermatitis, Phototoxic; Humans; Male; Middle Aged; Patch Tests; Phenothiazines; Photosensitizing Agents
PubMed: 23473285
DOI: No ID Found -
Molecules (Basel, Switzerland) May 2024In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10-phenothiazine salts is prepared. These title compounds and their precursors...
In this study, a library of 3,7-di(hetero)aryl-substituted 10-(3-trimethylammoniumpropyl)10-phenothiazine salts is prepared. These title compounds and their precursors are reversible redox systems with tunable potentials. The Hammett correlation gives a very good correlation of the first oxidation potentials with σ parameters. Furthermore, the title compounds and their precursors are blue to green-blue emissive. Screening of the salts reveals for some derivatives a distinct inhibition of several pathogenic bacterial strains (, , , , and ) in the lower micromolar range.
Topics: Anti-Bacterial Agents; Microbial Sensitivity Tests; Phenothiazines; Salts; Staphylococcus aureus; Quaternary Ammonium Compounds; Escherichia coli; Oxidation-Reduction; Bacteria; Molecular Structure; Structure-Activity Relationship
PubMed: 38731617
DOI: 10.3390/molecules29092126 -
Proceedings of the National Academy of... Aug 2001Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrP(Sc)) of the normal host prion protein (PrP(C)) and... (Comparative Study)
Comparative Study
Prion diseases in humans and animals are invariably fatal. Prions are composed of a disease-causing isoform (PrP(Sc)) of the normal host prion protein (PrP(C)) and replicate by stimulating the conversion of PrP(C) into nascent PrP(Sc). We report here that tricyclic derivatives of acridine and phenothiazine exhibit half-maximal inhibition of PrP(Sc) formation at effective concentrations (EC(50)) between 0.3 microM and 3 microM in cultured cells chronically infected with prions. The EC(50) for chlorpromazine was 3 microM, whereas quinacrine was 10 times more potent. A variety of 9-substituted, acridine-based analogues of quinacrine were synthesized, which demonstrated variable antiprion potencies similar to those of chlorpromazine and emphasized the importance of the side chain in mediating the inhibition of PrP(Sc) formation. Thus, our studies show that tricyclic compounds with an aliphatic side chain at the middle ring moiety constitute a new class of antiprion reagents. Because quinacrine and chlorpromazine have been used in humans for many years as antimalarial and antipsychotic drugs, respectively, and are known to pass the blood-brain barrier, we suggest that they are immediate candidates for the treatment of Creutzfeldt-Jakob disease and other prion diseases.
Topics: Acridines; Animals; Cells, Cultured; Chlorpromazine; Fatty Acids; Humans; Mice; Neuroblastoma; Phenothiazines; PrPSc Proteins; Prion Diseases; Protein Conformation; Quinacrine; Safety; Structure-Activity Relationship; Time Factors; Tumor Cells, Cultured
PubMed: 11504948
DOI: 10.1073/pnas.161274798 -
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 -
The Journal of Physical Chemistry. B Feb 2023In this study, we report a comprehensive time-resolved spectroscopic investigation of the excited-state deactivation mechanism in three push-pull isomers characterized...
In this study, we report a comprehensive time-resolved spectroscopic investigation of the excited-state deactivation mechanism in three push-pull isomers characterized by a phenothiazine electron donor, a benzothiazole electron acceptor, and a phenyl π-bridge where the connection is realized at the relative , , and positions. Spin-orbit charge-transfer-induced intersystem crossing takes place with high yield in these all-organic donor-acceptor compounds, leading also to efficient production of singlet oxygen. Our spectroscopic results give clear evidence of room-temperature phosphorescence not only in solid-state host-guest matrices but also in highly biocompatible aggregates of these isomers produced in water dispersions, as rarely reported in the literature. Moreover, aggregates of the isomers could be internalized by lung cancer and melanoma cells and display bright luminescence without any dark cytotoxic effect. On the other hand, the isomers showed significant cellular phototoxicity against the tumor cells due to light-induced reactive oxygen species generation. Our findings strongly suggest that nanoaggregates of the investigated isomers are promising candidates for imaging-guided photodynamic therapy.
Topics: Temperature; Isomerism; Luminescence; Phenothiazines
PubMed: 36735941
DOI: 10.1021/acs.jpcb.2c07717 -
International Journal of Molecular... Nov 2021A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of...
