1. Tetracyclines:

2. Tetracyclines:
-A broad-spectrum antibiotics. -It is commonly used to treat acne, infection, and other infections caused by bacteria. - They are obtained by fermentation procedures from streptomyces spp. Or by chemical transformation of the natural products. -The first of these compounds was chlortetracycline followed by oxytetracycline and tetracycline.

3. Classification :
A) Naturally occurring: Eg. Tetracycline Chlortetracycline Oxytetracycline Demeclocycline
B) Semisynthetic:
Eg.
Doxycycline
minocycline
meclocycline
methacycline
rolitetracycline

4. Structure and chemical characteristics

6. Structural features
They are the derivatives of an octahydronaphathacene, a hydrocarbon containing four annulated six membered rings.
The stereochemistry of the tetracyclines is very complex.
Carbon atoms 4, 4a, 5. 5a, 6 and 12a are potentially chiral depending on substitution.
Molecules with 5 –OH chiral centers
Molecules without 5 –OH chiral centers

8. Degradation of tetracyclines
1. At intermediate PH :-Formation of 4-Epitetracycline
At C-4 in acidic medium (pH 2-6), epimerization of the “natural” C-4 α-dimethylamino group to the C-4β-epimer occurs. Under acidic conditions, a 1:2 equilibrium is established in solution within a day.

9. 2. At acidic PH
The tetracycline molecule, as well as those that contain the 6β-hydroxy group, is labile to acid and base degradation.
At pH 2.0, tetracycline eliminates a molecule of water with concomitant aromatization of ring C to form anhydrotetracycline.

10. 3. At basic PH conditions
In basic medium, ring C of tetracycline is opened to form isotetracycline. Bases causes reaction between OH gp at C-6 and Keto gp at C-11 leading to breakage of bond between C-11 and C-11a and form lactone

11. These two unfaourable reactions stimulated the research that led to the development of the more stable(not affected by acidic or basic PH) and longer acting compounds.
6-deoxytetracycline
Methacycline
Doxycycline
Minocycline

12. 4. Formation of metal chelates
Stable chelate complexes are formed by the tetracyclines with many metals, including calcium, magnesium, and iron. Such chelates are usually very insoluble in water.
The affinity of tetracyclines for calcium causes them to incorporated into newly forming bones and teeth as tetracycline-calcium orthophosphated complexes. Deposits of these antibiotics in teeth cause a yellow discoloration.
The tetracyclines are distributed into the milk of lactating mothers and will cross the placental barrier into the fetus.
The possible effects of these agents on bones and teeth of the child should be considered before their use during pregnancy or in children under 8 years of age.

13. Bad for a patient’s teeth Good for bone research

14. Mechanism of Action of Tetracyclines:
Tetracyclines enter bacterial cell by Passive diffusion and active transport.
Tetracyclines inhibit bacterial protein synthesis by binding to 30S subunit of robosome thereby blocking the attachment of the t-RNA-amino acid to the m-RNA- ribosome complex.
Tetracyclines can also inhibit protein synthesis in the host, but are less likely to reach the concentration required because eukaryotic cells do not have a tetracycline uptake mechanism.

15. Mechanism of Resistance:
There are three types of tetracycline resistance:
1)Tetracycline efflux- mediated by transmembrane-spanning, active transport proteins.
2)Ribosomal protection- bacterial protein synthesis apparatus rendered resistant to Tetracyaclines.
3)Enzymatic oxidation- to cause tetracycline modifications.

17. SAR
All the derivatives containing less than 4 rings are inactive or nearly inactive.
The simplest tetracycline derivative that retains characteristic broad spectrum activity is 6-demethyl-6-deoxytetracycline.
The substituents at carbon 1,2,3,4,10,11,11a and 12, represents hydrophilic “southern and eastern” faces of molecule can not be voilated drastically to retain antibacterial activity of class.
Retention of the configuration of the asymmetric centres C-4, C-4a and C-12a is essential, whereas the configurations at C-5, C-5a and C-6 may be altered.
Cis fusion of ring A and B with beta OH gp at C12 is essential.
Esters of C12 OH gp are inactive

18. “A” ring substituent's can be modified slightly.
The enolized carbonyl system from C1 to C3 must remain intact for good activity.
Replacement of amide gp at C2 with other grps such as ALDEHYDE OR NITRILE abolishes activity.
At C-2 The amide hydrogen may be replaced with a methyl group, but larger groups have a deleterious effect.
Aminoalkylation of the amide nitrogen gives prodrugs eg. Rolitetracycline, which cleaves invivo to give tetracycline.

