Medicinal Chemistry of Aminoglycoside Antibiotics

Introduction
Antibiotics contain an aminocyclitol moiety to which aminosugars are glycosidically linked.

They may be more correctly called aminocyclitol antibiotics.

6'
H2C NH2

6'
R1H2C O

5'
HO

4' 3' 2
'

1
NH2

'

HO HO H2N

4' 3'

5' 2
'

1'
R2 H2N O

4 5
HO

3 6

2
NH2 O

4
HO

3 5
O

2
NH2

1 6''

6
O

HOH2C

6''

5''
O HO

1''
OH

5''
HO

HOH2C

1''
OH

4''

3''

NH2

2''

4''

3''

NH2

2''

Tobramycin

Kanamycins

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.
HO HO HN H2N NH HO

6 1

5 2

HO OH H N 3 OH NH NH2 HO H2N

6 1

5 2

4 3
OH

OH NH2

Streptamine

Streptidine
4 2
H2N OH NH2 HO

6
HO H2N

5 1

6 1

5 2

4 3
OH

1 5

NHCH3

OH NHCH3

HO HO

6 4

OH

H3CO

2-Deoxystreptamine

Spectinamine

Fortamine

All have an aminohexose as the amino sugar and some have a pentose as an extra sugar.
OH

6' 5'
HO

4'
HO

1' 2'
NH2 O

H2N

4 5
O

3 6
HO

2
NH2

3'

CH2OH

R1

4
HO HO

5 3 R2 2

4 1 3
O

1 2
OH

NH2

Paromomycin I: R1= H; R2= CH2NH2 Paromomycin II: R1= CH2NH2; R2= H

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.

Microbial Resistance against Aminoglycosides

Resistant strains have emerged against streptomycin, kanamycin and gentamycin. 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

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 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. 7

SAR of Aminoglycosides
Ring 1 is 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)
ANT-4''
6'' 4''
HO H2N

OH

APH- 3' ANT-4'

O

5'' 3''

AAC- 2'
1''
O H2N

OH

2 6 5 1 2 II 3
OH

'

3'
O

4'
OH

2'' HO III
''

H2N O NH2

5'

6'

NH2

1'

ANT-2 , APH-2

''

AAC- 6' AAC- 3

Kanamycin B
8

SAR of ring I .... cont

Methylation of C-6` or 6`- NH2 doesnt alter the antibacterial activity, but increases the resistance against AAC.

Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderance AAC Resisistant
R1

6'
HC

NHR2

4'

5' 3' 2
'

I
1'
H2N O

Lack 3`-OH APH Resistant Garosamine

II
3 2
NH2

2-Deoxystreptamine

NH2

4
HO

5
O

6
O

5''
H3C

1''
OH

III

4''

3''

NH

2''

Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H

OH CH3

Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin 9 ANT Resistant

SAR of ring I ..... cont

Omitting the 3`-OH and/or 4`-OH in kanamycin doesnt decrease the antibacterial activity but increases the resistance against AAC: 3`,4`-dideoxykanamycin B: Dibekacin. The same is true for gentamicin.
4`-deoxy derivative ANT Resistant
4' 3'

6'
R1H2C

5' 2 I
'

3`-deoxy APH Resistant

HO derivative HO

1'
R2 H2N O

2-Deoxystreptamine
4
HO

II 3 6

2
NH2 O

Kanosamine
HOH2C

5
O

6''

5''
HO

1''
OH

4''

3'' III

NH2

2''

Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2

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SAR of ring I.... cont

Omitting the 3`-OH and 4`-OH and the addition of a double bond between C-4` and C-5`has the same effect.
CH2OH

4' 3' 2
'

5'
O H2N

1
NH2 O

'

2 3 6 5
O O

NHR

HO

5''
H3C

1''
OH

4''

3''

2''
NHCH3

Sisomicin: R=H Netilmicin: R=C2H5

OH

11

SAR of Aminoglycosides... cont

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
6'
H2NH2C HO HO

2-Deoxystreptamine
5'
O

4' 3' 2

2'
OH

1'
H2N O

OH C H CH2 CH2 NH2

4
HO

3 5
O

2
NH C

6
O

Kanosamine

6''
HOH2C HO

5'' 3''

1''
OH NH2

4''

2''

Amikacin, L-AHBA derivative of Kanamycin A

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SAR of ring II ... cont

1-NH2 ethylation of sisomycin saves the antibacterial activity and increases the enzymatic resistance: Netilmycin
CH2OH

4' 3' 2
'

5'
O H2N

1
NH2 O

'

2 3 6 5
O O

NHR

HO

5''
H3C

1''
OH

4''

3''

2''
NHCH3

Sisomicin: R=H Netilmicin: R=C2H5

OH

13

SAR of Aminoglycosides... cont

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).
R1

6'
HC

NHR2

4' 3'

5' 2
'

1'
NH2 H2N O

2-Deoxystreptamine II
3 5
O

2
NH2

4
HO

Garosamine

6
O

5''
H3C

1''
OH

4''

3''

NH

2''

Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H

OH

III
CH3

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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.

