Phenothiazine

Last updated
Phenothiazine
Phenothiazine.svg
Phenothiazine-McDowell-3D-vdW.png
Phenothiazine-non-planar-McDowell-3D-balls.png
Names
Preferred IUPAC name
10H-Phenothiazine [1]
Other names
Thiodiphenylamine
Dibenzothiazine
Dibenzoparathiazine
10H-dibenzo-[b,e]-1,4-thiazine
PTZ
Identifiers
3D model (JSmol)
143237
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.001.997 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 202-196-5
KEGG
PubChem CID
RTECS number
  • SN5075000
UNII
  • InChI=1S/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H Yes check.svgY
    Key: WJFKNYWRSNBZNX-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H
    Key: WJFKNYWRSNBZNX-UHFFFAOYAI
  • c1ccc2c(c1)Nc3ccccc3S2
Properties
C12H9NS
Molar mass 199.27 g/mol
Appearancegreenish-yellow rhombic leaflets or diamond-shaped plates
Melting point 185 °C (365 °F; 458 K)
Boiling point 371 °C (700 °F; 644 K)
0.00051 g/L (20 °C) [2]
Solubility in other solvents benzene, ether, petroleum ether, chloroform, hot acetic acid, ethanol (slightly), mineral oil (slightly)
Acidity (pKa)approx 23 in DMSO
−114.8·10−6 cm3/mol
Hazards
GHS labelling:
GHS-pictogram-exclam.svg GHS-pictogram-silhouette.svg
Warning
H302, H317, H373, H412
P260, P261, P264, P270, P272, P273, P280, P301+P312, P302+P352, P314, P321, P330, P333+P313, P363, P501
NIOSH (US health exposure limits):
PEL (Permissible)
none [3]
REL (Recommended)
TWA 5 mg/m3 [skin]
IDLH (Immediate danger)
N.D. [3]
Pharmacology
QP52AX03 ( WHO )
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Phenothiazine, abbreviated PTZ, is an organic compound that has the formula S(C6H4)2NH and is related to the thiazine-class of heterocyclic compounds. Derivatives of phenothiazine are highly bioactive and have widespread use and rich history.

Contents

The derivatives chlorpromazine and promethazine revolutionized the fields of psychiatry and allergy treatment, respectively. An earlier derivative, methylene blue, was one of the first antimalarial drugs, and derivatives of phenothiazine are currently under investigation as possible anti-infective drugs. Phenothiazine is a prototypical pharmaceutical lead structure in medicinal chemistry.

Uses

Phenothiazine itself is only of theoretical interest, but derivatives of it revolutionized psychiatry, other fields of medicine, and pest management. Other derivatives have been studied for possible use in advanced batteries and fuel cells. [4]

Phenothiazine-derived drugs

In 1876, methylene blue, a derivative of phenothiazine, was synthesized by Heinrich Caro at BASF. The structure was deduced in 1885 by Heinrich August Bernthsen. Bernthsen synthesized phenothiazine in 1883. [4] In the mid 1880s, Paul Ehrlich began to use methylene blue in his cell staining experiments that led to pioneering discoveries about different cell types. He was awarded a Nobel Prize based in part on that work. He became particularly interested in its use to stain bacteria and parasites such as Plasmodiidae – the genus that includes the malaria pathogen – and found that it could be stained with methylene blue. He thought methylene blue could possibly be used in the treatment of malaria, tested it clinically, and by the 1890s methylene blue was being used for that purpose. [4]

