Upload
kevin-chapley
View
301
Download
5
Tags:
Embed Size (px)
DESCRIPTION
Medicinal Chemistry of Aminoglycoside Antibiotics
Citation preview
Medicinal Chemistry of Aminoglycoside Antibiotics
1REVOLUTIOPHARMD.COM
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
4REVOLUTIOPHARMD.COM
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.
5REVOLUTIOPHARMD.COM
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.
6REVOLUTIOPHARMD.COM
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
7REVOLUTIOPHARMD.COM
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
8REVOLUTIOPHARMD.COM
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
9REVOLUTIOPHARMD.COM
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
10REVOLUTIOPHARMD.COM
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''
Lack 3`-OHAPH Resistant
11REVOLUTIOPHARMD.COM
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.
12REVOLUTIOPHARMD.COM
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)
13REVOLUTIOPHARMD.COM
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
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
14REVOLUTIOPHARMD.COM
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
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
15REVOLUTIOPHARMD.COM
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.
16REVOLUTIOPHARMD.COM
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
17REVOLUTIOPHARMD.COM
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'
Sisomicin: R=HNetilmicin: R=C2H5
18REVOLUTIOPHARMD.COM
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
Gentamicin C1: R1=R2 = CH3Gentamicin C2: R1 = CH3 ; R2 = HGentamicin C1a: R1=R2 = H
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).
19REVOLUTIOPHARMD.COM
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.
20REVOLUTIOPHARMD.COM
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
Kanamycin A: R1= NH2 ; R2 = OHKanamycin B: R1 = NH2 ; R2 = NH2Kanamycin C: R1= OH; R2 = NH2
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.
21REVOLUTIOPHARMD.COM
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.
22REVOLUTIOPHARMD.COM
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
23REVOLUTIOPHARMD.COM
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
Gentamicin C1: R1=R2 = CH3Gentamicin C2: R1 = CH3 ; R2 = HGentamicin C1a: R1=R2 = H
OHCH3
NHR2R1
Lacks 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
24REVOLUTIOPHARMD.COM
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.
25REVOLUTIOPHARMD.COM
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'
Sisomicin: R=HNetilmicin: R=C2H5
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.
26REVOLUTIOPHARMD.COM
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).
27REVOLUTIOPHARMD.COM
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.
28REVOLUTIOPHARMD.COM
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
29REVOLUTIOPHARMD.COM
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.
30REVOLUTIOPHARMD.COM
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
31REVOLUTIOPHARMD.COM