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Molecules (Basel, Switzerland) Nov 2022Two unique structures were isolated from the phosphorylation reaction of 10-phenothiazine. The 5,5-dimethyl-2-(10-phenothiazin-10-yl)-1,3,2-dioxaphosphinane 2-oxide ()...
Two unique structures were isolated from the phosphorylation reaction of 10-phenothiazine. The 5,5-dimethyl-2-(10-phenothiazin-10-yl)-1,3,2-dioxaphosphinane 2-oxide () illustrates the product of -phosphorylation of phenothiazine. Moreover, a potential product of instability, a thiophosphoric acid , was successfully isolated and structurally characterized. Molecule , similarly to sulfoxide derivative , possesses interesting phosphorescence properties due to the presence of d-pπ bonds. The X-ray, NMR, and DFT computational studies indicate that compound exhibits an anomeric effect. Additionally, the syntheses of selected symmetrical and unsymmetrical pyridine-embedded phenazines were elaborated. To compare the influence of phosphorus and sulfur atoms on the structural characteristics of 10-phenothiazine derivatives, the high-quality crystals of (4a,12a-dihydro-12-benzo[5,6][1,4]thiazino[2,3-]quinoxalin-12-yl)(phenyl)methanone () and selected phenazines 5,12-diisopropyl-3,10-dimethyldipyrido[3,2-:3',2'-]phenazine () and 5-isopropyl-,3-trimethylpyrido[3,2-]phenazin-10-amine () were obtained. The structures of molecules , , 2-mercapto-5,5-dimethyl-1,3,2-dioxaphosphinane 2-oxide (), 3,7-dinitro-10-phenothiazine 5-oxide (), and were determined by single-crystal X-ray diffraction measurements.
Topics: Density Functional Theory; Phenothiazines; Magnetic Resonance Spectroscopy; Phenazines; Oxides
PubMed: 36364378
DOI: 10.3390/molecules27217519 -
Communications Biology Mar 2022Bacterial persister cells are temporarily tolerant to bactericidal antibiotics but are not necessarily dormant and may exhibit physiological activities leading to cell...
Bacterial persister cells are temporarily tolerant to bactericidal antibiotics but are not necessarily dormant and may exhibit physiological activities leading to cell damage. Based on the link between fluoroquinolone-mediated SOS responses and persister cell recovery, we screened chemicals that target fluoroquinolone persisters. Metabolic inhibitors (e.g., phenothiazines) combined with ofloxacin (OFX) perturbed persister levels in metabolically active cell populations. When metabolically stimulated, intrinsically tolerant stationary phase cells also became OFX-sensitive in the presence of phenothiazines. The effects of phenothiazines on cell metabolism and physiology are highly pleiotropic: at sublethal concentrations, phenothiazines reduce cellular metabolic, transcriptional, and translational activities; impair cell repair and recovery mechanisms; transiently perturb membrane integrity; and disrupt proton motive force by dissipating the proton concentration gradient across the cell membrane. Screening a subset of mutant strains lacking membrane-bound proteins revealed the pleiotropic effects of phenothiazines potentially rely on their ability to inhibit a wide range of critical metabolic proteins. Altogether, our study further highlights the complex roles of metabolism in persister cell formation, survival and recovery, and suggests metabolic inhibitors such as phenothiazines can be selectively detrimental to persister cells.
Topics: Anti-Bacterial Agents; Escherichia coli; Fluoroquinolones; Gram-Negative Bacteria; Phenothiazines
PubMed: 35264714
DOI: 10.1038/s42003-022-03172-8 -
Viruses Jul 2023Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented...
