medicinal chemistry of aminoglycoside antibiotics

Medicinal Chemistry of Aminoglycoside Antibiotics

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Introduction

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

They may be more correctly called aminocyclitol antibiotics.

O

O

O

O

H2C

NH2H2N

OH

NH2

HO

NH2

HO

NH2

Tobramycin

HOH2C

HO

1

1''

2''3''4''

5''

1'

5'4'

3' 2'

34

5 6

6'

2

6''

O

O

O

O

R1H2C

HOHO

R2H2N

OH

NH2

HOH2CHO

NH2

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6

Kanamycins 2REVOLUTIOPHARMD.COM

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.

NH2

OHHO

H2N

NH2

OHHO

H2N

OHH2N

HO

HO

HOHO

OH

NHCH3

H3CO

12

3

456

1 2 3

456

12

345

6

HN

OHHO

HN

HO

OH12

3

456

NH

NH2

NH

H2N StreptamineStreptidine

2-Deoxystreptamine

NHCH3

OHHO

1 23

456

OH

Spectinamine Fortamine 3REVOLUTIOPHARMD.COM

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

O

O

O

O

O

O

OH

CH2OH

H2N

NH2

HO

NH2HO

HO

OH

HO

HO

R1

R2 NH2

Paromomycin I: R1= H; R2= CH2NH2Paromomycin II: R1= CH2NH2; R2= H

1

2

3

34

5 6

1'

2'

3'

4'

5'6'

123

44 5 12


Spectrum of Antimicrobial Activity

Aminoglycosides are broad-spectrum antibiotics effective in:

1. Systemic Infections caused by aerobic G(-) bacillus (klebsiella, proteus, enterobacters).

2. Tuberculosis, Brucellusis, Tularaemia and yersinia infections.

3. Amoebic dysentery, shigellosis and salmonellosis.

4. 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 in clinic.

R factor is resposible for the production of aminoglycoside deactivating enzymes:

1) Acetyl transferases (AAC)2) Phosphotransferases (APH), 3) Nucleotidyl transferases (ANT) These enzymes transfer to hydroxyl and amino

groups of the drug.


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.

O

O

O

O

OH

NH2

OH

H2NOH

NH2H2N

HO

H2NHO

OH

1 23

456

1'

2'4'

1''3'

2''5'

3''

5''4''

6''

6'

I

II

III

ANT-4'ANT-4''

ANT-2'', APH-2''

AAC- 6'

AAC- 2'

APH- 3'

AAC- 3

Kanamycin B


Gentamycin and Deactivating Enzymes

O

O

O

O

HC

NH2H2N

OH

NH

H3C

NH2

HO

1''

2''3''4''

5''

1'

2'3'

4'

6'

5'

1

234

5 6Garosamine

2-Deoxystreptamine

Gentamicin C1: R1=R2 = CH3Gentamicin C2: R1 = CH3 ; R2 = HGentamicin C1a: R1=R2 = H

OHCH3

NHR2R1

Lack 3`-OHAPH Resistant

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

Secondary amino group at 6`-NH2 in Gentamycin C1, spacial hynderanceAAC Resisistant

I

II

III


Kanamycin and Deactivatig Enzymes

O

O

O

O

R1H2C

HOHO

R2H2N

OH

NH2

HOH2CHO

NH2

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6Kanosamine

2-Deoxystreptamine

Kanamycin A: R1= NH2 ; R2 = OHKanamycin B: R1 = NH2 ; R2 = NH2Kanamycin C: R1= OH; R2 = NH2

III

III3`-deoxy derivativeAPH Resistant

4`-deoxy derivativeANT Resistant


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.

O

O

O

O

H2NH2C

HOHO

OHH2N

OH

NH2

HOH2CHO

NH

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6

Amikacin, L-AHBA derivative of Kanamycin A

C C

O

CH2 CH2 NH2

OH

H

2

2-Deoxystreptamine

Kanosamine


Tobramycin and Deactivating Enzymes

O

O

O

O

H2C

NH2H2N

OH

NH2

HO

NH2

HO

NH2

2-Deoxystreptamine

Tobramycin

HOH2C

HO

1

1''

2''3''4''

5''

1'

5'4'

3' 2'

34

5 6

6'

2

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 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.


SAR of Aminoglycosides

O

O

O

O

OH

NH2

OH

H2NOH

NH2H2N

HO

H2NHO

OH

1 23

456

1'

2'4'

1''3'

2''5'

3''

5''4''

6''

6'

I

II

III

ANT-4'ANT-4''

ANT-2'', APH-2''

AAC- 6'

AAC- 2'

APH- 3'

AAC- 3

Kanamycin B

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)


SAR of ring I continued

Methylation of C-6` or 6`- NH2 doesn’t alter the antibacterial activity, but increases the resistance against AAC.

O

O

O

O

HC

NH2H2N

OH

NH

H3C

NH2

HO

1''

2''3''4''

5''

1'

2'3'

4'

6'

5'

1

234

5 6Garosamine

2-Deoxystreptamine


OHCH3

NHR2R1




I

II

III


SAR of ring I continuedOmitting 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.

