Editing Phenothiazine

{{short description|Heterocyclic compound containing a ring of four carbon, one nitrogen and one sulfur atom}}
{{chembox
|Verifiedfields = changed
|Watchedfields = changed
|verifiedrevid = 409955363
|Name = Phenothiazine
|ImageFile1 = Phenothiazine.svg
|ImageFile2 = Phenothiazine-McDowell-3D-vdW.png
|ImageFile3 = Phenothiazine-non-planar-McDowell-3D-balls.png
|PIN = 10''H''-Phenothiazine<ref name=iupac2013>{{cite book | title =  Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (Blue Book) | publisher = [[Royal Society of Chemistry|The Royal Society of Chemistry]] | date = 2014 | location = Cambridge | page = 216 | doi = 10.1039/9781849733069-FP001 | isbn = 978-0-85404-182-4| chapter = Front Matter }}</ref>
|OtherNames = Thiodiphenylamine<br />Dibenzothiazine<br />Dibenzoparathiazine<br />10''H''-dibenzo-[''b'',''e'']-1,4-thiazine<br />PTZ
|Section1 = {{Chembox Identifiers
|ChEBI_Ref = {{ebicite|correct|EBI}}
|ChEBI = 37931
|SMILES = c1ccc2c(c1)Nc3ccccc3S2
|UNII_Ref = {{fdacite|correct|FDA}}
|UNII = GS9EX7QNU6
|KEGG_Ref = {{keggcite|correct|kegg}}
|KEGG = D02601
|PubChem = 7108
|RTECS = SN5075000
|EC_number = 202-196-5
|Beilstein = 143237
|InChI = 1/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H
|InChIKey = WJFKNYWRSNBZNX-UHFFFAOYAI
|ChEMBL_Ref = {{ebicite|correct|EBI}}
|ChEMBL = 828
|StdInChI_Ref = {{stdinchicite|correct|chemspider}}
|StdInChI = 1S/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H
|StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
|StdInChIKey = WJFKNYWRSNBZNX-UHFFFAOYSA-N
|CASNo = 92-84-2
|CASNo_Ref = {{cascite|correct|CAS}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
|ChemSpiderID = 21106365
}}
|Section2 = {{Chembox Properties
|Formula = C<sub>12</sub>H<sub>9</sub>NS
|MolarMass = 199.27 g/mol
|Appearance = greenish-yellow rhombic leaflets or diamond-shaped plates
|Solubility = 0.00051 g/L (20 °C)<ref>{{cite web| url = https://www.sigmaaldrich.com/US/en/product/sial/88580| title = Sigma-Aldrich catalog of Phenothiazine| access-date = 2022-02-28}}</ref>
|Solvent = other solvents
|SolubleOther = [[benzene]], [[Diethyl ether|ether]], [[petroleum ether]], [[chloroform]], hot [[acetic acid]], [[ethanol]] (slightly), [[mineral oil]] (slightly)
|MeltingPtC = 185
|BoilingPtC = 371
|pKa = approx 23 in DMSO
|MagSus = −114.8·10<sup>−6</sup> cm<sup>3</sup>/mol
}}
|Section3 = {{Chembox Hazards
|PEL = none<ref name=PGCH>{{PGCH|0494}}</ref>
|IDLH = N.D.<ref name=PGCH/>
|REL = TWA 5 mg/m<sup>3</sup> [skin] 
|GHSPictograms = {{GHS07}}{{GHS08}}
|GHSSignalWord = Warning
|HPhrases = {{H-phrases|302|317|373|412}}
|PPhrases = {{P-phrases|260|261|264|270|272|273|280|301+312|302+352|314|321|330|333+313|363|501}}
}}
|Section6 = {{Chembox Pharmacology
|ATCvet = yes
|ATCCode_prefix = P52
|ATCCode_suffix = AX03
}}}}

'''Phenothiazine''', abbreviated '''PTZ''', is an [[organic compound]] that has the formula S(C<sub>6</sub>H<sub>4</sub>)<sub>2</sub>NH and is related to the [[thiazine]]-class of [[heterocyclic compound]]s.  Derivatives of phenothiazine are highly bioactive and have widespread use and rich history.