Novel coronavirus disease 2019 (COVID-19), a respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought an unprecedented public health crisis and continues to threaten humanity due to the persistent emergence of new variants. Therefore, developing more effective and broad-spectrum therapeutic and prophylactic drugs against infection by SARS-CoV-2 and its variants, as well as future emerging CoVs, is urgently needed. In this study, we screened several US FDA-approved drugs and identified phenothiazine derivatives with the ability to potently inhibit the infection of pseudotyped SARS-CoV-2 and distinct variants of concern (VOCs), including B.1.617.2 (Delta) and currently circulating Omicron sublineages XBB and BQ.1.1, as well as pseudotyped SARS-CoV and MERS-CoV. Mechanistic studies suggested that phenothiazines predominantly inhibited SARS-CoV-2 pseudovirus (PsV) infection at the early stage and potentially bound to the spike (S) protein of SARS-CoV-2, which may prevent the proteolytic cleavage of the S protein, thereby exhibiting inhibitory activity against SARS-CoV-2 infection. In summary, our findings suggest that phenothiazines can serve as a potential broad-spectrum therapeutic drug for the treatment of SARS-CoV-2 infection as well as the infection of future emerging human coronaviruses (HCoVs).
Topics: Humans; SARS-CoV-2; Phenothiazines; COVID-19; Spike Glycoprotein, Coronavirus
PubMed: 37632009
DOI: 10.3390/v15081666 -
Journal of Photochemistry and... Sep 2022Fluorescence probes, as analytical tools with the ability to perform rapid and sensitive detection of target analytes, have made outstanding contributions to... (Review)
Review
Fluorescence probes, as analytical tools with the ability to perform rapid and sensitive detection of target analytes, have made outstanding contributions to environmental analysis and bioassays. Considering the expanding developments in these areas, fluorophores play a key role in the de-sign of fluorescence probes. Compared to classical fluorophores, phenothiazines with elec-tron-rich characteristics have been widely applied to construct electron donor-acceptor dyes, which exhibit outstanding performance in both fluorimetric and colorimetric analysis. In addition, these probes also exhibit the pronounced ability in both solution and solid-state, achieving portable detection for environmental analysis. In this review, we summarize recent advances in the performance of phenothiazine-based fluorescent probes for detecting various analytes, especially in cations, anions, ROS/RSS, enzyme and other small molecules. The general design rules, response mechanisms and practical applications of the probes are analyzed, followed by a discussion of exiting challenges and future research perspectives. It is hoped that this review will provide a few strategies for the development of phenothiazine-based fluorescent probes.
Topics: Fluorescent Dyes; Phenothiazines
PubMed: 35907277
DOI: 10.1016/j.jphotobiol.2022.112528 -
Anticancer Research Sep 2020Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research.
BACKGROUND/AIM
Phenothiazines constitute a versatile family of compounds in terms of biological activity, which have also gained a considerable attention in cancer research.
MATERIALS AND METHODS
Three phenothiazines (promethazine, chlorpromazine and thioridazine) have been tested in combination with 11 active selenocompounds against MDR (ABCB1-overexpressing) mouse T-lymphoma cells to investigate their activity as combination chemotherapy and as antitumor adjuvants in vitro with a checkerboard combination assay.
RESULTS
Seven selenocompounds showed toxicity on mouse embryonic fibroblasts, while three showed selectivity towards tumor cells. Two compounds showed synergism with all tested phenothiazines in low concentration ranges (1.46-11.25 μM). Thioridazine was the most potent among the three phenothiazines.
CONCLUSION
Phenothiazines belonging to different generations showed different levels of adjuvant activities. All the tested phenothiazines are already approved medicines with known pharmacological and toxicity profiles, therefore, their use as adjuvants in cancer may be considered as a potential drug repurposing strategy.
