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

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

Oxymetazoline

IUPAC nomenclature

3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol.

Classification

Oxymetazoline is an α1-adenergic agonist.

 

Physiochemical Properties

S. NO. PHYSICAL AND CHEMICAL PROPERTIES
1 Molecular weight 260.37
2 Physical appearance Solid ; crystals from benzene
3 Melting point 182°C
4 Solubility Water solubility is 1.4 mg / L
5 Octanol/water partition coefficient 3.4
6 Presence of ring Benzene ring and imidazoline ring
7 Number of chiral centers Not present

Mechanism of Action

i. Oxymetazoline acts on α-adrenergic receptors in the arteriols of nasal mucosa and conjunctiva.

ii. This produces vasoconstriction.

iii. Decreased conjuctival congestion in ophthalmic

iv. Constriction in nasal which results in decreased blood flow and hence, decreased nasal congestion.

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. Chloromethylation of 2-tert-butyl-4,6-dimethylphenol.

ii. Transformation of the chloromethy derivative into a nitrile.

iii. Reaction of the above formed compound with ethylenediamine gives oxymetazoline.

 

Therapeutic Uses

Oxymetazoline is used for temporary relief of congestion.

Side Effects

Some of the side effects of oxymetazoline are

  • temporary burning,
  • stinging,
  • sneezing,
  • runny nose
  • dryness in nose.

Some other side effects are dizziness, weakness, sweating, tremors, trouble sleeping and irregular heartbeat.

MCQs

Q.1 Oxymetazoline produces ……….  and ………. Conjuctival congestion in ophthalmic.

a) Vasodilation, increases

b) Vasoconstriction, increases

c) Vasodilation, Decreases

d) Vasoconstriction, Decreases

Q.2 Therapeutic use of drug is?

a) Relief of congestion

b) Reducing blood cholesterol level

c) Antiarrhythmic drug

d) None of the above

Q.3 Which amongst the following are the correct statements with respect to the SAR of drug Oxymetazoline?

I. At least one of the groups is required at R2 which can form hydrogen bonds. And if only one group is present then it is preferred at 4’ position to retain the beta2 activity

II. 3’,4’-dihydroxy substitution at benzene ring has higher oral activity

III. Large lipophillic groups at R1 can afford compounds with alpha blocking activity

a) I, III

b) II

c) III

d) I, II, III

Q.4 The starting chemical required for the synthesis of drug Oxymetazoline?

a) 6-tert-butyl-2,3-dimethylphenol

b) 2-(tert-butylamino)-1-(3,4-dihydroxyphenyl)ethanone

c) 3-(benzyloxy)benzaldehyde

d) Pyrocatechol

Q.5 Correct sequence for the True/False for the physiochemical properties of the drug Oxymetazoline?

I. Imidazoline ring is absent in the structure.

II. Molecular weight: 260.37 gm/mol.

III. Octanol/water partition coefficient: 1.1.

IV. No chiral carbon is present in the structure.

a) TFTF

b) FTFT

c) TTFF

d)FFTT

Q.6 Correct statements for the IUPAC nomenclatures are?

I. Oxymetazoline: 3-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-2,4-dimethyl-6-tert-butyl-phenol

II. Bitolterol: (RS)-[4-(1-Hydroxy-2-tert-butylamino-ethyl)-2-(4-methylbenzoyl)oxy-phenyl] 4-methylbenzoate

III. Xylometazoline: 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]- 4,5-dihydro-1H-imidazole

IV. Epinephrine: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol

a) I, II, III

b) I, II, III, IV

c) I, II , IV

d) IV

 Q.7 Match the following drugs with their correct classifications-

i. Albuterol A. Selective α1-adrenergic agonist
ii. Dobutamine B. ß2-adrenergic agonist
iii. Oxymetazoline C. ß1-adrenergic agonist
iv. Methyldopa D. Selective α2-adrenergic agonist

 a) i-A, ii-C, iii-B, iv-D

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

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

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

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ANSWERS

1-d

2-a

3-a

4-a

5-b

6-a

7-d

 

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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