macrolides

MACROLIDES

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INTRODUCTION:

Macrolide antibiotics are so named as they possess a macrocyclic lactone usually having 12 to 17 atoms

SOURCE: These are produced by streptomyces

species and the products of actinomycetes

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Common Structural Features:

5 common chemical features they are

i. A macro cyclic lactone, usually having 12 to 17 atoms

ii. A ketone group

O

O

O

CH3

HO

H3C

CH3

CH3

OH3C

O

HO

CH3

N CH3

H3C

OH

H3C

CH3

OH

O

O

OH

O

H3CCH3

CH3

Erythromycin


iii. One or two aminosugars linked to the nucleus.

iv. A Neutral sugar linked either to amino sugar or to lactone ring

v. The presence of the dimethyl amino moiety on the sugar residue, which explains the basicity of these compounds and consequently formation salts.


SPECTRUM OF ACTIVITY:

active against most species of gram They are generally (+) bacteria both cocci and bacilli.

The antibacterial spectrum of activity of the more potent macrolides resembles that of pencillin.

They also exhibit useful effectiveness against gram(-)cocci, specially Neisseria Species


MECHANISM OF ACTION:


PHYSICAL PROPERTIES:

Occurs as crystalline powders.Water insoluble molecules.stable in aqueous solutions at or below

room temperature.Unstable in acidic conditions and

forms internal cyclic ketal.


CHEMICAL PROPERTIES:

Macrolides are stable in aqueous solutions at or below room temperature.

Macrolides are unstable under acidic conditions &undergo an intramolecular reactions to form an inactive cyclic ketone.


Chemical Instability Of Macrolides:

O

O

O

CH3

HO

H3C

CH3

CH3

OH3C

OH

H3C

CH3

OH

O

Erythromycin

O

O

CH3

HO

H3C

CH3

OH3C

OH

H3C

CH3

O

Erythromycin 6,9-hemiketal

S1

S2

S1

S2

O

OHCH3

1 3

12

9

1 3

5

12 6

89

O

O

CH3

CH3

OH3C

CH3

O

S1

S2

O

CH3

1 3

12 6

89

O

H3C

HO

H3C

O

O

CH3

HO

H3C

CH3

OH3C

OH

H3C

CH3

O

8,9-Anhydroerythromycin 6,9-hemiketal

S1

S2

O

CH3

1 3

12 6

89

Anhydroerythromycin 6,9;9,12-spiroketal

H+

H

H3O+

-H3O+

H3O+

H+


STRUCTURAL ACTIVITY RELATIONSHIP

As macrolide are unstable in acidic pH,a no. of strategies have been utilised to improve the acidic stability of erythromycin.

The addition of hydroxylamine to the ketone to form oxime e.g. roxithromycin


alteration of c-6 hydroxyl group: nucleophilic functionality which initiates erythromycin degradation.

The azalides (azithromycin) are semi-synthetic 15-membered congeners in which a nitrogen atom has been introduced to expand a 14-membered precursor- leads to an extended spectrum of action.


PHARMACOKINETIC ASPECTS:

These are administered orallyErythromycin can also be given

parenterally, through intravenous injections.

These diffuse readily into most tissues but do not cross the BBB & poor penetration into synovial fluid.


Therapeutic Agents Of Macrolides:

Erythromycin:

O

O

O

CH3

HO

H3C

CH3

CH3

OH3C

O

HO

CH3

N CH3

H3C

OH

H3C

CH3

OH

O

O

OH

O

H3CCH3

CH3

Erythromycin


Source: Isolated from streptomyces erythreus

Physical properties:Yellow to white crystalline powderSoluble in alcohol, slightly soluble in waterStable at neutral PH

Dosage forms:

Oral and topical dosage formsEnteric coted and delayed realese dosage

forms


Drug interactions:AnticoagulantsBenzodiazepinesCyclosporineAntihistaminic drugsThese agents potentiate the action of erythromycin

Adverse effects:AbdominalcrampsEpigastric distress JaundiceTransient deafness


USES: It is used to treat

The upper part of the respiratory tract infections,

Mycoplasma pneumonia Gonorrhoea.

It is a good choice for penicillin-sensitive cases


Therapeutic agents of erythromycinErythromycin ethylsuccinate Prodrug with more lipophilicity- longer duration of

actionErythromycin estolate

A lipid soluble,acid stable prodrug with better oral absorption

Erythromycin gluceptate A water-soluble salt of glucoheptanoic acid for

parentral dosage formsErythromycin lactobionate Erythromycin salt meant for parentral usage


Clarithromycin

Clarithromycin

Semisynthetic derivative of erythromycin obtained by selective methylation at c-6

position: 6-Methyl ether of erythromycin

O

O

O

CH3

HO

H3C

CH3

CH3

OH3C

OH

H3C

O

O

OHO

CH3

N

CH3

CH3

O OH

CH3

CH3

OH

1 3

5

9

12

1`

1``

Clarithromycin

H3C

CH3

6


Advantages: Cannot undergo cyclic ketal formation, so

doesn’t cause cramp in GI.Higher blood concentrations. More lipophyl.Lower doses with less intervals

USES: Effective against

•Borrelia burgdorferi,

•mycobacterium aviumcomplex


Azithromycin

• Nitrogen containing

15-membered lactone ring macrolides(azalides)

• Stable under acidic conditions, because it doesn’t form cyclic ketal.

O

O

CH3

HO

H3C

CH3

OH3C

OH

CH3

OH

O

OHO

CH3

N

CH3

CH3

O OH

CH3

CH3

OCH3

1 3

5

12

1`

1``

NCH3H3C

H3C

Azithromycin


USES:

• In the treatment of urogenital infections caused by N. gonorrhoeae and Chlamydia trachomatis.

• Widely prescribed for the treatment of respiratory tract infections.

• More active against gram(-)bacteria.


ROXITHROMYCIN:

Semi-synthetic 14-membered ring macrolide antibiotic in which the erythronolide lactone ring has been altered to prevent inactivation in the milieu. 22Visit www.bpharmstuf.com

USES:Active against both gram(+) & gram(-)

Treatment of skin, dental and genital infections

Treatment of upper and lower respiratory tract infections.


REFERENCES:S.N.Pandeya,Textbook of medicinal chemistry

Rama Rao Nadendla,Medicinal chemistry

Sri Ram, Medicinal chemistry

The Mechanism of Action of Macrolides, and Lovmar and Måns Ehrenberg .

Keicho N, Kudoh S (2002). "Diffuse panbronchiolitis: role of macrolides .

Lopez-Boado YS, Rubin BK (2008). "Macrolides as immunomodulatory therapeutic agents. Curr Opin Pharmacol.


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macrolides