What is Phenothiazine?

Alternately known as PTZ, phenothiazine is an organic compound with the chemical formula – S(C6H4)2NH. The compound has a connection to the thiazine class of heterocyclic compounds. The derivatives of phenothiazine are highly bioactive. They also have a history of widespread use. The phenothiazine class of organic compounds exhibits antiemetic, antipsychotic, antihistaminic, and anticholinergic properties. The derivatives of phenothiazine are genuinely revolutionary as many of them have usages in life-saving medicinal drugs. In medical chemistry, phenothiazine is a prototypical pharmaceutical lead structure.


Properties of Phenothiazine

  • The colour of phenothiazine is a light green to steel-blue powder, and it acquires a greenish-blue tint when exposed to sunlight.

  • The compound does not have any taste, and the odour is slightly pungent. 

  • The melting point of phenothiazine from 365.9 degrees Fahrenheit to 366.6 degrees Fahrenheit.

  • Phenothiazine is freely soluble in Benzene and hot acetic acid. 

  • It is slightly soluble in alcohol and mineral oils. 

  • The compound is practically insoluble in petroleum ether and chloroform.

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Uses of Phenothiazine

Even after comprehensive research, phenothiazine uses only have theoretical interests. The phenothiazine derivatives have ground-breaking applications in fields of medicine like psychiatry, anaesthetics, and pest management. Some derivatives have applications in advanced batteries and fuel cells. Many of phenothiazine's water-soluble derivatives like methylene blue, methylene green, thionine, etc., can be electropolymerized into conductive polymers used as electrocatalysts NADH oxidation in enzymatic biosensors and biofuel cells. Phenothiazine also has utilisation as an anaerobic restrictor for acrylic acid polymerisation. It is often used as an in-process inhibitor during the purification of acrylic acid. 


Formerly, phenothiazine was used as an insecticide and drug to treat infections with parasitic worms in livestock and people. But, now, its application for these purposes has been superseded by other more prominent chemicals. 


It was DuPont who first introduced phenothiazine as an insecticide in 1935. The USA sold about 3,500,000 pounds in 1944. However, as phenothiazine deteriorates in sunlight and air, its usage declined as a pesticide from the 1940s. With the arrival of better alternatives like DDT in the market, phenothiazine lost its significance as a pest controller. DDT was more durable and practical as a positive during those times.  


Phenothiazine was introduced as an anthelmintic in livestock during the 1940s. It is considered the world's first modern anthelmintic, along with thiabendazole.


In the 1940s, phenothiazine also was used as an anthelmintic for human beings. Other drugs superseded phenothiazine in the 1950s.


The phenothiazine derivatives treat psychosis, including schizophrenia, violent, agitated, disturbed behaviour, and the manic phase of bipolar disorder. Other applications include painkillers, curing headache, hiccups, anxiety, idiopathic dystonia, withdrawal, taste disorders, leishmaniasis, alleviation of nausea and vomiting and acute intermittent porphyria. Phenothiazines permit smoother induction of anaesthetic agents and allow treatment of behavioural symptoms secondary to Alzheimer’s and senile dementia. Some phenothiazines exert an antipruritic effect. They are helpful for the treatment of neurodermatitis and pruriginous eczema and may relieve psychogenic itching.


The Medical Use of Phenothiazine

Heinrich Caro first synthesised methylene blue – a derivative of phenothiazine in 1876. Methylene blue was used by Paul Ehrlich during the mid-1880s in his cell staining experiments that consequently lead to his pioneering discoveries on cell types. Ehrlich asserts that methylene blue could also be used to treat malaria, and he tested it clinically. Due to concerted efforts, Ehrlich discovered malaria's cure, and methylene blue was being used for that purpose since the 1890S.


From the 1940s, research on phenothiazine derivatives expanded, and chemists working with Paul Charpentier at Rhone-Poulenc Laboratories in Paris began making derivatives of the same. Such efforts revealed that although phenothiazine had no activity against organisms, it had appropriate antihistamine activities with a powerful sedative effect. Phenothiazine went into the market as a drug for allergies and anaesthesia. From the 1940s onwards, experts realised that the same lab-produced chlorpromazine had an even more potent sedative and soothing effect. Pioneers Jean Delay and Pierre Deniker began using it on psychiatric patients and published their findings in the early part of the 1950s. The robust results they yielded opened the door of modern psychiatry and led to the mushrooming of work on phenothiazine medications.


The word "phenothiazines" infers the biggest of the five primary classes of antipsychotic medicines. These drugs have antipsychotic elements and also antiemetic properties.


Phenothiazine Antipsychotics are Grouped into Three Categories that differ Concerning the Substituent on Nitrogen:

  • The aliphatic compounds

  • The "piperidines." 

  • The piperazine 

It is imperative to also remember the side effects of phenothiazine that range from extrapyramidal signs to weight gain and the fatal neuroleptic malignant syndrome. Some people may also develop tartrazine allergy in phenothiazine derivatives. Tartrazine is the most commonly used dye in psychotropic drugs and has proven to cause allergic reactions among a large number of people.


Conclusion

The topic of phenothiazine may seem very tricky to grasp. The concept does get manageable with thorough understanding, regularly solving questions and numerical, practising papers and proper revision. Before trying to understand the whole concept, we must grasp the basics of phenothiazine then move to its uses, medical applications, synthesis, and side effects and so on. Brushing up the basics of Chemistry always helps in learning challenging concepts. After learning the fundamentals of phenothiazine, it is imperative to learn about its class and structure as well.

FAQs (Frequently Asked Questions)

Q.1 What are Some of the Side Effects of Phenothiazine?

Ans.  Some of the severe side effects of phenothiazine are extrapyramidal signs that include akathisia and tardive dyskinesia. The rare but potentially deadly demerit of using phenothiazine is the neuroleptic malignant syndrome. Weight gain is also associated with the compound. Other issues like antiphospholipid syndrome are believed to be linked to the use of phenothiazines, but no causal relationships have been established.

Q2. How do we Synthesise Phenothiazine?

Ans. Berntsen initially prepared the compound in 1883 via diphenylamine reaction with sulfur, but more recent syntheses rely on the cyclisation of 2-substituted diphenyl sulfides. Few pharmaceutically significant phenothiazines are prepared from phenothiazine, although some of them are. Phenothiazines are electron donors, forming charge-transfer salts with many acceptors.