TETRACYCLINES

Zeynep Ates-Alagoz, Ph.DAnkara University, Faculty of Pharmacy

Department of Pharmaceutical Chemistry

Tetracyclines

- Are isolated from Streptomyces cultures

They have a partially saturated naphthacene core (octahydronaphthacene)

1

4

4 a

5

5 a

6

1 1

1 2 a

N a fta se n

O k ta h id r o n a fta se n

Tetracycline

4- (dimethylamino) -1,4,4a, 5,5a, 6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacene carboxamide

O H

O HO H

OH N ( C H3)

2

O H

C H3

OO

C O N H2

1

4

4 a

55 a

6

1 11 2 a

ABCD

11 1 a

1 2

2

3

7

8

9

Adı R1 R2 R3 R4 2.konum

Tetrasiklin H OH CH3 H H

7-Klorotetrasiklin H OH CH3 Cl H

5-Oksitetrasiklin OH OH CH3 H H

6-Demetil-7-klorotetrasiklin (Demeklosiklin) H OH H Cl H

6-Demetil-6-deoksi-5-hidroksi-6-metilen tetrasiklin (Metasiklin)

OH H =CH2 H H

6-Deoksi-5-hidroksi tetrasiklin

6-Deoksi-oksitetrasiklin (Doksisiklin)

OH H CH3 H H

Rolitetrasiklin H OH CH3 H

Minosiklin H H H N(CH3)3

Glomosiklin H OH CH3 CH3 -CH2OH

Limesiklin H OH CH3 H -CH2NH-CH(COOH)-(CH2)4-NH2

C O N H R

O H

O HO H

R 2 N ( C H3)

2

O H

R 3

OO

R 1R 4

1

4

4 a

5

5 a6

1 1

1 2 a

ABCD

1 0

1 1 a

1 2

2

3

7

8

9

N C H2-

Tetracycline, Clortetracycline, Oxytetracycline, Demethylcytortracycline natural tetracycline derivatives

Metacycline, Doxycycline, Rolitetracycline, Minocycline, Glomocycline, Limesiklin Semi-synthetic tetracycline derivatives

General Properties

- Amphoteric compounds. They form salts with acids and bases.

O H

O HO H

OH

O H

N ( C H3)

2

1

4

4 a

5

5 a6

1 11 2 a

1 01 1 a

1 2

2

3

7

8

9

-Enolic hydroxyls in positions 3 and 12 acid,dimethylamine basic

- Amine group HCl salt water soluble

- Enolic hydroxyl NaOH and KOH salts water soluble, not stable

- They can not be stored in solution for long periods. A solution prepared in neutral will quickly lose 90% activity.

O HO

OO H

1 1

1 1

1 2

1 2

M e

-Chelate complexes with two or three valent metals.

-The resulting chelates can not be absorbed from the GIT.

-Therefore, tetracyclines should not be taken with medicines (antacids) and foods (calcium-rich foods such as milk and products) that carry these metals.

Due to the chelate with calcium, it accumulates in the teeth and forms colored spots.

It should not be used in children until 8 years old and pregnant.

Genel Elde Edilişleri

H2/ C H

2O

N a2S

2O

4

O

N ( C H3)

2

O H

C O N H2

( C H2

O ) n

NH

O

N (C H3

)2

O H

C O N H C H2 N

O

N ( C H3)

2

O H

C O NH

C

H2

NH

CH

C O O H

C H2

C H2

C H2

C H2

N H2NH

2C

H2

C

H2

C

H2

C

H2

CH

N H2

C O O H

S .a u re o fa c ie n s K lo r te tra s ik l in

H2

T e tra s ik l in S .v a r ia n ts

M u ta n t k ü l tü rD e m e ti lk lo r te tra s ik l in

H2

D e m e ti ld e o k s i te tra s ik l in

H N O3

M in o s ik l in

S .r im o s u s O k s i te tra s ik l inN C S

H F

M e ta s ik l in

+

L im e s ik l in

R o lite tr a s ik l in

Structure-Activity Relations

O

N ( C H3)

2

O H

C O N H2

H

O

N ( C H3)

2

O H

C O N H2

H

p H = 4 -8

- Dimethylamine group at the 4th position is below the plane.

-The epimerization occurs at pH = 4-8 → epitetracyclins

-Epimerization can not be completely prevented.

-The best possible crystallized pure compound is 25% epimer derivative.

H

OHC H

3

O O H

C H3

O HO H

5 a

6

1 11 1 a

1 2

5 a

6

1 11 1 a

1 2

CC

A n h id r o te tr a s ik lin

In the acid medium, 1 molecule H2O is separated from the -OH at position 6 and H at

position 5a → (=) occurs between position 5a and position 6.

(=) between 11a-12 → shifts 11-11a → C ring aromatized → activity is lost .

OHC H

3

O

C H3

O

O

C H3

C O O H

OH

6

C

O H

_

6

I so te tr a s ik lin6

- The C ring is opened in strong basic medium

- the -COOH group which is released is esterified with the -OH group at the 6-position → the inactive isotetracycline occurs

-OH at the 6th position interacts with acids and bases → to increase stability; semi-

synthetic derivatives (Doxycycline, Minocycline) are prepared which carry no -OH

moiety at this position.

-Demethylation at 6th position does not change activity

-CONH2 at the 2nd position is replaced by -CN, -COCH3 → activity is decreased.

-"H" in [-CONH2 replaced with various groups to increase water solubility

(Rolitetracycline, Limesiklin)]

-If Ring A is aromatized (12a-OH is removed), the activity is reduced.

-Octahidronaphthacene ring is absolutely necessary. Splitting or breaking any of the rings

leads to loss of the activity.

O H

O HO H

OH N ( C H3)

2

O H

C H3

OO

C O N H2

1

4

4 a

55 a

6

1 11 2 a

ABCD

11 1 a

1 2

2

3

7

8

9

- Bacteriostatic effect by inhibiting protein synthesis in bacterial ribosomes.

- Antibacterial spectra are identical (Gr (-) meningococcus and gonococci,Gr (+) Streptomyces pneumoniae, S. pyogenes, S. viridans)

- Absorption ratios, elimination routes, biological half-lives are different.

- Average absorbtions are 60-70%.

- The most lipophilic tetracycline derivatives Doxycycline and Minocycline(used in acne treatment) are absorbed 90-95% of the gastrointestinaltract.

- Due to the formation of calcium chelates in the teeth, discolorations are brought to the spots.

- More frequent in blond people, causing photosensitization (absorbance at 360-370 nm due to strong chromophore groups) causesphotodermatosis.