A series of new tertiary phenothiazine derivatives containing a quinoline and a pyridine fragment was synthesized by the reaction of 1-methyl-3-benzoylthio-4-butylthioquinolinium chloride with 3-aminopyridine derivatives bearing various substituents on the pyridine ring. The direction and mechanism of the cyclization reaction of intermediates with the structure of 1-methyl-4-(3-pyridyl)aminoquinolinium-3-thiolate was related to the substituents in the 2- and 4-pyridine position. The structures of the compounds were analyzed using H, C NMR (COSY, HSQC, HMBC) and X-ray analysis, respectively. Moreover, the antiproliferative activity against tumor cells (A549, T47D, SNB-19) and a normal cell line (NHDF) was tested. The antibacterial screening of all the compounds was conducted against the reference and quality control strain ATCC 29213, three clinical isolates of methicillin-resistant (MRSA). In silico computation of the intermolecular similarity was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of structure/property-related descriptors calculated for the novel tetracyclic diazaphenothiazine derivatives. The distance-oriented property evaluation was correlated with the experimental anticancer activities and empirical lipophilicity as well. The quantitative shape-based comparison was conducted using the CoMSA method in order to indicate the potentially valid steric, electronic and lipophilic properties. Finally, the numerical sampling of similarity-related activity landscape (SALI) provided a subtle picture of the SAR trends.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Heterocyclic Compounds; Humans; Microbial Sensitivity Tests; Neoplasms; Phenothiazines; Staphylococcus aureus; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 34884631
DOI: 10.3390/ijms222312826 -
Identification of phenothiazine derivatives as UHM-binding inhibitors of early spliceosome assembly.Nature Communications Nov 2020Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM...
Interactions between U2AF homology motifs (UHMs) and U2AF ligand motifs (ULMs) play a crucial role in early spliceosome assembly in eukaryotic gene regulation. UHM-ULM interactions mediate heterodimerization of the constitutive splicing factors U2AF65 and U2AF35 and between other splicing factors that regulate spliceosome assembly at the 3' splice site, where UHM domains of alternative splicing factors, such as SPF45 and PUF60, contribute to alternative splicing regulation. Here, we performed high-throughput screening using fluorescence polarization assays with hit validation by NMR and identified phenothiazines as general inhibitors of UHM-ULM interactions. NMR studies show that these compounds occupy the tryptophan binding pocket of UHM domains. Co-crystal structures of the inhibitors with the PUF60 UHM domain and medicinal chemistry provide structure-activity-relationships and reveal functional groups important for binding. These inhibitors inhibit early spliceosome assembly on pre-mRNA substrates in vitro. Our data show that spliceosome assembly can be inhibited by targeting UHM-ULM interactions by small molecules, thus extending the toolkit of splicing modulators for structural and biochemical studies of the spliceosome and splicing regulation.
Topics: Alternative Splicing; Humans; Phenothiazines; Protein Binding; Protein Domains; RNA Precursors; RNA Splicing Factors; Repressor Proteins; Spliceosomes; Splicing Factor U2AF
PubMed: 33159082
DOI: 10.1038/s41467-020-19514-1 -
Daru : Journal of Faculty of Pharmacy,... Sep 2018Fluphenazine and prochlorperazine as phenothiazine-class antipsychotic drugs are widely used to treat schizophrenia, however their use is associated with significant...
PURPOSE
Fluphenazine and prochlorperazine as phenothiazine-class antipsychotic drugs are widely used to treat schizophrenia, however their use is associated with significant side effects such as extrapyramidal symptoms, as well as ocular and skin disorders. Our goal was to determine the effect of fluphenazine and prochlorperazine on cell viability and melanogenesis in lightly pigmented normal human melanocytes.
METHODS
The viability of melanocytes was evaluated by the WST-1 colorimetric assay, while melanin content and tyrosinase activity were tested spectrophotometrically.
RESULTS
It has been shown that both phenothiazines induce the concentration-dependent loss in cell viability. The EC values were calculated to be 6.13 and 0.63 μM for fluphenazine and prochlorperazine, respectively. Fluphenazine in the concentration of 5.0 μM and prochlorperazine in concentrations of 0.5 and 0.75 μM decreased melanin content and tyrosinase activity. The observed inhibition of melanogenesis may be explained by the decrease of enzyme activity.
CONCLUSIONS
The demonstrated changes in melanization process in lightly pigmented cells exposed to fluphenazine and prochlorperazine in vitro suggest a significant role of melanin and melanocytes in the mechanisms of undesirable side effects of these drugs in vivo. Graphical abstract Fluphenazine and prochlorperazine significantly inhibits melanogenesis in lightly pigmented melanocytes HEMn-LP.
Topics: Cell Survival; Cells, Cultured; Fluphenazine; Humans; Melanins; Melanocytes; Monophenol Monooxygenase; Prochlorperazine
PubMed: 30159761
DOI: 10.1007/s40199-018-0206-4 -
Molecules (Basel, Switzerland) May 2018We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three...
We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound showed the most potent inhibitory effect against MCF-7 cells, with an IC value of 0.8 μM. Importantly, compound could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.
Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Molecular Structure; Phenothiazines; Structure-Activity Relationship
PubMed: 29843370
DOI: 10.3390/molecules23061288