Editing Phenothiazine (section)

==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>