Topics: ATP Binding Cassette Transporter, Subfamily B; Animals; Antineoplastic Agents; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Lymphoma, T-Cell; Mice; Molecular Structure; Organoselenium Compounds; Phenothiazines
PubMed: 32878780
DOI: 10.21873/anticanres.14495 -
European Journal of Medicinal Chemistry Dec 2019A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the... (Review)
Review
A novel series of phenothiazine derivatives containing diethanolamine, methoxyethylamine, flavonoids, and a nitric oxide (NO) donor was designed and synthesized for the treatment of breast cancer. Phenothiazine derivatives (l) did not noticeably inhibit the growth of SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, whereas phenothiazine derivatives (ll) containing the NO donor were more potent or had comparable inhibitory activity to trifluoperazine (TFP) and thioridazine against SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells. Compounds 20a-c and 21a-c showed the strongest activity in SUM159, MDA-MB-231, MCF-7, and SKBR-3 cells, and more potent inhibitory activity than TFP against KG1a cells (IC = 1.63, 2.93, 1.14, 1.78, 2.20, and 1.20 vs. 4.58 μM). Compounds 20a and 21a had lower toxicity than compounds 20b-c and 21b-c, and inhibited colony formation in MCF-7 cells, decreased the formation of mammospheres in SUM159 cells, and inhibited the migration of MDA-MB-231 cells. Compounds 20a and 21a could inhibited pNF-κB-p65 as shown by dual-luciferase reporter assays and western blotting in MDA-MB-231 cells.
Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Phenothiazines; Structure-Activity Relationship
PubMed: 31541872
DOI: 10.1016/j.ejmech.2019.111692 -
Archives of Virology Nov 2022Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the...
Dengue virus (DENV), a member of the genus Flavivirus, family Flaviviridae, is the most widespread viral pathogen transmitted to humans by mosquitoes. Despite the increased incidence of DENV infection, there are no antiviral drugs available for treatment or prevention. Phenothiazines are heterocyclic compounds with various pharmacological properties that are very adaptable for drug repurposing. In the present report, we analyzed the antiviral activity against DENV and the related Zika virus (ZIKV) of trifluoperazine (TFP), a phenothiazine derivative in clinical use as an antipsychotic and antiemetic agent. TFP exhibited dose-dependent inhibitory activity against the four DENV serotypes and ZIKV in monkey Vero cells at non-cytotoxic concentrations with 50% effective concentration values in the range 1.6-6.4 µM. A similar level of antiviral efficacy was exhibited by TFP against flavivirus infection in the human cell lines A549 and HepG2. Mechanistic studies, performed using time-dependent infectivity assays, real-time RT-PCR, Western blot, and immunofluorescence techniques, indicated that uncoating of the virus during penetration into the cell was the main target for TFP in infected cells, but the compound also exerted a minor effect on a late stage of the virus multiplication cycle. This study demonstrates that TFP, a pharmacologically active phenothiazine, is a selective inhibitor of DENV multiplication in cell culture. Our findings open perspectives for the repositioning of phenothiazines like TFP with a wide spectrum of antiviral efficacy as potential agents for the control of pathogenic flaviviruses.
Topics: Animals; Antiemetics; Antipsychotic Agents; Antiviral Agents; Chlorocebus aethiops; Dengue; Dengue Virus; Humans; Phenothiazines; Trifluoperazine; Vero Cells; Virus Replication; Zika Virus; Zika Virus Infection
PubMed: 35920983
DOI: 10.1007/s00705-022-05555-y -
Anticancer Research Nov 2016Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has... (Review)
Review
Thioridazine (TZ), an antipsychotic drug, renders multidrug-resistant (MDR) cancer cells susceptible to cytotoxic agents to which they were initially resistant, has anti-prolilferative activity and apoptosis-inducing properties in various tumor cell lines and cancer stem cells. Whereas the anti-proliferative activity takes place at high concentrations that ensure the intercalation of the compound between nucleic bases (especially rich in G/C bases), much lower concentrations inhibit the export function of the ABCB1 (P-glycoprotein), which is responsible for the MDR phenotype of the cancer cell. The co-administration of TZ with doxorubicin inhibits efflux of doxorubicin and, hence, increases the intracellular concentration of anticancer drug. The (+) and (-) enantiomers of TZ have the same activities as TZ. The main focus of this review is to present extensive evidence provided by our work, confirmed by much later studies, as it supports adjuvant use of TZ with an anticancer drug for MDR cancer therapy.
Topics: Antineoplastic Agents; Antipsychotic Agents; Apoptosis; DNA Damage; Drug Resistance, Neoplasm; Humans; Neoplasms; Phenothiazines; Thioridazine
PubMed: 27793891
DOI: 10.21873/anticanres.11153 -
Veterinary Anaesthesia and Analgesia Mar 2021To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
OBJECTIVE
To evaluate the effects of incremental doses of acepromazine on hemodynamics in isoflurane-anesthetized dogs.
