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In Vivo (Athens, Greece) 2004Multidrug-resistant Mycobacterium tuberculosis (MDRTB) and antibiotic-resistant Plasmodium falciparum are the major global lethal infections accounting for over 4... (Review)
Review
Multidrug-resistant Mycobacterium tuberculosis (MDRTB) and antibiotic-resistant Plasmodium falciparum are the major global lethal infections accounting for over 4 million deaths per year. Methicillin-resistant Staphylococcus aureus (MRSA) is the major global nosocomial infection and resistance to vancomycin is evident and may become common. This review provides the scientific and medical basis that support the use of one particular group of compounds, the phenothiazines, and in particular thioridazine, for the management of the above antibiotic-resistant infections. Because thioridazine, a relatively mild neuroleptic as compared to its parental compound chlorpromazine, kills intracellular MDRTB and MRSA at clinical concentrations, its use for the management of these infections may be considered. The review also discusses the activity of phenothiazines against protozoa and parasites, the mechanisms by which phenothiazines promote their antimicrobial effects, their potential for regulating efflux pumps that are a cause for mono or multidrug resistance, as well as their potential for the therapy of problematic infections caused by bacteria that have acquired plasmid-antibiotic-resistant genes.
Topics: Animals; Anti-Infective Agents; Drug Resistance; Humans; Phenothiazines; Thioridazine
PubMed: 15646813
DOI: No ID Found -
Revista Brasileira de Psiquiatria (Sao... 2021
Topics: Antipsychotic Agents; Antiviral Agents; COVID-19; Humans; Phenothiazines; SARS-CoV-2
PubMed: 33440401
DOI: 10.1590/1516-4446-2020-0024 -
Canadian Medical Association Journal Aug 1972
Topics: Antidepressive Agents; Canada; Community Mental Health Services; Depression; Fluphenazine; Humans; Methods; Motivation; Patient Care Team; Phenothiazines; Psychotherapy; Schizophrenia
PubMed: 5056113
DOI: No ID Found -
British Medical Journal Apr 1968
Topics: Central Nervous System; Chlordiazepoxide; Chlorpromazine; Diazepam; Haloperidol; Humans; Meprobamate; Phenothiazines; Promethazine; Tranquilizing Agents
PubMed: 5653035
DOI: No ID Found -
British Medical Journal Oct 1959
Topics: Antipsychotic Agents; Heterocyclic Compounds; Phenothiazines; Trifluoperazine
PubMed: 13856813
DOI: No ID Found -
Cell Apr 2020Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class...
Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.
Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Enzyme Activators; G1 Phase; Humans; Multiprotein Complexes; Phenothiazines; Phosphorylation; Protein Phosphatase 2; Protein Subunits; Trans-Activators; Transcription Factors
PubMed: 32315619
DOI: 10.1016/j.cell.2020.03.051 -
Prion Sep 2017Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death.... (Review)
Review
BACKGROUND
Sporadic fatal insomnia (sFI) is a rapid progressive neurodegenerative disease characterised by gradual to perpetual insomnia, followed by dysautonomia, coma and death. The cause of sFI was recently mapped to a mutation in a protein, the prion, found in the human brain. It is the unfolding of the prion that leads to the generation of toxic oligomers that destroy brain tissue and function. Recent studies have confirmed that a methionine mutation at codon 129 of the human Prion is characteristic of sFI. Current treatment slows down the progression of the disease, but no cure has been found, yet.
METHODS
We used Molecular Docking and Molecular Dynamics simulation methods, to study the toxic Fatal-Insomnia-prion conformations at local unfolding. The idea was to determine these sites and to stabilise these regions against unfolding and miss-folding, using a small ligand, based on a phenothiazine "moiety".
CONCLUSION
As a result we here discuss current fatal insomnia therapy and present seven novel possible compounds for in vitro and in vivo screening.
Topics: Antipsychotic Agents; Brain; Chlorpromazine; Drug Design; Humans; Insomnia, Fatal Familial; Molecular Docking Simulation; Molecular Dynamics Simulation; Mutation; Phenothiazines; Prion Proteins; Protein Unfolding
PubMed: 28976233
DOI: 10.1080/19336896.2017.1368937 -
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 -
Molecules (Basel, Switzerland) Oct 2020Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products,...
Based on reported results for the potential medicinal impact of phenothiazine core, as well as the chalcone skeleton that is widely present in many natural products, together with their reported bioactivities, the present work was aimed at combining both moieties in one molecular skeleton and to synthesize and characterize a novel series of chalone-based phenothiazine derivatives. For this purpose, 2-acetylphenothiazine was N-alkylated, followed by the Claisen-Schmidt reaction to produce the chalcones with good yield. Antioxidant activity, as evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, was assessed to determine if their antioxidant potential was comparable with ascorbic acid, and attributable to the phenothiazine core. Screening anticancer activities of the synthesized chalone-based phenothiazine derivatives against human breast cancer cell line MCF-7 cells, and human hepatocellular carcinoma HepG-2 cells, compared with standard drugs cisplatin and doxorubicin, was evaluated. The results revealed that compounds 4a 4b 4d 4h 4j 4k 4m 4o and 4p were good against human hepatocellular carcinoma HepG-2 cells, and among these compounds 4b and 4k were the most effective compounds, with IC values of 7.14 μg/mL and 7.6 1 μg/mL, respectively. On the other hand, compounds 4a 4b 4k and 4m were good against human breast cancer cell line MCF-7 cells and, among these compounds, 4k and 4b were the most effective compounds, with IC values of 12 μg/mL and 13. 8 μg/mL, respectively. The overall results suggest that these compounds could, potentially, be further modified for the formation of more potent antioxidant and anticancer agents.
Topics: Antineoplastic Agents; Antioxidants; Cell Proliferation; Cell Survival; Chalcones; Hep G2 Cells; Humans; MCF-7 Cells; Phenothiazines
PubMed: 33036301
DOI: 10.3390/molecules25194566 -
Journal of Enzyme Inhibition and... Dec 2023Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming...
Antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants potently activate pharmacologically relevant human carbonic anhydrase isoforms II and VII.
Carbonic anhydrases (CAs) are important regulators of pH homeostasis and participate in many physiological and pathological processes. CA activators (CAAs) are becoming increasingly important in the biomedical field since enhancing CA activity may have beneficial effects at neurological level. Here, we investigate selected antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants (TCAs) as potential activators of human CAs I, II, IV, and VII. Our findings indicate that these compounds are more effective at activating hCA II and VII compared to hCA I and IV. Overall, hCA VII was the most efficiently activated isoform, particularly by phenothiazines and TCAs. This is especially relevant since hCA VII is the most abundant isoform in the central nervous system (CNS) and is implicated in neuronal signalling and bicarbonate balance regulation. This study offers additional insights into the pharmacological profiles of clinically employed drugs and sets the ground for the development of novel optimised CAAs.
Topics: Humans; Antipsychotic Agents; Antidepressive Agents, Tricyclic; Carbonic Anhydrases; Protein Isoforms; Phenothiazines; Histamine Antagonists; Carbonic Anhydrase Inhibitors; Structure-Activity Relationship; Molecular Structure
PubMed: 36912265
DOI: 10.1080/14756366.2023.2188147