For the next several decades, research on derivatives lapsed until phenothiazine itself came to market as an insecticide and deworming drug. In the 1940s, chemists working with Paul Charpentier at Rhone-Poulenc Laboratories in Paris (a precursor company to Sanofi), began making derivatives. This work led to promethazine which had no activity against infective organisms, but did have good antihistamine activity, with a strong sedative effect. It went to market as a drug for allergies and for anesthesia. As of 2012 it was still on the market. [4] At the end of the 1940s the same lab produced chlorpromazine which had an even stronger sedative and soothing effect, and Jean Delay and Pierre Deniker attempted to use it on their psychiatric patients, publishing their results in the early 1950s. The strong effects they found opened the door of the modern field of psychiatry and led to a proliferation of work on phenothiazine derivatives. [4] The systematic research conducted by chemists to explore phenothiazine derivatives and their activity was a pioneering example of medicinal chemistry; phenothiazine is often discussed as a prototypical example of a pharmaceutical lead structure. [4] [5]

A number of phenothiazines other than methylene blue have been shown to have antimicrobial effects. In particular, thioridazine has been shown to make extensively drug-resistant tuberculosis (XDR-TB) drug-susceptible again [6] [7] and make methicillin-resistant Staphylococcus aureus (MRSA) susceptible to beta-lactam antibiotics. [7] [8] The major reason why thioridazine has not been utilized as an antimicrobial agent is due to adverse effects on the central nervous system and cardiovascular system (particularly QT interval prolongation). [7]

The term "phenothiazines" describes the largest of the five main classes of antipsychotic drugs. These drugs have antipsychotic and, often, antiemetic properties, although they may also cause severe side effects such as extrapyramidal symptoms (including akathisia and tardive dyskinesia), hyperprolactinaemia, and the rare but potentially fatal neuroleptic malignant syndrome, as well as substantial weight gain. [4] Use of phenothiazines has been associated with antiphospholipid syndrome, but no causal relationship has been established. [9]

Phenothiazine antipsychotics are classified into three groups that differ with respect to the substituent on nitrogen: the aliphatic compounds (bearing acyclic groups), the "piperidines" (bearing piperidine-derived groups), and the piperazine (bearing piperazine-derived substituents). [5]

GroupAnticholinergicExampleSedation Extrapyramidal side effects
Aliphatic compounds moderate Chlorpromazine (marketed as Thorazine, Aminazine, Chlor-PZ, Klorazine, Promachlor, Promapar, Sonazine, Chlorprom, Chlor-Promanyl, Largactil)strongmoderate
Promazine (trade name Sparine, Propazine)moderatemoderate
Triflupromazine (trade names Clinazine, Novaflurazine, Pentazine, Terfluzine, Triflurin, Vesprin)strongmoderate/strong
Levomepromazine in Germany, Russia, most American countries (e.g., Brazil) and methotrimeprazine in USA (trade names Nozinan, Levoprome, Tisercin)extremely stronglow
Piperidines strong Mesoridazine (trade name Serentil)strongweak
Thioridazine (trade names Mellaril, Novoridazine, Thioril, Sonapax)strongweak
Piperazines weak Fluphenazine (trade names Prolixin, Permitil, Modecate, Moditen)weak/moderatestrong
Perphenazine (sold as Trilafon, Etrafon, Triavil, Phenazine, Etaperazin)weak/moderatestrong
Prochlorperazine (trade names Compazine, Stemetil)
Trifluoperazine (trade name Stelazine, Triphtazine)moderatestrong

Nondrug applications

The synthetic dye methylene blue, containing the structure, was described in 1876. Many water-soluble phenothiazine derivatives, such as methylene blue, methylene green, thionine, and others, can be electropolymerized into conductive polymers used as electrocatalysts for NADH oxidation in enzymatic biosensors and biofuel cells. [10] [11] [12]

Phenothiazine is used as an anaerobic inhibitor for acrylic acid polymerization, often used as an in-process inhibitor during the purification of acrylic acid. [13]

Trade names

Like many commercially significant compounds, phenothiazine has numerous trade names, including AFI-Tiazin, Agrazine, Antiverm, Biverm, Dibenzothiazine, Orimon, Lethelmin, Souframine, Nemazene, Vermitin, Padophene, Fenoverm, Fentiazine, Contaverm, Fenothiazine, Phenovarm, Ieeno, ENT 38, Helmetina, Helmetine, Penthazine, XL-50, Wurm-thional, Phenegic, Phenovis, Phenoxur, and Reconox. [14]

Former uses

Phenothiazine was formerly used as an insecticide and as a drug to treat infections with parasitic worms (anthelminthic) in livestock and people, but its use for those purposes has been superseded by other chemicals.