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 [[Pharmacophore|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.<ref name=DDD>{{cite journal|author=M. J. Ohlow |author2=B. Moosmann |title= Phenothiazine: the seven lives of pharmacology's first lead structure|journal=Drug Discov. Today|year=2011|volume=16|issue= 3–4|pages=119–31|pmid=21237283|doi=10.1016/j.drudis.2011.01.001}}</ref>

=== 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.<ref name=DDD/> 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.<ref name=DDD/>

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.<ref name=DDD/>  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.<ref name=DDD/>  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 [[Pharmacophore|lead structure]].<ref name=DDD/><ref name=Jaszczyszyn/>

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<ref name = XDR>{{cite journal|title=Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections|journal=International Journal of Antimicrobial Agents|date=May 2012|volume=39|issue=5|pages=376–380|doi=10.1016/j.ijantimicag.2012.01.012|pmid=22445204|author1=Amaral, L |author2=Viveiros, M }}</ref><ref name=Thioridazineres>{{cite journal|title=Thioridazine: resurrection as an antimicrobial agent?|journal=British Journal of Clinical Pharmacology|volume=64|issue=5|pages=566–574|doi=10.1111/j.1365-2125.2007.03021.x|pmid=17764469|pmc=2203271|date=November 2007|author=Thanacoody, HKR}}</ref> and make [[methicillin-resistant Staphylococcus aureus]] (MRSA) susceptible to beta-lactam antibiotics.<ref name=Thioridazineres/><ref>{{cite journal|title=Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300|journal=PLOS ONE|date=May 2013|volume=8|issue=5|pages=e64518|doi=10.1371/journal.pone.0064518|pmid=23691239|author1=Thorsing, M |author2=Klitgaard, JK |author3=Atilano, ML |author4=Skov, MN |author5=Kolmos, HJ |author6=Filipe, SR |author7=Kallipolitis, BH |pmc=3656896|bibcode=2013PLoSO...864518T|doi-access=free}}</ref> 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).<ref name=Thioridazineres/>

The term "phenothiazines" describes the largest of the five main classes of [[antipsychotic|antipsychotic drugs]]. These drugs have antipsychotic and, often, [[antiemetic]] properties, although they may also cause severe [[Adverse drug reaction|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.<ref name=DDD/>   Use of phenothiazines has been associated with [[antiphospholipid syndrome]], but no causal relationship has been established.<ref>{{Cite web|title = Antiphospholipid Syndrome - Doctor's Information {{!}} Patient|url = http://patient.info/doctor/antiphospholipid-syndrome-pro|website = Patient|access-date = 2015-07-25}}</ref>

Phenothiazine antipsychotics are classified into three groups that differ with respect to the substituent on nitrogen: the [[aliphatic compound]]s (bearing [[Open chain compound|acyclic]] groups), the "piperidines" (bearing [[piperidine]]-derived groups), and the piperazine (bearing [[piperazine]]-derived substituents).<ref name=Jaszczyszyn>{{cite journal | last1 = Jaszczyszyn | first1 = A | display-authors = etal | year = 2012 | title = Chemical structure of phenothiazines and their biological activity | url = http://www.if-pan.krakow.pl/pjp/pdf/2012/1_16.pdf | journal = Pharmacol. Rep. | volume = 64 | issue = 1 | pages = 16–23 | pmid = 22580516 | doi = 10.1016/s1734-1140(12)70726-0 | archive-date = 2020-07-28 | access-date = 2015-07-26 | archive-url = https://web.archive.org/web/20200728094234/http://www.if-pan.krakow.pl/pjp/pdf/2012/1_16.pdf | url-status = dead }}</ref>
{| class="wikitable"
|+
!Group
!Anticholinergic
!Example
!Sedation
![[Extrapyramidal side effect]]s
|-
| rowspan="4" |[[Aliphatic compound]]s
| rowspan="4" |moderate
|[[Chlorpromazine]] (marketed as Thorazine, Aminazine, Chlor-PZ, Klorazine, Promachlor, Promapar, Sonazine, Chlorprom, Chlor-Promanyl, Largactil)
|strong
|moderate
|-
|[[Promazine]] (trade name Sparine, Propazine)
|moderate
|moderate
|-
|[[Triflupromazine]] (trade names Clinazine, Novaflurazine, Pentazine, Terfluzine, Triflurin, Vesprin)
|strong
|moderate/strong
|-
|[[Levomepromazine]] in Germany, Russia, most American countries (e.g., Brazil) and [[methotrimeprazine]] in USA (trade names Nozinan, Levoprome, Tisercin)
|extremely strong
|low
|-
| rowspan="2" |[[Piperidines]]
| rowspan="2" |strong
|[[Mesoridazine]] (trade name Serentil)
|strong
|weak
|-
|[[Thioridazine]] (trade names Mellaril, Novoridazine, Thioril, Sonapax)
|strong
|weak
|-
| rowspan="4" |[[Piperazines]]
| rowspan="4" |weak
|[[Fluphenazine]]  (trade names Prolixin, Permitil, Modecate, Moditen)
|weak/moderate
|strong
|-
|[[Perphenazine]] (sold as Trilafon, Etrafon, Triavil, Phenazine, Etaperazin)
|weak/moderate
|strong
|-
|[[Prochlorperazine]] (trade names Compazine, Stemetil)
|
|
|-
|[[Trifluoperazine]] (trade name Stelazine, Triphtazine)
|moderate
|strong
|}