19. The dimethyl amino group at C4 must have α orientation :4 epitetracyclines are much less active that natural isomers.
Removal of dimethyl amino group at C4 further reduses activity.
The dimethyl amino group may be replaced by a primary amino group without loss of in vitro activity but all other changes so far lead to decreased bacteriostatic action .
5-epitetracyclines are more active invitro but invivo shows no activity.
6- epitetracyclines are inactive.

21. The substituents at 5, 5a, 6, 7, 8and 9 represents Hydrophobic “northen and western” faces of molecule.
The hydrophobic part of the molecule from C-5 to C-9 may be altered in various ways with retention and, sometimes, improvement of antibacterial activity.
5-OH gp improves p’cokinetics but not antibacterial profile.eg. Oxytetracyacline and Doxycyacline.
modifications at C-6 and C-7 in particular afford products having greater chemical stability, increased antibiotic activity and more favourable pharmacokinetics.
CH3 gp and OH gp at C6 are not essential for activity. Infact Doxycyacline and Methacycline are more active than parent oxytetracycline.

22. Dehydrogenation to form a double bond between C-5a and C-11a markedly decreases activity
Polar substituents (such as OH gp) at C-5 and C-6 contribute decreased lipid versus water solubility to the tetracycline.
Oddly, Strong electropositive groups (eg. Chloro) and strongly electron donating groups (eg. Dimethylamino) enhances activity.
eg.C-7 Chloro- chlortetracycline,roltetracycline
C-7 Dimethylamino -Minocycline

23. . The drugs are amphoteric, meaning they will form salts with both strong acids and bases. Thus, they may exist as salts of sodium or chloride.

24. Spectrum:
-The tetracyclines are broad-spectrum antibiotics. -They are active against the following microorganisms: 1_ gram-positive and gram-negative bacteria 2_ spirochetes 3_ mycoplasmas, 4_ rickettsiae, 6_ Candida albicans

25. 7_Mycoplasma pneumoniae 8_Chlamydia trachomatis 9_Borrelia recurrentis
7_Mycoplasma pneumoniae 8_Chlamydia trachomatis 9_Borrelia recurrentis. 10_Yersinia pestis 11_Vibrio cholerae 12_ Campylabacter fetus 13_Brucella specie 14_Streptococcus pneumoniee. 15_Neisserie gonorrhoeae

26. 1-tetracycline:
Uses: -Tetracycline's primary use is for the treatment of acne vulgaris and rosacea. -It is also used to treat a very wide range of infections.

27. Side effects:
-Gastrointestinal: anorexia, nausea, vomiting, diarrhea, -Skin: rashes, dermatitis. -Renal Toxicity -Hepatic Cholestasis: -Hypersensitivity Reactions:Anaphylaxis, Miscellaneous: Dizziness and headache

28. Drug interaction of tetracyclines::
antacids containing aluminum, calcium, or magnesium, and iron-containing preparations
Impaire the Absorption of tetracyclines
anticoagulant therapy
Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.
bacteriostatic drugs
interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracycline-class drugs in conjunction with penicillin.

29. oral contraceptives
Concurrent use of tetracyclines with oral contraceptives may render oral contraceptives less effective.
ergot alkaloids or their derivatives are given with tetracyclines.
Increased risk of ergotism
Bile acid sequestrants
May decrease tetracycline absorption
Iron preparations
May decrease absorption of tetracyclines

30. Methoxyflurane: Methoxyflurane anesthes
when concurrent with tetracycline) may cause fatal nephrotoxicity; concurrent use is contraindicated.
Methotrexate:
Clearance of methotrexate (high-dose therapy) may be decreased by tetracyclines.

31. Tetracycline 4-dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro-
3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide

32. Chlortetracycline
7-chloro- 4-dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro-
3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide

33. Oxytetracycline 4-dimethyl amino-1,4,4a,5,5a,6,11,12a-octahydro-
3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide

34. THANK YOU -PHARMA STREET