ZeynepAtes-Alagoz, Ph.D TETRACYCLINES

(1)

TETRACYCLINES

Zeynep Ates-Alagoz, Ph.D

Ankara University, Faculty of Pharmacy

Department of Pharmaceutical Chemistry

(2)

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 f t a s e n O k t a h id r o n a f t a s e n

(3)

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 H O H O H N ( C H 3)2 O H C H 3 O O C O N H 2 1 4 4 a 5 5 a 6 1 1 1 2 a A B C D 1 1 1 a 1 2 2 3 7 8 9

(4)

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 H O H R 2 N ( C H 3)2 O H R 3 O O R 1 R 4 1 4 4 a 5 5 a 6 1 1 1 2 a A B C D 1 0 1 1 a 1 2 2 3 7 8 9 N C H₂

(5)

-Tetracycline, Clortetracycline, Oxytetracycline,

Demethylcytortracycline



natural tetracycline derivatives

Metacycline, Doxycycline, Rolitetracycline, Minocycline,

Glomocycline, Limesiklin



Semi-synthetic tetracycline

(6)

General Properties

-

Amphoteric compounds. They form salts with acids and bases.

O H O H O H O H O H N ( C H 3)2 1 4 4 a 5 5 a 6 1 1 1 2 a 1 0 1 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.

(7)

O H O O O 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.

(8)

Genel Elde Edilişleri

H 2/ C H2O N a 2S2O4 O N ( C H 3)2 O H C O N H 2 ( C H 2O ) n N H O N ( C H₃)₂ O H C O N H C H₂N O N ( C H 3)2 O H C O N H C H 2 N H C H C O O H C H 2C H2C H2C H2N H2 N H₂ C H₂ C H₂ C H₂ C H₂ C H N H₂ C O O H S .a u r e o f a c i e n s _{K l o r t e t r a s i k l i n} H₂ T e t r a s i k l i n S .v a r i a n t s M u t a n t k ü l t ü r D e m e t i l k l o r t e t r a s i k l i n H₂ D e m e t i l d e o k s i t e t r a s i k l i n H N O₃ M i n o s i k l i n S .r i m o s u s O k s i t e t r a s i k l i n N C S H F M e t a s i k l i n + L i m e s i k l i n R o l i t e t r a s i k l i n

(9)

Structure-Activity Relations

O N ( C H 3)2 O H C O N H 2 H O N ( C H 3)2 O H C O N H 2 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.

(10)

H O H C H 3 O O H C H 3 O H O H 5 a 6 1 1 1 1 a 1 2 5 a 6 1 1 1 1 a 1 2 C C A n h id r o t e t r 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.

(11)

O H C H 3 O C H 3 O O C H 3 C O O H O H 6 C O H _ 6 I s o t e t r a s ik lin 6

- 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.

(12)

-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 H O H O H N ( C H 3)2 O H C H 3 O O C O N H 2 1 4 4 a 5 5 a 6 1 1 1 2 a A B C D 1 1 1 a 1 2 2 3 7 8 9

ZeynepAtes-Alagoz, Ph.D TETRACYCLINES

TETRACYCLINES