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16

Therapeutic Agents Kanamycin

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 GI6'before an operation.
R1H2C HO HO

4' 3'

5' 2' I

1'
R2 H2N O

2-Deoxystreptamine
4
HO

II 3 6

2
NH2 O

Kanosamine
6''
HOH2C

5
O

5''
HO

1''
OH

4''

3'' III

NH2

2''

Kanamycin A: R1= NH2 ; R2 = OH Kanamycin B: R1 = NH2 ; R2 = NH2 Kanamycin C: R1= OH; R2 = NH2

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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.
6'
H2NH2C HO HO

2-Deoxystreptamine
5'
O

4' 3' 2

'

1'
OH H2N O

OH C H CH2 CH2 NH2

4
HO

3 5
O

2
NH C

6
O

Kanosamine

HOH2C

6''

5''
HO

1''
OH

4''

3''

NH2

2''
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Amikacin

Tobramycin
Isolated from cultures of Streptomyces tenebrarius. Antimicrobial activity against resistance P.aeroginosa.
H2C

5'
HO

O
'

4' 3' 2
NH2

1'
H2N O

2-Deoxystreptamine
4 5
HO

Lacks 3`-OH APH Resistant

3 6

2
NH2 O

HOH2C

6''

5''
O HO

1''
OH

4''

3''

NH2

2''

Tobramycin
19

Gentamicin
Isolated from cultures of Micromonospora purpurea. The suffix micin denotes its origin. It is used against urinary infections caused by G(-) and pseudomona. Secondary amino group at 6`-NH2 in
Gentamycin C1, spacial hynderance AAC Resisistant
R1

6'
HC

NHR2

4'

5' 3' 2
'

I
1'
H2N O

Lacks 3`-OH APH Resistant Garosamine

II
3 2
NH2

2-Deoxystreptamine

NH2

4
HO

5
O

6
O

5''
H3C

1''
OH

III

4''

3''

NH

2''

Gentamicin C1: R1=R2 = CH3 Gentamicin C2: R1 = CH3 ; R2 = H Gentamicin C1a: R1=R2 = H

OH CH3

Axial and tertiary 4``-OH instead of equatorial secondary 4``-OH in Kanamycin ANT Resistant

20

Neomycin
Isolated from cultures of Streptomyces fradia along with an antifungal subsance: Fradicin. Effective against GI and dermal infections.
NH2

Neosamine C
HO

6' 5' 4'

HO
'

2-Deoxystreptamine
O

1' 2
NH2 O

H2N

4 5
O

3 6
HO

2
NH2

3'

CH2OH O

H2NH2C

4
HO HO

5 3 R2 2

4 1 3
O

1 2
OH

NH2

Neosamine C

D-Ribose Neomycin

21

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.
CH2OH

4' 3' 2
'

5'
O H2N

1
NH2 O

'

2 3 6 5
O O

NHR

HO

5''
H3C

1''
OH

4''

3''

''

Sisomicin: R=H Netilmicin: R=C2H5

OH

NHCH3

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Streptomycin
Has a different aminocyclito (a 1,3-diguanidinoinositol).
NH

Streptidine

H2N HO

NH

2 3 4

1 5
O

OH OH

H2N

H N

HN

CHO O 4'

1' 2'
O

L-Streptose

N- Methyl-L-Glucosamine
HO

H3C HO

3'

5''
HO

1''
O NHCH3

3'' 4''
OH

2''

Streptomycin

23

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.

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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.
OH NHCH3 OH

Spectinamine
H3CHN O

HO O

Sugar

Spectinomycin

CH3
25

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

D-Glucosamine
HO

6' 5' 4'

HO R1
'

2-Deoxystreptamine
O

1' 2
NH2 O

H2N

4 5
O

3 6
HO

2
NH2

3'

CH2OH O

4
HO HO

5 3 R2 2

4 1 3
O

1 2
OH

NH2

Neosamine B or C Paromomycin I: R1= H; R2= CH2NH2 Paromomycin II: R1= CH2NH2; R2= H
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Mechanism of Chemical incompatility of Aminoglycosides with -lactams Acylation of aminocyclitol portion by the -lactam molecule. Begins with nucleophilic addition of the amino group to the carbonyl group of -lactam ring.
N HOOC

NHCOR

H2N SUGAR O HO O SUGAR NH2

HOOC

NHCOR

HN SUGAR O HO

O NH2 O

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SUGAR

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