Phenothiazine was introduced by DuPont as an insecticide in 1935. [15] About 3,500,000 pounds were sold in the US in 1944. [16] However, because it was degraded by sunlight and air, it was difficult to determine how much to use in the field, and its use waned in the 1940s with the arrival of new pesticides like DDT that were more durable. [17] : 161–162  As of July 2015 it is not registered for pesticide use in the US, Europe, [18] or Australia. [19]

It was introduced as anthelminthic in livestock in 1940 and is considered, with thiabendazole, to be the first modern anthelminthic. [20] The first instances of resistance were noted in 1961. [20] Among anthelmintics, Blizzard et al. 1990 found only paraherquamide to have similar activity to phenothiazine. It is possible that they share the same mode of action. [21] Uses for this purpose in the US are still described [22] but it has "virtually disappeared from the market." [23] : 369 

In the 1940s it also was introduced as antihelminthic for humans; since it was often given to children, the drug was often sold in chocolate, leading to the popular name, "worm chocolate." Phenothiazine was superseded by other drugs in the 1950s. [4]

Structure and synthesis

The central C4SN ring is folded in phenothiazines. [24]

The compound was originally prepared by Bernthsen in 1883 via the reaction of diphenylamine with sulfur, but more recent syntheses rely on the cyclization of 2-substituted diphenyl sulfides. Few pharmaceutically significant phenothiazines are prepared from phenothiazine, [25] although some of them are. [26]

Phenothiazines are electron donors, forming charge-transfer salts with many acceptors.

Related Research Articles

<span class="mw-page-title-main">Piperidine</span> Chemical compound

Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor described as objectionable, typical of amines. The name comes from the genus name Piper, which is the Latin word for pepper. Although piperidine is a common organic compound, it is best known as a representative structure element within many pharmaceuticals and alkaloids, such as natural-occurring solenopsins.

<span class="mw-page-title-main">Chlorpromazine</span> Antipsychotic medication

Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar disorder, severe behavioral problems in children including those with attention deficit hyperactivity disorder, nausea and vomiting, anxiety before surgery, and hiccups that do not improve following other measures. It can be given orally, by intramuscular injection, or intravenously.

<span class="mw-page-title-main">Methylene blue</span> Blue dye also used as a medication

Methylthioninium chloride, commonly called methylene blue, is a salt used as a dye and as a medication. As a medication, it is mainly used to treat methemoglobinemia by chemically reducing the ferric iron in hemoglobin to ferrous iron. Specifically, it is used to treat methemoglobin levels that are greater than 30% or in which there are symptoms despite oxygen therapy. It has previously been used for treating cyanide poisoning and urinary tract infections, but this use is no longer recommended.

<span class="mw-page-title-main">Thioridazine</span> Typical antipsychotic medication

Thioridazine is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwide in 2005 because it caused severe cardiac arrhythmias. However, generic versions are still available in the US.

<span class="mw-page-title-main">Carbamate</span> Chemical group (>N–C(=O)–O–)

In organic chemistry, a carbamate is a category of organic compounds with the general formula R2NC(O)OR and structure >N−C(=O)−O−, which are formally derived from carbamic acid. The term includes organic compounds, formally obtained by replacing one or more of the hydrogen atoms by other organic functional groups; as well as salts with the carbamate anion H2NCOO−.

<span class="mw-page-title-main">Organophosphate</span> Organic compounds with the structure O=P(OR)3

In organic chemistry, organophosphates are a class of organophosphorus compounds with the general structure O=P(OR)3, a central phosphate molecule with alkyl or aromatic substituents. They can be considered as esters of phosphoric acid. Organophosphates are best known for their use as pesticides.