STUDY DESIGN
Prospective, experimental study.
ANIMALS
Healthy, adult, mixed-breed dogs (two male and four female) weighing 16.8 ± 5.1 kg (mean ± standard deviation).
METHODS
Dogs were anesthetized with propofol (7 mg kg) intravenously (IV) and isoflurane. Thermodilution and arterial catheters were placed for hemodynamic monitoring and arterial blood sampling for blood gas analysis. Baseline measurements were performed with stable expired concentration of isoflurane (Fe'Iso) at 1.8%. Each dog was then administered four incremental acepromazine injections (10, 15, 25 and 50 μg kg) IV, and measurements were repeated 20 minutes after each acepromazine injection with Fe'Iso decreased to 1.2%. The four acepromazine injections resulted in cumulative doses of 10, 25, 50 and 100 μg kg (time points ACP, ACP, ACP and ACP, respectively).
RESULTS
Compared with baseline, cardiac index (CI) increased significantly by 34%, whereas systemic vascular resistance index (SVRI) decreased by 25% at ACP and ACP. Arterial oxygen content (CaO) was significantly lower than baseline after all acepromazine injections (maximum decreases of 11%) and was lower at ACP and ACP than at ACP. No significant change was found in heart rate, stroke index, oxygen delivery index and systolic, mean and diastolic blood pressures. Hypotension (mean arterial pressure < 60 mmHg) was observed in one dog at baseline, ACP, ACP and ACP, and in two dogs at ACP.
CONCLUSIONS AND CLINICAL RELEVANCE
Compared with isoflurane alone, anesthesia with acepromazine-isoflurane resulted in increased CI and decreased SVRI and CaO values. These effects were dose-related, being more pronounced at ACP and ACP. Under the conditions of this study, acepromazine administration did not change blood pressure.
Topics: Acepromazine; Animals; Blood Pressure; Cross-Over Studies; Dogs; Female; Heart Rate; Hemodynamics; Isoflurane; Male; Prospective Studies
PubMed: 33388251
DOI: 10.1016/j.vaa.2020.11.003 -
International Microbiology : the... Mar 2015Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the... (Review)
Review
Historically, multiplicity of actions in synthetic compounds is a rule rather than exception. The science of non-antibiotics evolved in this background. From the antimalarial and antitrypanosomial dye methylene blue, chemically similar compounds, the phenothiazines, were developed. The phenothiazines were first recognised for their antipsychotic properties, but soon after their antimicrobial functions came to be known and then such compounds were designated as non-antibiotics. The emergence of highly drug-resistant bacteria had initiated an urgent need to search for novel affordable compounds. Several phenothiazines awakened the interest among scientists to determine their antimycobacterial activity. Chlorpromazine, trifluoperazine, methdilazine and thioridazine were found to have distinct antitubercular action. Thioridazine took the lead as researchers repeatedly claimed its potentiality. Although thioridazine is known for its central nervous system and cardiotoxic side-effects, extensive and repeated in vitro and in vivo studies by several research groups revealed that a very small dose of thioridazine is required to kill tubercle bacilli inside macrophages in the lungs, where the bacteria try to remain and multiply silently. Such a small dose is devoid of its adverse side-effects. Recent studies have shown that the (-) thioridazine is a more active antimicrobial agent and devoid of the toxic side effects normally encountered. This review describes the possibilities of bringing down thioridazine and its (-) form to be combined with other antitubercular drugs to treat infections by drug-resistant strains of Mycobacterium tuberculosis and try to eradicate this deadly disease.
Topics: Antipsychotic Agents; Antitubercular Agents; Chlorpromazine; Humans; Mycobacterium tuberculosis; Phenothiazines; Thioridazine; Trifluoperazine; Tuberculosis, Multidrug-Resistant
PubMed: 26415662
DOI: 10.2436/20.1501.01.229