Medicinal Chemistry of Aminoglycosides

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Medicinal Chemistry of Aminoglycoside Antibiotics : 

Medicinal Chemistry of Aminoglycoside Antibiotics 1 REVOLUTIOPHARMD.COM

Introduction : 

Introduction Antibiotics contain an aminocyclitol moiety to which aminosugars are glycosidically linked. They may be more correctly called aminocyclitol antibiotics. 2 REVOLUTIOPHARMD.COM

Aminocyclitols??? : 

Aminocyclitols??? Cyclohexanes with several substituted or unsubstituted amino and hydroxyl groups which bring them high water solubility. Streptidine and Streptamine can be called 1,3-diguanidino and 1,3-diamino inositol, respectively. 3 REVOLUTIOPHARMD.COM

Slide 4: 

All have an aminohexose as the amino sugar and some have a pentose as an extra sugar. 4 REVOLUTIOPHARMD.COM

Spectrum of Antimicrobial Activity : 

Spectrum of Antimicrobial Activity Aminoglycosides are broad-spectrum antibiotics effective in: Systemic Infections caused by aerobic G(-) bacillus (klebsiella, proteus, enterobacters). Tuberculosis, Brucellusis, Tularaemia and yersinia infections. Amoebic dysentery, shigellosis and salmonellosis. Pneumonia and urinary infections caused by Pseudomona aeroginosa. G(+) and G(-) aerobic cocci except staphylococci and anaerobic bacteria are less susceptible. 5 REVOLUTIOPHARMD.COM

Microbial Resistance against Aminoglycosides : 

Microbial Resistance against Aminoglycosides Resistant strains have emerged against streptomycin, kanamycin and gentamycin in clinic. R factor is resposible for the production of aminoglycoside deactivating enzymes: Acetyl transferases (AAC) Phosphotransferases (APH), Nucleotidyl transferases (ANT) These enzymes transfer to hydroxyl and amino groups of the drug. 6 REVOLUTIOPHARMD.COM

Aminoglycoside Deactivating Enzymes : 

Aminoglycoside Deactivating Enzymes AAC acetylates 3-NH2 of the ring II, and 2`, 6`- NH2 of the ring I. APH phosphorylates 3`-OH of the ring I and 2``-OH of the ring III. ANT adenylates 2``,4``-OH of the ring III and 4`-OH of the ring I. 7 REVOLUTIOPHARMD.COM

Gentamycin and Deactivating Enzymes : 

Gentamycin and Deactivating Enzymes 8 REVOLUTIOPHARMD.COM

Kanamycin and Deactivatig Enzymes : 

Kanamycin and Deactivatig Enzymes 9 REVOLUTIOPHARMD.COM

Amikacin and Dactivating Enzymes : 

Amikacin and Dactivating Enzymes 1-N-L-(-)-amino-α-hydroxybutyric acid derivative of kanamycin A. Susceptible only against the action of AAC 6`-amino and ANT 4`-OH, resistant against all other deactivating enzymes. 10 REVOLUTIOPHARMD.COM

Tobramycin and Deactivating Enzymes : 

Tobramycin and Deactivating Enzymes 11 REVOLUTIOPHARMD.COM

The Minor Mechanism for Microbial Resistance : 

The Minor Mechanism for Microbial Resistance Decreased uptake of the drug in some strains of p. aeroginosa in hospital infections because of blockade in the active transport of aminoglycosides. Aminoglycoside molecules attach through their cationic groups to anionic portions of membrane phospholipids of bacteria. Upon this attachment the the ATP-dependent uptake occurs. Bivalent cations such as Ca2+ and Mg2+ compete with the drug in this process and antagonise them. Anaerobic bacteria lack the ATP-dependent uptake process, so they are resistant to aminoglycosides. 12 REVOLUTIOPHARMD.COM

SAR of Aminoglycosides : 

SAR of Aminoglycosides Ring I is very necessary for broad-spectrum antibacterial activity. 2` and 6`-NH2 groups are specially important. Exchanging of one of them in kanamycin B with hydroxyl group decreases the activity (kanamycin A, C) 13 REVOLUTIOPHARMD.COM

SAR of ring I continued : 

SAR of ring I continued Methylation of C-6` or 6`- NH2 doesn’t alter the antibacterial activity, but increases the resistance against AAC. 14 REVOLUTIOPHARMD.COM

SAR of ring I continued : 

SAR of ring I continued Omitting the 3`-OH and/or 4`-OH in kanamycin doesn’t decrease the antibacterial activity but increases the resistance against AAC: 3`,4`-dideoxykanamycin B: Dibekacin. The same is true for gentamicin. 15 REVOLUTIOPHARMD.COM