Halocarbon compounds are chemical compounds in which one or more carbon atoms are linked by covalent bonds with one or more halogen atoms resulting in the formation of organofluorine compounds, organochlorine compounds, organobromine compounds, and organoiodine compounds. Chlorine halocarbons are the most common and are called organochlorides.

<span class="mw-page-title-main">Formamide</span> Chemical compound

Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticides, and in the manufacture of hydrocyanic acid. It has been used as a softener for paper and fiber. It is a solvent for many ionic compounds. It has also been used as a solvent for resins and plasticizers. Some astrobiologists suggest that it may be an alternative to water as the main solvent in other forms of life.

Demeton-S-methyl is an organic compound with the molecular formula C6H15O3PS2. It was used as an organothiophosphate acaricide and organothiophosphate insecticide. It is flammable. With prolonged storage, Demeton-S-methyl becomes more toxic due to formation of a sulfonium derivative which has greater affinity to the human form of the acetylcholinesterase enzyme, and this may present a hazard in agricultural use.

<span class="mw-page-title-main">Maleic anhydride</span> Chemical compound

Maleic anhydride is an organic compound with the formula C2H2(CO)2O. It is the acid anhydride of maleic acid. It is a colorless or white solid with an acrid odor. It is produced industrially on a large scale for applications in coatings and polymers.

<span class="mw-page-title-main">Ethylenediamine</span> Chemical compound

Ethylenediamine (abbreviated as en when a ligand) is the organic compound with the formula C2H4(NH2)2. This colorless liquid with an ammonia-like odor is a basic amine. It is a widely used building block in chemical synthesis, with approximately 500,000 tonnes produced in 1998. Ethylenediamine is the first member of the so-called polyethylene amines.

<span class="mw-page-title-main">Diphenylamine</span> Chemical compound

Diphenylamine is an organic compound with the formula (C6H5)2NH. The compound is a derivative of aniline, consisting of an amine bound to two phenyl groups. The compound is a colorless solid, but commercial samples are often yellow due to oxidized impurities. Diphenylamine dissolves well in many common organic solvents, and is moderately soluble in water. It is used mainly for its antioxidant properties. Diphenylamine is widely used as an industrial antioxidant, dye mordant and reagent and is also employed in agriculture as a fungicide and antihelmintic.

<span class="mw-page-title-main">Hexamethylene diisocyanate</span> Chemical compound

Hexamethylene diisocyanate (HDI) is the organic compound with the formula (CH2)6(NCO)2. It is classified as an diisocyanate. It is a colorless liquid. It has sometimes been called HMDI but this not usually done to avoid confusion with Hydrogenated MDI.

Copper(I) hydroxide is the hydroxide of the metal copper with the chemical formula of CuOH. It is a mild, highly unstable alkali. The color of pure CuOH is yellow or orange-yellow, but it usually appears rather dark red because of impurities. It is extremely easily oxidized even at room temperature. It is useful for some industrial processes and in preventing condensation of formaldehyde. It is also an important reactant and intermediate for several important products including Cu2O3 and Cu(OH)2. Additionally, it can act as a catalyst in the synthesis pyrimidopyrrolidone derivatives.

<span class="mw-page-title-main">Tiospirone</span> Atypical antipsychotic drug

Tiospirone (BMY-13,859), also sometimes called tiaspirone or tiosperone, is an atypical antipsychotic of the azapirone class. It was investigated as a treatment for schizophrenia in the late 1980s and was found to have an effectiveness equivalent to those of typical antipsychotics in clinical trials but without causing extrapyramidal side effects. However, development was halted and it was not marketed. Perospirone, another azapirone derivative with antipsychotic properties, was synthesized and assayed several years after tiospirone. It was found to be both more potent and more selective in comparison and was commercialized instead.

Dinitro-<i>ortho</i>-cresol Chemical compound

Dinitro-ortho-cresol (DNOC) is an organic compound with the structural formula CH3C6H2(NO2)2OH. It is a yellow solid that is only slightly soluble in water. It is extremely toxic to humans and was previously used as a herbicide and insecticide.

