Aminoglycosides medicinal chemistry (Sadhana Dahal)

1. Aminoglycosides,
AIM:
At the end of this lecture students must be able to understand
Aminoglycosides: Members, Mode of Action and uses of Aminoglycoside. SAR of
Streptomycin..
Sadhana Dahal
M.Phil Pharmaceutical
chemistry
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2. Members of Aminoglycosides:
Streptomycin
Neomycin
Kanamycin
Amikacin
Gentamycin
Tobramycin
Sisomycin
Spectinomycin.
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3. General introduction
These are a bunch of closely related chemically basic carbohydrates that are
mostly water-soluble.
Their respective hydrochlorides and sulphates are crystalline in nature.
They are found to be effective in inhibiting the growth of gram-positive as well
as gram-negative bacteria.
They are also effective to a great extent against mycobacteria.
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4. CHEMISTRY OF
AMINOGLYCOSIDES
Aminoglycosides contain an amino cyclitol(highly substituted 1,3-diaminocyclo
hexane) moiety which is a centrally placed ring to which two or more amino sugars
are linked gradually.
The ring is a 2-deoxy streptamine in all aminoglycosides except streptomycin and
dihydrostreptomycin, where it is streptidine.
Thus,
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5. CONT..
In kanamycin and gentamycin families, two amino sugars are attached to 2-deoxy
streptamine.
In neomycin family, there are amino sugars attached to 2-deoxy streptamine.
In streptomycin, two amino sugars are attached to strepidine
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6. CONT
In general, they are prepared biosynthetically exclusively from an admixture of
carbohydrate components of the fermentation media.
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7. Systemic aminoglycosides:
Streptomycin Amikacin
Gentamicin Sisomicin
Kanamycin Netilmicin
Tobramycin
Topical aminoglycosides:
Neomycin Framycetin
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8. PHARMACOKINETICS
Because they have poor oral absorption,these drugs are given parenterally.
Can cross placenta
Cannot cross blood brain barrier.
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9. MECHANISM OF ACTION:
Irreversible inhibitors of protein synthesis.
They bind to specific 30S-subunit ribosomal proteins
And inhibits protein synthesis by at least three ways:
interference with the initiation of complex of peptide formation;
misreading of mRNA, which causes incorporation of incorrect amino acids into
the peptide and results in a nonfunctional or toxic protein;
breakup of polysomes into nonfunctional monosomes.
These activities occur more or less simultaneously, and the overall effect is
irreversible and lethal for the cell.
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10. Streptomycin sulphate
5-(2,4-diguanidino-3,5,6-trihydroxycyclohexoxy) - 4-[4,5-
dihydroxy-6-(hydroxymethyl)-3-methylamino- tetrahydropyran-2-
yl]oxy-3-hydroxy-2- methyl
-tetrahydrofuran-3-carbaldehyde sulfate
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streptos
e
streptidin
e
N methyl L
glucosami
ne

11. Physicochemical Properties:
Streptomycin is a water-soluble aminoglycoside derived
from Streptomyces griseus.
triacidic base having aldose sugar.
colourless,odourless,
available as streptomycin sulphate and chloride
very soluble in water insoluble in acetone.
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12. Pharmacokinetics:
Streptomycin is highly ionized.
neither absorbed nor destroyed in the GIT.
absorption from injection site in muscles is rapid.
distributed only extracellularly.
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13. Uses:
Tuberculosis
Subacute bacterial endocarditis (SABE): .
Plague (infection of rodents caused by Yersinia pestis, transmitted to
human by the bite of flea):
Note:Streptomycin (now mostly gentamicin) is given in conjunction
with penicillin
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14. Streptomycin:
O
CH3
OH O
N-Methyl-L- Glucosamine
Streptomycin
L-Streptose
OH
OH
NH
HO
NH O
H2N
NH
H2N
NH CHO
O
NHCH3
OH
HO
HO
Streptidine
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15. STRUCTURAL ACTIVITY RELATIONSHIP(SAR)
α streptose ring:
Reduction of aldehyde to alcohol results in a compound called dihydrostreptomycin
whose activity is similar to streptomycin but produces severe deafness.
Oxidation of aldehyde group to oxime,semicarbazone,phenylhydrazone,Schiff base
derivatives results in inactive analogues.
Oxidation of CH3 group in streptose to methylene hydroxy gives an active analogue
but has no advantage over streptomycin.
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16. SAR
Streptidine ring
Guanidino group of streptidine ring is necessary for antibacterial
activity. Replacement of guanidino group by any other group reduces
the antibacterial activity.
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17. SAR
N methyl L glucosamine ring:
NHCH3 group is necessary for the activity.
N atom present shall be secondary amine.
Replacement of amino methyl group in glucosamine by larger alkyl groups reduces
the activity.
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18. Neomycin
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(2RS,3S,4S,5R)-5-amino-2-(aminomethyl)-
6-((2R,3S,4R,5S)-5-((1R,2R,5R,6R)-3,5-
diamino-2-((2R,3S,4R,5S)-3-amino-6-
(aminomethyl)-4,5-dihydroxytetrahydro-
2H-pyran-2-yloxy)-6-
hydroxycyclohexyloxy)-4-hydroxy-2-
(hydroxymethyl)tetrahydrofuran-3-yloxy)
tetrahydro-2H-pyran-3,4-diol

