THIORIDAZINE Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

THIORIDAZINE Synthesis, SAR, MCQ,Structure,Chemical Properties and Therapeutic Uses

Thioridazine hydrochloride

IUPAC nomenclature

10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine;hydrochloride

Classification

Thioridazine hydrochloride is phenothiazine antipsychotic drug.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 407 g/mol
2 Physical appearance Pale yellow solid
3 Melting point 158-160°C
4 Solubility Soluble in water
5 Octanol/water partition coefficient N/a
6 Presence of ring Phenothiazine, piperidine
7 Number of chiral centers 1

 

Mechanism of Action

  • Thioridazine blocks postsynaptic dopaminergic D1 and D2 receptors in brain.
  • Thioridazine also blocks α-adrenergic effects
  • Depresses the release of hypothalamic and hypophyseal hormones
  • Depresses the reticular activating system
  • Due to these, basal metabolism, temperature, wakefulness, vasomotor tone and emesis of the body is affected.

 

Structure Activity Relationship

Structure activity relationship of phenothiazine can be described as follows:

  • Tilting of side chain towards ring A grants favorable Vander Waal’s interaction of the side chain. This interaction decides the potency of the drug towards the dopamine receptors.
  • Optimal neuroleptic activity occurs when the ring A substituent is in the 2nd-position.
  • A trifluoromethyl substituent provides a greater number of favorable Van der Waal’s contacts with the side chain than the chlorine substituent. Thus, phenothiazne with trifluoromethyl substituents are more potent than those with chlorine substituent.
  • A piperazine side chain provides more Van der Waal’s contacts with 2-substituent than the alkylamino side chain. Thus, piperizine phenothiazine are more potent in antischizophrenic effects than alkylamino phenothiazines.
  • Hydroxyethylpiperazine side chain phenothiazines displays more favorable Van der Waal’s interactions with ring A than simple piperazines.
  • In the thioxanthene and xanthenes containing ring systems, the cis forms are more potent neuroleptics than the trans isomers.
  • Phenothiazine analogues having the presence of exolytic double bond are more potent than the corresponding compounds lacking the exolytic double bonds. [1]

 

Method of synthesis

Thioridazine can be synthesized through reaction of 2-(methylthio)-10H-phenothiazine with 2-(2-chloroethyl)-N-methylpiperidine in refluxing xylene in the presence of refluxing sodium amide.

Therapeutic Uses

Thioridazine hydrochloride is used for:

  • Treatment of schizophrenia
  • Reducing nervousness
  • Reducing aggression
  • Reducing negative thoughts
  • Reducing hallucinations

 

Side Effects

Side effects of Thioridazine hydrochloride are:

  • Dizziness
  • Lightheadedness
  • Blurred vision
  • Headache
  • Restlessness
  • Drowsiness
  • Difficulty in urinating
  • Constipation
  • Tremors
  • Infections
  • Jerking movements

 

MCQs

Q.1 What are the correct statements related with the physicochemical properties of thioridazine hydrochloride drug?

I. Molecular weight = 407 gm/mol

II. It appears as pale yellow solid

III. It is soluble in water

IV. Phenothiazine ring is present in the structure

a) I, II, III

b) I, II, IV

c)III, IV

d) I. II. III. IV

Q.2 Match the following of the drugs with their correct IUPAC names.

i. Thioridazine A. 10-[2-(1-methylpiperidin-2-yl)ethyl]-2-methylsulfanylphenothiazine
ii. Mephobarbital B. 5-ethyl-5-pentan-2-yl-2-sulfanylidene-1,3-diazinane-4,6-dione
iii. Triflupromazine C. Phenyl-5-ethyl-1-methylbarbituric acid
iv. Thiopental D. N,N-dimethyl-3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propan-1-amine

 a) i-B, ii-C, iii-A, iv-D

b) i-C, ii-A, iii-D, iv-B

c) i-A, ii-C, iii-D, iv-B

d) i-D, ii-A, iii-C, iv-B

Q.3 Types of receptors blocked by the Thioridazine hydrochloride drug?

I. Dopaminergic D1

II. Dopaminergic D2

III. ß-adrenoceptors

IV. α-adrenoceptors

a) I, III, IV

b) I, II

c) III, IV

d) I, II, IV

Q.4 Correct sequence for True/false for the classification of the drug can be?

  • Thioridazine hydrochloride: Phenothiazine antipsychotic drug
  • Oxazepam: benzodiazepine sedative hypnotic
  • Triazolam: Guanosine nucleoside antiviral drug
  • Ribavirin: Benzodiazepine sedative hypnotic

a) TFTF

b) TTFF

c) FFTT

d) FFFT

Q.5 Greater potency of phenothiazines with trifluoromethyl substitution is due to?

a) Greater number of favourable Van der Waal’s contacts

b) Bleaching action of chlorine

c) Affinity of fluorine with potassium is higher

d) High molecular weight of fluorine

Q.6 Starting chemicals requires for the synthesis of thioridazine drug are?

I. 2-(methylthio)-10H-phenothiazine

II. 2-(2-chloroethyl)-N-methylpiperidine

III. Sodium amide

IV. 4-chloro-3-cyclopentene

a) I, III, IV

b) I, II, III

c) II, III, IV

d) I, II, IV 

Q.7 Side effect of drug Thioridazine hydrochloride are?

a) Tremors

b) Infections

c) Difficulty in urination

d) All of the above

 

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ANSWERS

1-d

2-c

3-d

4-b

5-a

6-b

7-d

 

REFERENCES

[1] Feinberg AP, Snyder SH. Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine. Proceedings of the National Academy of Sciences. 1975 May 1;72(5):1899-903.

[2] Vardanyan R. Piperidine-based drug discovery. Elsevier; 2017 Jun 12.

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