O

O

O

O

R1H2C

HOHO

R2H2N

OH

NH2

HOH2CHO

NH2

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6Kanosamine

2-Deoxystreptamine


III

III3`-deoxy derivativeAPH Resistant

4`-deoxy derivativeANT Resistant


SAR of ring I continued

O

OH

H3C

NHCH3

OH

O

NHR

HOO

O

NH2

CH2OH

H2N

16

24 3

5

1'2'3'

4'

1''

2''3''

5''

4''

5'

Sisomicin: R=HNetilmicin: R=C2H5

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


SAR of Aminoglycosides continued

O

O

O

O

H2NH2C

HOHO

OHH2N

OH

NH2

HOH2CHO

NH

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6

Amikacin, L-AHBA derivative of Kanamycin A

C C

O

CH2 CH2 NH2

OH

H

2

2-Deoxystreptamine

Kanosamine

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


SAR of ring II continued

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

O

OH

H3C

NHCH3

OH

O

NHR

HOO

O

NH2

CH2OH

H2N

16

24 3

5

1'2'3'

4'

1''

2''3''

5''

4''

5'



SAR of Aminoglycosides continued

O

O

O

O

HC

NH2H2N

OH

NH

H3C

NH2

HO

1''

2''3''4''

5''

1'

2'3'

4'

6'

5'

1

234

5 6Garosamine

2-Deoxystreptamine


OHCH3

NHR2R1

III

III

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).


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.


Therapeutic AgentsKanamycin

O

O

O

O

R1H2C

HOHO

R2H2N

OH

NH2

HOH2CHO

NH2

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6Kanosamine

2-Deoxystreptamine


III

III

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.


Amikacin

O

O

O

O

H2NH2C

HOHO

OHH2N

OH

NH2

HOH2CHO

NH

HO

1''

2''3''4''

5''6''

1'

2'3'

4'

6'

5'

1

234

5 6

Amikacin

C C

O

CH2 CH2 NH2

OH

H

2

2-Deoxystreptamine

Kanosamine

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.


Tobramycin

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

O

O

O

O

H2C

NH2H2N

OH

NH2

HO

NH2

HO

2-Deoxystreptamine

Tobramycin

HOH2C

HO

1

1''

2''3''4''

5''

1'

5'4'

3' 2'

34

5 6

2

6''

Lacks 3`-OHAPH Resistant


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

pseudomona.

O

O

O

O

HC

NH2H2N

OH

NH

H3C

NH2

HO

1''

2''3''4''

5''

1'

2'3'

4'

6'

5'

1

234

5 6Garosamine

2-Deoxystreptamine


OHCH3

NHR2R1

Lacks 3`-OHAPH Resistant



I

II

III


Neomycin

O

O

O

O

O

O

OH

CH2OH

H2N

NH2

HO

NH2HO

HO

NH2

HO

HO

H2NH2C

R2 NH2

2-DeoxystreptamineNeosamine C

Neosamine C

1

2

3

34

5 6

1'

2'

3'

4'

5'6'

123

44 5 12

D-Ribose

Neomycin

Isolated from cultures of Streptomyces fradia along with an antifungal subsance: Fradicin.

Effective against GI and dermal infections.


Netilmicin

O

OH

H3C

NHCH3

OH

O

NHR

HOO

O

NH2

CH2OH

H2N

16

24 3

5

1'2'3'

4'

1''

2''3''

5''

4''

5'


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.


Streptomycin

O

O

HN

HOOH

OH

NH

NH

H2N

OHOH3C

CHO

O NHCH3

OH

HO

HO

H2N

HN

Streptidine

L-Streptose

N- Methyl-L-Glucosamine

Streptomycin

1''

2'3'

4'

12

3 4

1'

2''3''4''

5''

6

5

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


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.


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.

O

O

O

CH3

O

H3CHN

OHNHCH3 OH

HO

Spectinomycin

Sugar

Spectinamine


Paromomycin

O

O

O

O

O

O

OH

CH2OH

H2N

NH2

HO

NH2HO

HO

OH

HO

HO

R1

R2 NH2

2-DeoxystreptamineD-Glucosamine

Paromomycin I: R1= H; R2= CH2NH2Paromomycin II: R1= CH2NH2; R2= H

Neosamine B or C

1

2

3

34

5 6

1'

2'

3'

4'

5'6'

123

44 5 12

Isolated from Streptomyces rimosus. In the tratment of GI infections caused by shigella,

salmonella, E.coli, amoebas.


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.

N

O

NHCOR

HOOC

O

NHCOR

HN

HOO

O

SUGAR

NH2

N

SUGAR

HOOC

H2N

HOO

O

SUGAR

NH2

SUGAR


medicinal chemistry of aminoglycoside antibiotics

Documents

amino groups

comsar of aminoglycosides

deactivatig enzymes

hydroxyl groups

amino sugar

nh2 groups

yersinia infections

urinary infections