19. PROPERTIES
white or yellowish-white hygroscopic powder, very soluble in water,
very slightly soluble in alcohol, and practically insoluble in acetone

20. Uses:
local infection such as burns, ulcers, wounds, impetigo, infected dermatoses,
furunculosis, conjunctivitis, etc.
employed as an adjuvant in topical steroid preparations to control secondary
infections in case of inflammatory disorders.
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21. Kanamycin
D-Streptamine, 0-3-amino-3-deoxy-α-D-glucopyranosyl - (1→6)-0- [6-amino-6-
deoxy-α-D-glucopyranosyl - (1→4)]-2-deoxy, sulfate 1:1 (salt)
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22. Kanamycin A: R1= NH2; R2= OH
Kanamycin B: R1= NH2; R2= NH2
Kanamycin C: R1= OH; R2= NH2
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23. Properties:
Kanamycin is basic and forms salts of acids through its amino
groups.
It is water soluble as the free base, but it is used in therapy as the
sulfate salt, which is very soluble.
It is stable to both heat and chemicals.
Note:
Kanamycin and penicillin salts should not be combined in the
same solution due to possible inactivation of either agent,
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24. Uses:
Used alone or in combination for
Acute staphylococcal infections,
Gonorrhea,
Tuberculosis,
Acute UTIs,
Bowel sterilization in hepatic coma and prior to bowel surgery.
Effective against some Mycoplasma and gram-positive bacteria, for instance,
Staphylococcus pyogenes and epidermidis.
With penicillin it is found to be effective against Streptomyces fecalis.
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25. Amikacin
D-Streptamine,O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→6)-O-[6-amino-6-
deoxy-α-D-glucopyranosyl-(1→4)]-N1-(4-amino-2-hydroxy-1-oxobutyl)-2-
deoxy-, (S)-, sulfate (1:2) (salt)
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26. PROPERTIES
Amikacin is a semisynthetic drug derived form kanamycin A.
Soluble in water.
It retains 50% of the original activity of kanamycin A. L-Isomer is
more active than D-isomer.
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27. Uses:
bacterial septicemia (including neonatal sepsis);
in serious infections of the Respiratory tract
bones and joints infection
CNS (including meningitis) infection
skin and soft tissue infection
intra-abdominal infections (including peritonitis);
burns and postoperative infections.
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28. GENTAMICIN
(3R,4R,5R)-2-{[(1S,2S,3R,4S,6R)-4,6-diamino -3-{[(2R,3R,6S)-3-amino -6-
[(1R)-1-(methylamino)ethyl]oxan -2-yl]oxy}-
2-hydroxycyclohexyl]oxy}-5-methyl-
4-(methylamino)oxane-3,5-diol
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29. PROPERTIES
Gentamycin sulphate exists as white hygroscopic powder, soluble in water, and
practically insoluble in alcohol
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30. Uses:
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• .respiratory infections in critically ill patients;
• Pseudomonas, Proteus or Klebsiella infections: burns, UTI, pneumonia, lung
abscesses
• Meningitis caused by gram-negative bacilli.
• SABE: Subacute bacterial endocarditis
Note:gentamicin is more commonly used in place of streptomycin to accompany
penicillin. However, because of low therapeutic index, its use should be
restricted to serious gram –ve bacillary infections.

31. Tobramycin
O-3-amino-3-deoxy- α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-
trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxy-L-streptamine sulfate
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32. Properties:
a water-soluble antibiotic of the aminoglycoside group,
derived from the actinomycete Streptomyces tenebrarius.
Tobramycin injection USP is a clear and colorless sterile aqueous solution for
parenteral administration.
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33. Uses:
Serious infections caused by Pseudomonas and Proteus
Septicemia in the pediatric patient and adult caused by P. aeruginosa, E. coli.,
and Klebsiella spp.
Intra-abdominal infections, including peritonitis, caused by E. coli, Klebsiella
spp, and Enterobacter spp.
Serious central nervous system infections (meningitis) caused by susceptible
organisms.
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34. Sisomycin
(2R,3R,4R,5R)-2-[(1S,2S,3R,4S,6R)-4,6-diamino-3-[[(2S,3R)-3-amino-6-
(aminomethyl)-3,4-dihydro-2H-pyran-2-yl]oxy]-2-hydroxycyclohexyl]oxy-5-
methyl-4-(methylamino)oxane-3,5-diol
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35. Sisomicin is an aminoglycoside antibiotic, isolated from the fermentation broth of
Micromonospora inositola
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36. Uses:
Sisomicin is an antibiotic used to treat bacterial skin infections.
used to treat infected cuts and wounds.
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37. Spectinomycin
(1R,3S,5R,8R,10R,11S,12S,13R,14S)-8,12,14-trihydroxy-5-methyl-11,13-
bis(methylamino)-2,4,9-trioxatricyclo[8.4.0.03,8]tetradecan-7-one
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38. Spectinomycin is produced in nature by many organisms including
cyanobacteria and various plant species.
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39. Uses:
given by injection to treat gonorrhea, especially in patients who are allergic
to penicillins.
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40. REFERENCES
Textbook of Medicinal Chemistry II by V. Algarsamy
Foye's Principles of Medicinal Chemistry by Lemke; David A. Williams.
Pharmacology by Richard A. Harvey |