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Mini Reviews in Medicinal Chemistry 2018The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs... (Review)
Review
The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.
Topics: Antitubercular Agents; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Phenothiazines; Tuberculosis
PubMed: 28486909
DOI: 10.2174/1389557517666170220152651 -
Bioorganic & Medicinal Chemistry Jan 2022Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of...
Inhibitors of the monoamine oxidase (MAO) enzymes are important agents for the treatment of central nervous system disorders and have established roles in the therapy of neuropsychiatric diseases such as depression and in the neurodegenerative disorder, Parkinson's disease. A number of good potency MAO inhibitors consist of tricyclic ring systems as exemplified by the structures of harmine and the phenothiazine compound methylene blue. In an attempt to discover novel MAO inhibitors, 30 phenothiazine, anthraquinone and related tricyclic derivatives were selected and evaluated as potential inhibitors of human MAO-A and MAO-B. The results show that, in general, the tricyclic compounds are specific inhibitors of MAO-A over the MAO-B isoform. Quinizarin (IC = 0.065 µM), 2-chloro-7-methoxy-10H-phenothiazine (IC = 0.576 µM) and xanthone (IC = 0.623 µM) proved to be the most potent MAO-A inhibitors, while the most potent MAO-B inhibition was recorded with 2-chloro-7-methoxy-10H-phenothiazine (IC = 1.34 µM), 1,2-diaminoanthraquinone (IC = 2.41 µM) and emodin (IC = 3.24 µM). These compounds may undergo further preclinical evaluation and development, and may also serve as potential lead compounds for the future design of MAO inhibitors.
Topics: Anthraquinones; Dose-Response Relationship, Drug; Humans; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Phenothiazines; Structure-Activity Relationship
PubMed: 34915314
DOI: 10.1016/j.bmc.2021.116558 -
Apoptosis : An International Journal on... Apr 2020Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing...
Glioblastoma remains the most malignant of all primary adult brain tumours with poor patient survival and limited treatment options. This study adopts a drug repurposing approach by investigating the anti-cancer activity of a derivative of the antipsychotic drug phenothiazine (DS00329) in malignant U251 and U87 glioblastoma cells. Results from MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and clonogenic assays showed that DS00329 inhibited short-term glioblastoma cell viability and long-term survival while sparing non-cancerous cells. Western blot analysis with an antibody to γH2AX showed that DS00329 induced DNA damage and flow cytometry and western blotting confirmed that it triggered a G1 cell cycle arrest which correlated with decreased levels in Cyclin A, Cyclin B, Cyclin D1 and cyclin dependent kinase 2 and an increase in levels of the cyclin dependent kinase inhibitor p21. DS00329 treated glioblastoma cells exhibited morphological and molecular markers typical of apoptotic cells such as membrane blebbing and cell shrinkage and an increase in levels of cleaved PARP. Flow cytometry with annexin V-FITC/propidium iodide staining confirmed that DS00329 induced apoptotic cell death in glioblastoma cells. We also show that DS00329 treatment of glioblastoma cells led to an increase in the autophagosome marker LC3-II and autophagy inhibition studies using bafilomycin A1 and wortmannin, showed that DS00329-induced-autophagy was a pro-death mechanism. Furthermore, DS00329 treatment of glioblastoma cells inhibited the phosphatidylinositol 3'-kinase/Akt cell survival pathway. Our findings suggest that DS00329 may be an effective treatment for glioblastoma and provide a rationale for further exploration and validation of the use of phenothiazines and their derivatives in the treatment of glioblastoma.
Topics: Antineoplastic Agents; Apoptosis; Autophagy; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; DNA Damage; Drug Repositioning; Glioblastoma; Humans; Phenothiazines; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 32036474
DOI: 10.1007/s10495-020-01594-5 -
Molecules (Basel, Switzerland) Jan 2022The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this... (Review)
Review
The molecular hybridization approach has been used to develop compounds with improved efficacy by combining two or more pharmacophores of bioactive scaffolds. In this context, hybridization of various relevant pharmacophores with phenothiazine derivatives has resulted in pertinent compounds with diverse biological activities, interacting with specific or multiple targets. In fact, the development of new drugs or drug candidates based on phenothiazine system has been a promising approach due to the diverse activities associated with this tricyclic system, traditionally present in compounds with antipsychotic, antihistaminic and antimuscarinic effects. Actually, the pharmacological actions of phenothiazine hybrids include promising antibacterial, antifungal, anticancer, anti-inflammatory, antimalarial, analgesic and multi-drug resistance reversal properties. The present review summarizes the progress in the development of phenothiazine hybrids and their biological activity.