=== 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 [[electropolymerization|electropolymerized]] into [[conductive polymers]] used as [[electrocatalyst]]s for NADH oxidation in enzymatic biosensors and biofuel cells.<ref>{{cite journal | doi=10.1016/0003-2670(94)85016-X | volume=285 | issue=1–2 | title=Electrocatalytic oxidation of reduced nicotinamide coenzymes at Methylene Green-modified electrodes and fabrication of amperometric alcohol biosensors | journal=Analytica Chimica Acta | pages=125–133| date=1994-01-20 | last1=Chi | first1=Qijin | last2=Dong | first2=Shaojun | bibcode=1994AcAC..285..125C }}</ref><ref>{{cite journal | doi = 10.1002/(SICI)1521-4109(199906)11:8<553::AID-ELAN553>3.0.CO;2-6 | volume=11 | issue=8 | title=Electropolymerized Azines: Part II. In a Search of the Best Electrocatalyst of NADH Oxidation | journal=Electroanalysis | pages=553–557| year=1999 | last1=Karyakin | first1=Arkady A. | last2=Karyakina | first2=Elena E. | last3=Schuhmann | first3=Wolfgang | last4=Schmidt | first4=Hanns-Ludwig }}</ref><ref>{{cite journal | doi=10.1016/j.bios.2008.07.043 | pmid=18774285 | volume=24 | issue=4 | title=Citric acid cycle biomimic on a carbon electrode | journal=Biosensors and Bioelectronics | pages=939–944| date=December 2008 | last1=Sokic-Lazic | first1=Daria | last2=Minteer | first2=Shelley D. }}</ref>

Phenothiazine is used as an anaerobic inhibitor for [[acrylic acid]] polymerization, often used as an in-process inhibitor during the purification of acrylic acid.<ref>{{Cite journal|title=Inhibition of acrylic acid polymerization by phenothiazine and p-methoxyphenol. II. Catalytic inhibition by phenothiazine|journal = Journal of Polymer Science Part A: Polymer Chemistry|volume = 30|issue = 4|pages = 569–576|last=Levy|first=Leon B.|date=1992-03-30|language=en|doi=10.1002/pola.1992.080300407|bibcode = 1992JPoSA..30..569L}}</ref>

== 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.<ref>{{Cite web |url=http://www.osha.gov/dts/chemicalsampling/data/CH_261200.html |title=U.S. Department of Labor Occupational Safety & Health Administration Chemical Sampling Information Phenothiazine |access-date=2007-07-06 |archive-date=2007-08-08 |archive-url=https://web.archive.org/web/20070808104312/http://www.osha.gov/dts/chemicalsampling/data/CH_261200.html  }}</ref>

==Former uses==
Phenothiazine was formerly used as an insecticide and as a drug to treat infections with [[Helminths|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.<ref>[http://www.clemson.edu/extension/pest_ed/histor.html History of Insecticides and Control Equipment] Clemson University Pesticide Information Program.</ref> About 3,500,000 pounds were sold in the US in 1944.<ref>Robert Lee Metcalf. The Mode of Action of Organic Insecticides, Issues 1-5. National Academies, 1948, [https://books.google.com/books?id=PmcrAAAAYAAJ&pg=PA44 page 44]</ref> 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.<ref>G. Matolcsy, M. Nádasy, V. Andriska. Studies in Environmental Science: Pesticide Chemistry. Elsevier, 1989 {{ISBN|9780080874913}}</ref>{{rp|161–162}} As of July 2015 it is not registered for pesticide use in the US, Europe,<ref name=ECHA>ECHA [http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d8a9700-2e5f-5bea-e044-00144f67d249/AGGR-ace2c169-b0aa-4d83-a1dc-a483c2da0f88_DISS-9d8a9700-2e5f-5bea-e044-00144f67d249.html#L-28c67e5f-9c26-4e31-b58f-d4649bdc13f8 phenothiazine at the European Chemicals Authority]{{Dead link|date=May 2020 |bot=InternetArchiveBot |fix-attempted=yes}} Page accessed July 26, 2015. Note - Registered uses are only in manufacturing.</ref> or Australia.<ref name=APVMA>Australian Pesticides and Veterinary Medicine Authority [http://apvma.gov.au/node/12681 Phenothiazine Chemical Review] Page accessed July 26, 2015</ref>

