Continuation of Antibiotics

Continuation of Antibiotics

CLASSIFICATIN F ANTIBITICS According to their mechanism of action

Antibiotics as disturber with the biosynthesis of protein These antibiotics all target the bacterial ribosome and interfere in the process of translation of the messenger RNA into protein and thus block a fundamental process in bacterial metabolism. Inhibitors of 30s Ribosomal subunit: Aminoglycosides and Tetracyclines Inhibitors of the 50s Ribosomal subunit: Macrolides and Chloramphenicol

Antibiotics. Tetracyclines. Aminoglycoside Macrolides Chloramphenicol

Tetracycline Antibiotics R X Y Z N(C 3 ) 2 Tetracyclines CN 2

Chemistry Numbering and naming system of the tetracyclines. Naphthacene(tetracene) 8 9 7 6 C 3 5 10 11 12 N(C 3 ) 2 4 3 2 1 Tetracycline CN 2 four annelated six-membered rings Tetracyclines is octahydronaphthacene

Molecular interaction of tetracyclines with the target receptor (30S)

Tetracycline pharmacophore and numbering Positions at the bottom of the molecule (10, 11, 1) and most of ring A (positions 2, 3, and 4) represent the invariant pharmacophore region of the molecule, where modifications are not tolerated without loss of antibiotic activity.

Tetracyclines interfere with the 30s ribosomal subunit, disrupting protein synthesis in bacteria nly major site of variability between drugs Lots of chirality Tautomerization and conjugation critical to structure and antibacterial activity

Tetracycline Derivatives R X Y Z N(C 3 ) 2 CN 2 Tetracyclines

C 3 N(C 3 ) 2 C 3 N(C 3 ) 2 CN 2 CN 2 Tetracycline xytetracycline Tetracyclines is octahydronaphthacene C 3 N(C 3 ) 2 C 3 N(C 3 ) 2 CN 2 CN 2 Tautomerization of Tetracycline

Tetracyclines are obtained by fermentation from Streptomyces species and by chemical modifications of natural products. Tetracyclines are amphoteric compounds forming salts with either bases or acids. ydrochloride salt is usually used encapsulated to mask their bitter taste. Sodium and potassium salts are unstable in aqueous solutions.

Mechanism of Action: Tetracyclines inhibit bacterial protein synthesis by blocking the attachment of the t-rna-amino acid to the ribosome. 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.

Bacterial resistance Bacterial resistance may develop due to inability of tetracycline to penetrate cell wall or presence of tetracycline-binding proteins at the cell surface. No bacterial inactivating enzyme for tetracyclines are known.

Effect of p Intermediate p Epimerization C 3 Tetracycline Active A N(C 3 ) 2 CN 2 _ + + + N(C 3 ) 2 A + + CN 2 + _ + ( 3 C) 2 N A CN 2 4-Epitetracycline Inactive

Stability under acid condition The tetracycline molecule, as well as those that contain the 6β-hydroxy group, is labile to acid and base degradation. At p 2.0, tetracycline eliminates a molecule of water with concomitant aromatization of ring C to form anhydrotetracycline. N + + 2 N - 2 CN 2 CN 2 + N - + N CN 2 CN 2 ÍÑË Îï

In strong acids + C 3 C B A Tetracycline Active N(C 3 ) 2 CN 2 + _ + 2 C 3 C N(C 3 ) 2 CN 2 Anhydrotetracycline Inactive Aromatization of ring C

Formation of 4-Epitetracycline At C-4 in acidic medium (p 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. N CN 2 + N CN 2 N CN 2 N CN 2 4-Epitetracycline

Stability under base condition In basic medium, ring C of tetracycline is opened to form isotetracycline. N CN 2 - - N CN 2 N N N - CN 2 - CN 2 CN 2

In strong bases C C 3 N(C 3 ) 2 C 3 N(C 3 ) 2 CN 2 CN 2 Tetracycline Active Isotetracycline Inactive

The role of 6-hydroxy group in the unstability of tetracyclines!!!!! 6-Deoxy derivatives are acid stable, base stable, well absorbed orally but acid isomerization is still possible. igh protein binding, low rate of clearance lead to long duration of action

Formation of metal chelates N(C 3 ) 2 M n+ CN 2 M n+ N(C 3 ) 2 CN 2 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.

