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

Tolmetin        

IUPAC nomenclature

[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid.

Classification

  • Nonsteroidal anti-inflammatory drug

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 257.28 g/mol
2 Physical appearance Crystals from acetonitrile
3 Melting point 156°C
4 Solubility 222 mg/L
5 Octanol/water partition coefficient 2.79
6 Presence of ring Pyrrole, phenyl
7 Number of chiral centers Not present

 

Mechanism of Action

  • Prostaglandin synthetase enzyme is inhibited by tolmetin which lowers the plasma level of prostaglandin in man. This is responsible for the anti-inflammatory action of the drug.

Structure Activity Relationship

SAR of Tolmetin can be summarized as follows:

  • Replacement of the 5-p-toluoyl group with p-chlorobenzoyl moiety have little changes on the activity of drug.
  • 4-methyl-5-p-chlorobenzoyl analog is 4 times more potent then tolmetin.
  • Substituting the chloro group with the p-methyl group blocks the oxidative metabolism which increases the duration of action by 1 day.
  • Propionic acid analogue is less potent.

 

Method of synthesis

i. 1-methylindole is aminomethylated using formaldehyde and dimethylamine to form 2-dimethylaminomethyl-1-methylindol.

ii. Last is methylated by methyl iodide to produce the corresponding quarternary salt.

iii.Eaction of the above formed compound with sodium cyanide produces 1-methylpyrrole-2-acetonitrile.

iv. The product is then acylated at the free α-position of te pyrole ring by 4-methylbenzoylchloride in the presence o aluminum chloride to give 1-methyl-5-n-toluylpyrrol-2-acetonitrile.

v. The last further undergoes alkaline hydrolysis to finally produce tolmetin. [2]

Therapeutic Uses

Tolmetin is used for:

  • Reducing pain, joint stiffness and swelling due to arthritis.
  • Treatment of juvenile rheumatoid arthritis

 

Side Effects

Side effects of Tolmetin are:

  • Nausea
  • Vomiting
  • Heartburn
  • Diarrhea
  • Upset stomach
  • Dizziness
  • Headache
  • Hypertension
  • Ringing in ears
  • Mood changes
  • Symptoms of heart failures
  • Kidney problems
  • Stiff neck
  • Liver disease
  • Allergic reactions

 

MCQs

Q.1 Choose the correct statements related with the physicochemical properties of drug Tolmetin.

I. Molecular weight = 147.0 gm/mol

II. It forms crystals from Acetonitrile

III. Melting point is 156 oC

 a) I, III

b) II, III

c) III

d) I, II

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

i. Tolmetin A. Navane

 

ii. Thiotixene B. Halidol

 

iii. Haloperidol C. Tolectin

 

iv. Chloraquine D. Aralen

 a) i-C, ii-A, iii-B, iv-D

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

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

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

Q.3 Tolmetin inhibits

I. DNA polymerase enzyme

II. DNA dependent RNA polymerase enzyme

III. Prostaglandin synthetase enzyme

IV. Nucleosidases

a) I , II

b) III

c) III , IV

d) IV

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

  • Tolmetin: Opioid Antagonist
  • Asenapine: Benzodiazepine
  • Clozapine: Benzazepine
  • Haloperidol: buterophenone

a) TFFT

b) TTTT

c) TTFF

d) FFTT

Q.5 Find the INCORRECT statement amongst the following related with the SAR of Tolmetin?

I. Replacement of the 5-p-toluoyl group with p-chlorobenzoyl moiety have little changes on the activity of drug.

II. 4-methyl-5-p-chlorobenzoyl analog is 4 times more potent then tolmetin.

III. Substituting the chloro group with the p-methyl group blocks the oxidative metabolism which increases the duration of action by 1 day.

IV. Propionic acid analogue is more potent

Q.6 Number of chiral carbons present in the structure of tolmetin?

a) 0

b) 1

c) 2

d) 3 

Q.7 Side effect of drug Tolmetin include?

a) Symptoms of heart failure

b) Upset stomach

c) Kidney problems

d) All of the above

 

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ANSWERS

1-b

2-a

3-b

4-d

5-d

6-a

7-d

 

REFERENCES

[1]  Lemke TL, Williams DA, Roche VF, Zito SW. FOYE. S Principles of Medicinal Chemistry. Seventh Edition Copyright. 2013.

[2] Vardanyan, Ruben, and Victor Hruby. Synthesis of essential drugs. Elsevier, 2006.

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