The psychopharmacology revolution covers the introduction of various psychiatric drugs into clinical practice as well as their continued development. Although not exclusively limited to the 1950s period, the literature tends to suggest that this decade was a particularly fruitful time for CNS drug discovery and it has been referred to as a "golden era".

<span class="mw-page-title-main">Tetraethyl pyrophosphate</span> Chemical compound

Tetraethyl pyrophosphate, abbreviated TEPP, is an organophosphate compound with the formula [(C2H5O)2P(O)]2O. It is the tetraethyl derivative of pyrophosphate (P2O74-). It is a colorless oil that solidifies near room temperature. It is used as an insecticide. The compound hydrolyzes rapidly.

<span class="mw-page-title-main">August Bernthsen</span> German chemist

Heinrich August Bernthsen was a German chemist who was among the first to synthesize and study the structures of methylene blue and phenothiazine.

Antimicrobial photodynamic therapy (aPDT), also referred to as photodynamic inactivation (PDI), photodisinfection (PD), or photodynamic antimicrobial chemotherapy (PACT), is a photochemical antimicrobial method that has been studied for over a century. Supported by in vitro,in vivo and clinical studies, aPDT offers a treatment option for broad-spectrum infections, particularly in the context of rising antimicrobial resistance. Its multi-target mode of action allows aPDT to be a viable therapeutic strategy against drug-resistant microorganisms. The procedure involves the application of photosensitizing compounds, also called photoantimicrobials, which, upon activation by light, generate reactive oxygen species (ROS). These ROS lead to the oxidation of cellular components of a wide array of microbes, including pathogenic bacteria, fungi, protozoa, algae, and viruses.

