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

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

Naphazoline

IUPAC nomenclature

2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole.

 

Classification

Naphazoline is a α1-adenergic agonist.

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 210.27
2 Physical appearance Solid
3 Melting point 257°C
4 Solubility Water solubility is 0.0381 mg / ml
5 Octanol/water partition coefficient 3.88
6 Presence of ring Naphthalene and imidazoline rings present
7 Number of chiral centers Not present

 

Mechanism of Action

  • Naphazoline helps in decreasing congestion at the site of administration through stimulation of the α-adrenergic receptors in the arteriols.
  • It also stimulates the release of norepinephrine in the sympathetic nerves, which later binds with α-adrenergic receptors which causes vasoconstriction.
  • Naphazoline also acts as mild ß-adrenergic agonist which causes vasodilation after he effect of α-adrenergic is over.
  • Due to trigger of negative feedback loop, results in rhinitis medicamentosa after long time administration of Naphazoline when it is stopped.

 

Structure Activity Relationship

  • Primary or secondary aliphatic amine separated by two carbons from a substituted benzene ring is essential for the high agonist activity.
  • The hydroxyl substituted carbon must be in the R configuration for the maximal direct activity.

R1 substitution:

  • When R1 is increased in size, activity of alpha receptors decreases and activity of the beta receptors increases
  • Activity of both alpha and beta receptors is maximum when R1 is methyl group.
  • Alpha agonist activity decreases when R1 is larger than methyl, and went negligible when R1 is isopropyl.
  • Large lipophillic groups can afford compounds with alpha blocking activity.
  • N-substituent provides selectivity for different receptors.
  • Arylalkyl group can provide beta selectivity, increased cell penetration and increased lipophillicity for the longer duration of action.

R2 substitution:

  • Ethyl group can eliminate the alpha activity of the drug.
  • Erythrostero isomers have maximal activity.
  • The additional methyl group makes the drug more selective for the alpha2

R3 substitution on the aromatic ring:

  • 3’,4’-dihydroxy substituted benzene ring has poor oral activity.
  • 3’, 5’-dihydroxy compounds are orally active.
  • At least one of the groups is required which can form hydrogen bonds. And if only one group is present then it is preferred at 4’ position to retain the beta2
  • If phenyl group has no phenolic substituent then it may act directly or indirectly.[2]

 

Method of synthesis

i. (1-naphthyl)acetonitrile reacts with ethanol to give an iminoester.

ii. The iminoester undergoes cyclization reaction when reacts with ethylinediamine to give naphazoline.

 

Therapeutic Uses

Naphazoline is used as a degongestant.

Side Effects

Some of the side effects of naphazoline are

  • rhinitis medicamentosa
  • several hypertensive disorders.

MCQs

Q.1 Correct statements for the Naphazoline drug are?

I. Molecular weight is 210.27gm/mol

II. Water solubility is 31 mg/ml

III. Present as yellow oily liquid at room temperature.

IV. Octanol/water partition coefficient is 3.88

a) I, III

b) I, IV

c) I, II, III

d) IV

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

i. Naphazoline A. (RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl] 4-methylbenzoate
ii. Bitolterol B. 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]- 4,5-dihydro-1H-imidazole
iii. Xylometazoline C. 3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol
iv. Oxymetazoline D. 2-(naphthalen-1-ylmethyl)-4,5-dihydro-1H-imidazole

 a) i-D, ii-A, iii-B, iv-C

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

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

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

Q.3 Correct steps for the mechanism of action of the drug Naphazoline?

I. Vasoconstriction

II. Realease of norepinephrine

III. Decrease in the congestion

IV. Stimulation of αadrenergic receptors

a) I – IV – III – II

b) III – II – I – IV

c) I – III – II – IV

d) IV – III – II – I

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

  • Terbutaline: Selective α-adrenergic agonist
  • Dopamine: ß-adrenergic agonist
  • Phenoxybenzamine: Nonselective adrenergic agonist
  • Naphazoline: Mixed acting sympathomimetics

a) FFTF

b) FTFF

c) TFFF

d) FFFF

Q.5 Large lipophillic groups at R1 substitution can-

a) Afford compounds with α-blocking activity

b) Provides maximal direct activity

c) Increase both α and ß activity

d) None of the above

Q.6 The correct sequence for the steps for synthesis of drug naphazoline from (1-naphthyl)acetonitrile?

I. Reaction with ethanol

II. Reaction with Sulfuric acid

III. Reaction with ethylenediamine

IV. Hydrogenation

a) I – III

b) II – III

c) III – II

d) III – IV

Q.7 Side effect of drug Naphazoline includes?

a) Hair loss

b) Decrease in blood count

c) Rhinitis medicamentosa

d) Liver abnormalities

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ANSWERS

1-b

2-a

3-d

4-d

5-a

6-a

7-c

 

REFERENCES

[1] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 340

[2] Lemke TL, Zito SW, Roche VF, Williams DA. Essentials of Foye’s principles of medicinal chemistry. Wolters Kluwer; 2017, 348-352

 

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