Topics: Animals; Drug Development; Humans; Phenothiazines; Structure-Activity Relationship
PubMed: 35011508
DOI: 10.3390/molecules27010276 -
Journal of Photochemistry and... Mar 2021Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through...
Ultraviolet B (UVB) light corresponds to 5% of ultraviolet radiation. It is more genotoxic and mutagenic than UVA and causes direct and indirect cellular damage through the generation of reactive oxygen species (ROS). Even after radiation, ROS generation may continue through activation of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme. Long-term exposure can progress to premature skin aging and photocarcinogenesis. To prevent damage that is caused by UVB radiation, several studies have focused on the topical administration of compounds that have antioxidant properties. 2-Acetylphenothiazine (ML171) is a potent and selective inhibitor of NOX1. The present study investigated the antioxidant potential and photoprotective ability of ML171 in UVB-irradiated L929 fibroblasts. ML171 had considerable antioxidant activity in both the DPPH and xanthine/luminol/xanthine oxidase assays. ML171 did not induce cytotoxicity in L929 fibroblasts and increased the viability of UVB-irradiated cells. ML171 also inhibited ROS production, the enzymatic activity of NOX, depolarization of the mitochondrial membrane, and DNA damage. Additionally, ML171 protected cell membrane integrity and induced fibroblast migration. These results suggest that the incorporation of ML171 in topical administration systems may be a promising strategy to mitigate UVB-induced oxidative damage in L929 fibroblasts.
Topics: Antioxidants; Apoptosis; Cell Line; DNA Damage; Fibroblasts; Humans; Lipid Peroxidation; NADPH Oxidases; Oxidants, Photochemical; Oxidation-Reduction; Oxidative Stress; Phenothiazines; Reactive Oxygen Species; Skin; Ultraviolet Rays
PubMed: 33561688
DOI: 10.1016/j.jphotobiol.2021.112130 -
Cells Nov 2019Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the... (Review)
Review
Cancer cells activate stress-response mechanisms to adapt themselves to a variety of stressful conditions. Among these protective mechanisms, those controlled by the stress-induced nuclear protein 1 (NUPR1 ) belong to the most conserved ones. NUPR1 is an 82-residue-long, monomeric, basic and intrinsically disordered protein (IDP), which was found to be invariably overexpressed in some, if not all, cancer tissues. Remarkably, we and others have previously showed that genetic inactivation of the gene antagonizes the growth of pancreatic cancer as well as several other tumors. With the use of a multidisciplinary strategy by combining biophysical, biochemical, bioinformatic, and biological approaches, a trifluoperazine-derived compound, named ZZW-115, has been identified as an inhibitor of the NUPR1 functions. The anticancer activity of the ZZW-115 was first validated on a large panel of cancer cells. Furthermore, ZZW-115 produced a dose-dependent tumor regression of the tumor size in xenografted mice. Mechanistically, we have demonstrated that NUPR1 binds to several importins. Because ZZW-115 binds NUPR1 through the region around the amino acid Thr68, which is located into the nuclear location signal (NLS) region of the protein, we demonstrated that treatment with ZZW-115 inhibits completely the translocation of NUPR1 from the cytoplasm to the nucleus by competing with importins.
Topics: Adenocarcinoma; Animals; Basic Helix-Loop-Helix Transcription Factors; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Proteins; Pancreatic Neoplasms; Phenothiazines; Protein Transport; Xenograft Model Antitumor Assays
PubMed: 31744261
DOI: 10.3390/cells8111453 -
ACS Chemical Neuroscience May 2021Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called...
