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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 -
The European Respiratory Journal Mar 2014Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for... (Review)
Review
Treatment of multidrug-resistant (MDR) tuberculosis (TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration than for drug-susceptible TB patients. In order to speed up novel treatment for MDR-TB, we suggest considering expanding the indications of already available drugs. Six drugs with antimicrobial activity (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) are not listed in the World Health Organization guidelines on MDR-TB treatment but could be potential candidates for evaluation against Mycobacterium tuberculosis. A systematic review was conducted to evaluate antituberculous activity of these drugs against M. tuberculosis. We searched PubMed, Google Scholar and Embase for English articles published up to December 31, 2012. We reviewed in vitro, in vivo and clinical antituberculous activity of these drugs in addition to pharmacokinetics and side-effects. Of the drugs effective against actively replicating M. tuberculosis, co-trimoxazole seems to be the most promising, because of its consistent pharmacokinetic profile, easy penetration into tissue and safety profile. For the dormant state of TB, thioridazine may play a potential role as an adjuvant for treatment of MDR-TB. A strategy consisting of pharmacokinetic/pharmacodynamic studies, dose finding and phase III studies is needed to explore the role of these drugs in MDR-TB treatment.
Topics: Anti-Infective Agents; Antitubercular Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Disulfiram; Doxycycline; Drug Design; Humans; Metronidazole; Minocycline; Mycobacterium tuberculosis; Phenothiazines; Tigecycline; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Multidrug-Resistant
PubMed: 23988774
DOI: 10.1183/09031936.00113713 -
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 -
Postgraduate Medical Journal Feb 1975Fifty-nine (42%) of 140 schizophrenic patients taking phenothiazines were found to have abnormal electrocardiograms. The abnormalities included T wave changes, S-T...
Fifty-nine (42%) of 140 schizophrenic patients taking phenothiazines were found to have abnormal electrocardiograms. The abnormalities included T wave changes, S-T depression, P-R and Q-T prolongation, persistent sinus tachycardia (110 or more/min) and right bundle branch block. In forty-eight (34%) of the fifty-nine patients, the ECG abnormalities disappeared after stopping the phenothiazine and reappeared on its resumption.
Topics: Adult; Bundle-Branch Block; Electrocardiography; Female; Heart; Humans; Male; Middle Aged; Phenothiazines; Schizophrenia; Tachycardia
PubMed: 1114149
DOI: 10.1136/pgmj.51.592.65 -
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 -
British Journal of Anaesthesia Apr 1962
Topics: Phenothiazines
PubMed: 13888457
DOI: 10.1093/bja/34.4.247 -
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 -
PloS One 2021The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are...
The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial activity against C. difficile. The purpose of this present study was to investigate the potential of a novel phenothiazine derivative, JBC 1847, as an oral antimicrobial for treatment of intestinal pathogens and CDIs. The minimal inhibition concentration and the minimum bactericidal concentration of JBC 1847 against C. difficile ATCC 43255 were determined 4 μg/mL and high tolerance after oral administration in mice was observed (up to 100 mg/kg bodyweight). Pharmacokinetic modeling was conducted in silico using GastroPlusTM, predicting low (< 10%) systemic uptake after oral exposure and corresponding low Cmax in plasma. Impact on the intestinal bacterial composition after four days of treatment was determined by 16s rRNA MiSeq sequencing and revealed only minor impact on the microbiota in non-clinically affected mice, and there was no difference between colony-forming unit (CFU)/gram fecal material between JBC 1847 and placebo treated mice. The cytotoxicity of the compound was assessed in Caco-2 cell-line assays, in which indication of toxicity was not observed in concentrations up to seven times the minimal bactericidal concentration. In conclusion, the novel phenothiazine derivative demonstrated high antimicrobial activity against C. difficile, had low predicted gastrointestinal absorption, low intestinal (in vitro) cytotoxicity, and only induced minor changes of the healthy microbiota, altogether supporting that JBC 1847 could represent a novel antimicrobial candidate. The clinical importance hereof calls for future experimental studies in CDI models.
Topics: Administration, Oral; Animals; Caco-2 Cells; Clostridioides difficile; Clostridium Infections; Feces; Gastrointestinal Microbiome; Humans; Mice; Phenothiazines; RNA, Ribosomal, 16S
PubMed: 34597343
DOI: 10.1371/journal.pone.0258207 -
Pharmacological Reports : PR 2012Phenothiazines belong to the oldest, synthetic antipsychotic drugs, which do not have their precursor in the world of natural compounds. Apart from their fundamental... (Review)
Review
Phenothiazines belong to the oldest, synthetic antipsychotic drugs, which do not have their precursor in the world of natural compounds. Apart from their fundamental neuroleptic action connected with the dopaminergic receptors blockade, phenothiazine derivatives also exert diverse biological activities, which account for their cancer chemopreventive-effect, as: calmodulin- and protein kinase C inhibitory-actions, anti-proliferative effect, inhibition of P-glycoprotein transport function and reversion of multidrug resistance. According to literature data on relations between chemical structure of phenothiazines and their biological effects, the main directions for further chemical modifications have been established. They are provided and discussed in this review paper.
Topics: Antipsychotic Agents; Chemoprevention; Drug Resistance, Multiple; Phenothiazines; Structure-Activity Relationship
PubMed: 22580516
DOI: 10.1016/s1734-1140(12)70726-0 -
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