Chelation with metal C 3 N(C 3 ) 2 M C 3 N(C 3 ) 2 C B CN 2 M CN 2 M= metal ion like Ca, Mg, Al or F

Structure activity relationship SAR. 8 7 6 C 3 5 N(C 3 ) 2 4 3 9 10 11 12 1 2 CN 2 Tetracycline

Various modifications in teracyclines tested for activity Arrows point to permissible modification ;arrows with an X point to non-permissible modifications

Tetracycline 8 7 6 5 N(C 3 ) 2 4 3 9 2 10 11 12 1 CN 2 6-Methyl-4-(dimethylamino)-3,6,10,12,12a- pentahydroxy-1,4,4a,5,5a,6,11,12a-octahydro-2- naphthacenecarboxamide

Tetracycline (Achromycin) 4-Dimethylamino-l,4,4a,5,5a,6, 11, 12a-octahydro- 3,6,10,12, 12a-pentahyd roxy-6-methyl-l, 11-dioxo-2- naphthacenecarboxamide. C 3 N(C 3 ) 2 CN 2 Tetracycline Preparation: 1- By catalytic hydrogenation of 7-chlorotetracycline Draw the equation

2- Also from fermentation of Streptomycin species. Chlorotetracycline hydrochloride (Aureomycin Cl) Cl C 3 N(C 3 ) 2 CN 2 Chlorotetracycline nly as ointment

xytetracycline (Terramycin) C 3 N(C 3 ) 2 CN 2 xytetracycline Isolated from S. Rimosus. It is used for parenteral (I.M. & I. V.), oral ointment. administration or as

Methacycline ydrochloride (Rondomycin) 6- Deoxy-6-demethyl-6-methylene-5-oxytetracycline C 2 N(C 3 ) 2 Methacycline CN 2 It is more potent than tetracycline and has long serum half-life. lt is more stable as the result of modification of 6-position.

Demeclocycline (Declomycin) 7 -Chloro-6-demethyltetracycline. Cl N(C 3 ) 2 CN 2 Demeclocycline It has low rate of elimination through kidneys.

Doxycycline (vibramycin) α-6- Deoxy-5-oxytetracycline What is the structure???? It is prepared by catalytic hydrogenation of methacycline. Discussion in the lab. Draw the equation The 6-α-methyl epimer is more than 3 times as active as 6β-epimer. The absence of 6- Comment.

Doxycycline is very well absorbed from G.1.T. It is well distributed in the tissues, but it does not accumulate in the body, so it is given to patients with impaired renal functions.

Minocycline hydrochloride (Minocin) 6-Demethyl-6-deoxy-7-N-dimethylamino tetracycline N(C 3 ) 2 N(C 3 ) 2 Minocycline It is obtained by reductive methylation of 7-nitro derivative. Draw the equation Minocycline is active against tetracycline resistant bacteria. CN 2

It is very effective against grampositive bacteria and also eradicate N. meningitis in asymptomatic carriers. Minocycline has very long serum half-life due to slow urinary excretion. The improved distribution properties is attributed to greater degree of lipid solubility.

Sancycline N(C 3 ) 2 Sancycline CN 2 The simplist structure of tetracycline.

Rolitetracycline Prodrug of sancycline N(C 3 ) 2 Rolitetracycline CNC 2 N Increase water solubility of the compound, so the compound is suitable for parenteral preparation.

Tigecycline N N N(C 3 ) 2 N(C 3 ) 2 N 2 Tigecycline Tigecycline is a novel tetracycline characterized by having glycylamido moiety at 9-position. It is developed to overcome the increased incidence of resistance to tetracycline. It is administered via IV route.

The 6-thia isostere,(6-deoxy-6-demethyl-6- thiatetracycline) has been explored and found to have superior activity over known tetracyclines, especially, against gramnegative bacteria. S N(C 3 ) 2 CN 2