Phenothiazine

Phenothiazine

Names
Preferred IUPAC name 10H-Phenothiazine[1]
Other names Thiodiphenylamine Dibenzothiazine Dibenzoparathiazine 10H-dibenzo-[b,e]-1,4-thiazine PTZ
Identifiers
CAS Number	92-84-2 Y
3D model ( JSmol )	Interactive image
Beilstein Reference	143237
ChEBI	CHEBI:37931 Y
ChEMBL	ChEMBL828 Y
ChemSpider	21106365 Y
ECHA InfoCard	100.001.997
EC Number	202-196-5
KEGG	D02601 Y
PubChem CID	7108
RTECS number	SN5075000
UNII	GS9EX7QNU6 Y
CompTox Dashboard (EPA)	DTXSID5021126
InChI InChI=1S/C12H9NS/c1-3-7-11-9(5-1)13-10-6-2-4-8-12(10)14-11/h1-8,13H Y Key: WJFKNYWRSNBZNX-UHFFFAOYSA-N Y 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
SMILES c1ccc2c(c1)Nc3ccccc3S2
Properties
Chemical formula	C12H9NS
Molar mass	199.27 g/mol
Appearance	greenish-yellow rhombic leaflets or diamond-shaped plates
Melting point	185 °C (365 °F; 458 K)
Boiling point	371 °C (700 °F; 644 K)
Solubility in water	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
Magnetic susceptibility (χ)	−114.8·10−6 cm3/mol
Hazards
GHS labelling:
Pictograms
Signal word	Warning
Hazard statements	H302, H317, H373, H412
Precautionary statements	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
ATCvet code	QP52AX03 (WHO )
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). N verify (what is YN ?) Infobox references

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.

The derivatives

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

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

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

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.

References