SAR of ring I continued : 

SAR of ring I continued Omitting the 3`-OH and 4`-OH and the addition of a double bond between C-4` and C-5`has the same effect. 16 REVOLUTIOPHARMD.COM

SAR of Aminoglycosides continued : 

SAR of Aminoglycosides continued Ring II is flexible toward changes. 1-NH2 in kanamycin can be acylated and the antibacterial activity remains almost unchanged , but resistance against deactivating enzymes increases: Amikacin 17 REVOLUTIOPHARMD.COM

SAR of ring II continued : 

SAR of ring II continued 1-NH2 ethylation of sisomycin saves the antibacterial activity and increases the enzymatic resistance: Netilmycin 18 REVOLUTIOPHARMD.COM

SAR of Aminoglycosides continued : 

SAR of Aminoglycosides continued Ring III functional groups are less sensitive to modifications: 2``-deoxy gentamicins are less active than 2``-OH ones, but 2``-NH2 derivative (seldomycin) are very active. 3``- NH2 can be primary or secondary. 4``-OH can be axial or equatorial, the former is resistant against the deactivating enzymes (ANT). 19 REVOLUTIOPHARMD.COM

Mechanism of Action of Aminoglycosides : 

Mechanism of Action of Aminoglycosides Inhibition of protein biosynthesis initiation upon attachment to 30s portion of ribosomes. Misreading mutation of the genetic code and the synthesis of nonesense proteins which are not normal proteins so they cannot take part in cellular activities. Nonesense proteins disturb the semipermeability of the bacterial cell and aminoglycoside molecules enter the cell easily and kill it. 20 REVOLUTIOPHARMD.COM

Therapeutic AgentsKanamycin : 

Therapeutic AgentsKanamycin Isolated from cultures of Streptomyces kanamyceticus. The least toxic member in the market is kanamycin A. It is used for the treatment of GI infections, such as dysentery and systemic G(-) bacillus infections caused by klebsiella, proteus, enterobacters. For disinfection of GI before an operation. 21 REVOLUTIOPHARMD.COM

Amikacin : 

Amikacin A semisynthetic derivative of kanamycin A. It is used in the treatment of infections caused by Mycobacterium tuberculosis, Yersinia tularensis, Pseudomona aeroginosa. The suffix “micin” denotes its origin. 22 REVOLUTIOPHARMD.COM

Tobramycin : 

Tobramycin Isolated from cultures of Streptomyces tenebrarius. Antimicrobial activity against resistance P.aeroginosa. 23 REVOLUTIOPHARMD.COM

Gentamicin : 

Gentamicin Isolated from cultures of Micromonospora purpurea. The suffix “micin” denotes its origin. It is used against urinary infections caused by G(-) and pseudomona. 24 REVOLUTIOPHARMD.COM

Neomycin : 

Neomycin Isolated from cultures of Streptomyces fradia along with an antifungal subsance: Fradicin. Effective against GI and dermal infections. 25 REVOLUTIOPHARMD.COM

Netilmicin : 

Netilmicin A semisynthetic ethyl derivative of sisomicin isolated from Micromonospora inyoensis. Ethylation causes spacial hynderance against APH and ATN enzymes. Against gentamicin resistant pseudomona and proteus. 26 REVOLUTIOPHARMD.COM

Streptomycin : 

Streptomycin Has a different aminocyclito (a 1,3-diguanidinoinositol). 27 REVOLUTIOPHARMD.COM

Streptomycin continued : 

Streptomycin continued Isolated from cultures of Streptomyces griseus. It was introduced against tuberculosis in 1943, kanamycin and amikacin are effective against tuberculosis, but not as much as streptomycin. Streptomycin brought Waxman the Noble prize in 1952. 28 REVOLUTIOPHARMD.COM

Spectinomycin : 

Spectinomycin An unusual aminoglycoside isolated from cultures of streptomyces spectabilis. The sugar portion has a carbonyl group and is fused through glycosidic bonds to the aminocyclitol portion, spectinamine. It is used in a single dose against Neisseria gonhorea. 29 REVOLUTIOPHARMD.COM

Paromomycin : 

Paromomycin Isolated from Streptomyces rimosus. In the tratment of GI infections caused by shigella, salmonella, E.coli, amoebas. 30 REVOLUTIOPHARMD.COM

Mechanism of Chemical incompatility of Aminoglycosides with β-lactams : 

Mechanism of Chemical incompatility of Aminoglycosides with β-lactams Acylation of aminocyclitol portion by the β-lactam molecule. Begins with nucleophilic addition of the amino group to the carbonyl group of β-lactam ring. 31 REVOLUTIOPHARMD.COM

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