=== As an anthelminthic ===

It was introduced as anthelminthic in livestock in 1940 and is considered, with [[thiabendazole]], to be the first modern anthelminthic.<ref name=Nielsen>{{cite journal | last1 = Nielsen | first1 = MK | display-authors = etal | date = Jul 2014 | title = Anthelmintic resistance in equine parasites--current evidence and knowledge gaps | journal = Vet Parasitol | volume = 204 | issue = 1–2| pages = 55–63 | pmid = 24433852 | doi = 10.1016/j.vetpar.2013.11.030}}</ref> The first instances of resistance were noted in 1961.<ref name=Nielsen/> 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]].<ref name="Monaghan-Tkacz-1990">{{cite journal | last1=Monaghan | first1=Richard L. | last2=Tkacz | first2=Jan S. | title=Bioactive Microbial Products: Focus upon Mechanism of Action | journal=[[Annual Review of Microbiology]] | publisher=[[Annual Reviews (publisher)|Annual Reviews]] | volume=44 | issue=1 | year=1990 | issn=0066-4227 | doi=10.1146/annurev.mi.44.100190.001415 | pages=271–331| pmid=2252385 }}</ref> Uses for this purpose in the US are still described<ref>The Texas A&M University System; Texas AgriLife Extension Service [http://animalscience.tamu.edu/wp-content/uploads/sites/14/2012/04/dairy-integrated-pest-mgmt.pdf Integrated pest management of flies in Texas dairies] {{Webarchive|url=https://web.archive.org/web/20140811054151/http://animalscience.tamu.edu/wp-content/uploads/sites/14/2012/04/dairy-integrated-pest-mgmt.pdf |date=2014-08-11 }}</ref> but it has "virtually disappeared from the market."<ref>Heinz Mehlhorn, Philip M. Armstrong.  Encyclopedic Reference of Parasitology: Diseases, Treatment, Therapy, Volume 2. Springer Science & Business Media, 2001 {{ISBN|9783540668299}}</ref>{{rp|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.<ref name=DDD/>

== Structure and synthesis==
The central C<sub>4</sub>SN ring is folded in phenothiazines.<ref>{{cite journal|title=The crystal and molecular structure of phenothiazine
|author=J. J. H. McDowell |doi=10.1107/S0567740876002215|journal=Acta Crystallographica Section B |volume=32|year=1976|issue=1 |page=5|bibcode=1976AcCrB..32....5M }}
</ref>

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,<ref>Gérard Taurand, "Phenothiazine and Derivatives" in ''Ullmann's Encyclopedia of Industrial Chemistry'', Wiley-VCH, Weinheim, 2005.{{doi|10.1002/14356007.a19_387}}</ref> although some of them are.<ref>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.</ref>

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

== References ==
{{reflist}}

== External links ==
* [http://msds.chem.ox.ac.uk/PH/phenothiazine.html MSDS] {{Webarchive|url=https://web.archive.org/web/20090114071135/http://msds.chem.ox.ac.uk/PH/phenothiazine.html |date=2009-01-14 }}
* Hendricks, Christensen, J.B., and Kristiansen, Jette E. Sonderborg, Denmark. "[https://web.archive.org/web/20080910131246/http://www.wissenschaftliche-verlagsgesellschaft.de/CTJ/CTJ2004/CTJ5-2004/hendricks-203-205.pdf Antibakterielle Eigenschaften der Phenothiazine: Eine Behandlungsoption für die Zukunft?]" ''Chemotherapie Journal.'' 13.5. (2004): 203–205. ''Wissenschaftliche Verlagsgesesellschaft mbH.'' 21 August 2005. (PDF).
* [https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=359599 PubChem Substance Summary: Phenothiazine] National Center for Biotechnology Information.
* [https://www.cdc.gov/niosh/npg/npgd0494.html CDC - NIOSH Pocket Guide to Chemical Hazards]

{{Antipsychotics}}
{{Adrenergics}}
{{Cholinergics}}
{{Dopaminergics}}
{{Histaminergics}}
{{Serotonergics}}
{{Chemical classes of psychoactive drugs}}
{{Authority control}}

[[Category:Phenothiazines| ]]