Since 2002, no clinical candidate against Alzheimer's disease has reached the market; hence, an effective therapy is urgently needed. We followed the so-called "multitarget directed ligand" approach and designed 36 novel tacrine-phenothiazine heterodimers which were evaluated for their anticholinesterase properties. The assessment of the structure-activity relationships of such derivatives highlighted compound as a potent and selective acetylcholinesterase inhibitor with IC = 8 nM and as a potent butyrylcholinesterase inhibitor with IC = 15 nM. Selected hybrids, namely, , , , , and , showed a significant inhibitory activity toward τ peptide aggregation with percent inhibition ranging from 50.5 to 62.1%. Likewise, and exerted a remarkable ability to inhibit self-induced Aβ aggregation. Notwithstanding, studies displayed cytotoxicity toward HepG2 cells and cerebellar granule neurons; no pathophysiological abnormality was observed when was administered to mice at 14 mg/kg (i.p.). was also able to permeate to the CNS as shown by and models. The maximum brain concentration was close to the IC value for acetylcholinesterase inhibition with a relatively slow elimination half-time. showed an acceptable safety and good pharmacokinetic properties and a multifunctional biological profile.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Drug Design; Mice; Phenothiazines; Structure-Activity Relationship; Tacrine
PubMed: 33852284
DOI: 10.1021/acschemneuro.1c00184 -
European Journal of Medicinal Chemistry Sep 2017For the last two decades, classical phenothiazines have attracted attention of researchers, as the hitherto investigations have revealed many significant biological... (Review)
Review
For the last two decades, classical phenothiazines have attracted attention of researchers, as the hitherto investigations have revealed many significant biological activities within this class of compounds, other than originally discovered neuroleptic ones. Important, new pharmaceutical results on phenothiazines, as 10-substituted dibenzothiazines, were recently highlighted in several reviews. Azaphenothiazines are structurally modified phenothiazines by substitution of one or both benzene rings in the phenothiazine ring system with the azine rings, such as: pyridine, pyridazine, pyrimidine, pyrazine, 1,2,4-triazine, quinoline, quinoxaline, benzoxazine and benzothiazine. They form over 50 different heterocyclic systems, of tri-, tetra-, penta- and hexacyclic structures, and contain from one to even four azine nitrogen atoms. This review summarizes the methodical knowledge on azaphenothiazines, referring to their nomenclature, synthesis, structure analysis and above all significant varied biological activities, examined in vitro and in vivo. It describes, in addition, current trends in the synthesis of azaphenothiazines. The influence of the azaphenothiazine ring system, the nature of the substituents, predominantly at the thiazine nitrogen atom, as well as at the azine nitrogen atom and carbon atom, on the biological activities, were also discussed.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Antiprotozoal Agents; Antipsychotic Agents; Bacteria; Fungi; Humans; Leishmania; Molecular Structure; Neoplasms; Phenothiazines
PubMed: 28734245
DOI: 10.1016/j.ejmech.2017.07.009 -
Photochemical & Photobiological... Jun 2019We report herein the physicochemical properties and antimicrobial activity of a new monobrominated derivative of Azure B and its parent compound. These dyes are used as...
We report herein the physicochemical properties and antimicrobial activity of a new monobrominated derivative of Azure B and its parent compound. These dyes are used as photosensitizers for photodynamic therapy and photodynamic antimicrobial chemotherapy. Relevant pharmaceutical properties (pKa, chemical and photochemical stability, and in vitro antimicrobial activity) were determined. A UV-visible spectrophotometry method was developed and validated according to the International Conference on Harmonization (ICH) guidelines for use in stability indicating studies and determination of the acid dissociation constant of Azure B and its monobrominated derivative. The results showed that both dyes were chemically stable. In addition, bromination of the phenothiazine dye decreased its photochemical stability and pKa value without affecting the ionization rate at physiological pH. The analytical parameters for validation of the method were linearity (r2 > 0.9981), limit of detection (LOD) (0.2-0.9 μM), limit of quantification (LOQ) (0.6-2.7 μM), and intra-day precision (0.76-1.40%) expressed as relative standard deviation (RSD). Recoveries ranging from 99.5 to 100.9% were obtained for the two dyes. Thus, this method provides a simple, sensitive, accurate, and precise assay for the determination of all compounds. The effect of photosensitizer concentration and visible irradiation time on lethal photosensitization against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli was investigated. Both photosensitizers were active against the evaluated bacteria. However, the new monobrominated derivative was more effective than its predecessor and managed to eradicate these microorganisms by using different doses of the dye and light. In other words, a lower concentration of AzBBr and irradiation time were required to cause bacterial death equal to or greater than its precursor. The photodynamic efficacy of the two photosensitizers presented the following order: S. aureus > E. coli > P. aeruginosa. These studies indicated that the tested dyes satisfy the conditions of potential photosensitizers in terms of physicochemical and antimicrobial properties.
Topics: Anti-Bacterial Agents; Dose-Response Relationship, Drug; Escherichia coli; Hydrogen-Ion Concentration; Microbial Sensitivity Tests; Molecular Structure; Phenothiazines; Photochemotherapy; Photosensitizing Agents; Pseudomonas aeruginosa; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 31066390
DOI: 10.1039/c8pp00584b -
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