References

  1. ↑ "Front Matter". Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 216. doi:10.1039/9781849733069-FP001 (inactive 2024-05-14). ISBN   978-0-85404-182-4.{{cite book}}: CS1 maint: DOI inactive as of May 2024 (link)
  2. ↑ "Sigma-Aldrich catalog of Phenothiazine" . Retrieved 2022-02-28.
  3. 1 2 NIOSH Pocket Guide to Chemical Hazards. "#0494". National Institute for Occupational Safety and Health (NIOSH).
  4. 1 2 3 4 5 6 7 8 M. J. Ohlow; B. Moosmann (2011). "Phenothiazine: the seven lives of pharmacology's first lead structure". Drug Discov. Today. 16 (3–4): 119–31. doi:10.1016/j.drudis.2011.01.001. PMID   21237283.
  5. 1 2 Jaszczyszyn, A; et al. (2012). "Chemical structure of phenothiazines and their biological activity" (PDF). Pharmacol. Rep. 64 (1): 16–23. doi:10.1016/s1734-1140(12)70726-0. PMID   22580516.
  6. ↑ Amaral, L; Viveiros, M (May 2012). "Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections". International Journal of Antimicrobial Agents. 39 (5): 376–380. doi:10.1016/j.ijantimicag.2012.01.012. PMID   22445204.
  7. 1 2 3 Thanacoody, HKR (November 2007). "Thioridazine: resurrection as an antimicrobial agent?". British Journal of Clinical Pharmacology. 64 (5): 566–574. doi:10.1111/j.1365-2125.2007.03021.x. PMC   2203271 . PMID   17764469.
  8. ↑ Thorsing, M; Klitgaard, JK; Atilano, ML; Skov, MN; Kolmos, HJ; Filipe, SR; Kallipolitis, BH (May 2013). "Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300". PLOS ONE. 8 (5): e64518. Bibcode:2013PLoSO...864518T. doi: 10.1371/journal.pone.0064518 . PMC   3656896 . PMID   23691239.
  9. ↑ "Antiphospholipid Syndrome - Doctor's Information | Patient". Patient. Retrieved 2015-07-25.
  10. ↑ Chi, Qijin; Dong, Shaojun (1994-01-20). "Electrocatalytic oxidation of reduced nicotinamide coenzymes at Methylene Green-modified electrodes and fabrication of amperometric alcohol biosensors". Analytica Chimica Acta. 285 (1–2): 125–133. Bibcode:1994AcAC..285..125C. doi:10.1016/0003-2670(94)85016-X.
  11. ↑ Karyakin, Arkady A.; Karyakina, Elena E.; Schuhmann, Wolfgang; Schmidt, Hanns-Ludwig (1999). "Electropolymerized Azines: Part II. In a Search of the Best Electrocatalyst of NADH Oxidation". Electroanalysis. 11 (8): 553–557. doi:10.1002/(SICI)1521-4109(199906)11:8<553::AID-ELAN553>3.0.CO;2-6.
  12. ↑ Sokic-Lazic, Daria; Minteer, Shelley D. (December 2008). "Citric acid cycle biomimic on a carbon electrode". Biosensors and Bioelectronics. 24 (4): 939–944. doi:10.1016/j.bios.2008.07.043. PMID   18774285.
  13. ↑ Levy, Leon B. (1992-03-30). "Inhibition of acrylic acid polymerization by phenothiazine and p-methoxyphenol. II. Catalytic inhibition by phenothiazine". Journal of Polymer Science Part A: Polymer Chemistry. 30 (4): 569–576. Bibcode:1992JPoSA..30..569L. doi:10.1002/pola.1992.080300407.
  14. ↑ "U.S. Department of Labor Occupational Safety & Health Administration Chemical Sampling Information Phenothiazine". Archived from the original on 2007-08-08. Retrieved 2007-07-06.
  15. ↑ History of Insecticides and Control Equipment Clemson University Pesticide Information Program.
  16. ↑ Robert Lee Metcalf. The Mode of Action of Organic Insecticides, Issues 1-5. National Academies, 1948, page 44
  17. ↑ G. Matolcsy, M. Nádasy, V. Andriska. Studies in Environmental Science: Pesticide Chemistry. Elsevier, 1989 ISBN   9780080874913
  18. ↑ ECHA phenothiazine at the European Chemicals Authority [ permanent dead link ] Page accessed July 26, 2015. Note - Registered uses are only in manufacturing.
  19. ↑ Australian Pesticides and Veterinary Medicine Authority Phenothiazine Chemical Review Page accessed July 26, 2015
  20. 1 2 Nielsen, MK; et al. (Jul 2014). "Anthelmintic resistance in equine parasites--current evidence and knowledge gaps". Vet Parasitol. 204 (1–2): 55–63. doi:10.1016/j.vetpar.2013.11.030. PMID   24433852.
  21. ↑ Monaghan, Richard L.; Tkacz, Jan S. (1990). "Bioactive Microbial Products: Focus upon Mechanism of Action". Annual Review of Microbiology . 44 (1). Annual Reviews: 271–331. doi:10.1146/annurev.mi.44.100190.001415. ISSN   0066-4227. PMID   2252385.
  22. ↑ The Texas A&M University System; Texas AgriLife Extension Service Integrated pest management of flies in Texas dairies Archived 2014-08-11 at the Wayback Machine
  23. ↑ Heinz Mehlhorn, Philip M. Armstrong. Encyclopedic Reference of Parasitology: Diseases, Treatment, Therapy, Volume 2. Springer Science & Business Media, 2001 ISBN   9783540668299
  24. ↑ J. J. H. McDowell (1976). "The crystal and molecular structure of phenothiazine". Acta Crystallographica Section B. 32 (1): 5. Bibcode:1976AcCrB..32....5M. doi:10.1107/S0567740876002215.
  25. ↑ Gérard Taurand, "Phenothiazine and Derivatives" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005. doi : 10.1002/14356007.a19_387
  26. ↑ T. Kahl, K.-W. Schröder, F. R. Lawrence, W. J. Marshall, Hartmut Höke, Rudolf Jäckh, "Aniline" in Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH: Weinheim.
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