Transcript Aminoglycosides

Lecture 6
Medicinal Chemistry 1
(PC 509)
Prof. Dr/ Ghaneya Sayed Hassan
[email protected]
1
Aminoglycosides
Warning
Patients treated with aminoglycosides should be under close clinical
observation because of the potential toxicity associated with their use.
 They are antibiotics obtained from m.o. in the soil:
(1) Streptomyces [end with suffix mycin].
(2) Micromonospora [end with suffix micin].
 Prototype of this class [first one used] is Streptomycin.
M.O.A: [inhibition of bacterial protein biosynthesis]
Irreversibly binding the 30S ribosomal subunit of m.o. through
specific receptor protein  inhibit initiation of protein synthesis 
cause misreading of genetic code on recognition region of ribosome
 insertion of wrong amino acids  non-functional protein [antisense protein]  destruction of cell membrane  bactericidal
action.
2
General properties:
1) They are BACTERICIDAL, effective only ≠ aerobic bacteria [they are
inactive ≠ anaerobic bacteria that transport through cell membrane is
energy-requiring process that is oxygen-dependent].
2) They are limited use and for only severe G-ve infections due to their 
toxicity [cause ototoxicity & nephrotoxicity by action on 8th cranial
nerve].
3) Freely water soluble  used by injection.
But Neomycin must not be given parentrally [ toxicity], only used
topically or orally in hepatic coma to  intestinal bacterial population.
4) Very poorly absorbed from GIT [highly polar compounds] 
when used orally it's intended for local GIT infections.
But given I.M. for systemic infections.
There is no oral form available as aminoglycosides
are not absorbed orally
3
5) Aminoglycosides + -lactams  synergism but must not be combined
in the same solution [should be given into different tissue comportments,
as given each preparation one in each arm]  they are chemically
incompatible.
Inactivate if put with β-lactam antibiotics in same preparation  Nacylation by β-lactam ring  inactivation of both antibiotics.
COOH
NH
H2N
RCOHN
Sugar O
NH2
HO
O
+
O
RCOHN
O
N
COOH
Sugar
HN
Sugar O
HO
NH2
O
GenamicnC-2a
Active
B-Lactam Antibiotic
Active
Inactive
Sugar
6) Aminoglycosides can exacerbate weakness in patients with
myasthenia
gravis ,and use is therefore avoided in these patients
4
Resistance: There are three mechanisms:
(1) Reduced uptake or decreased cell permeability: Permeability defect: by
outer membrane change   active transport into cell  drug can't reach
ribosome.
(2) Alterations at the ribosomal binding sites: Lack of specific protein receptor
on 30 S subunit  lower affinity of binding site to aminoglycosides.
(3) Production of aminoglycoside modifying enzymes: Several of the
aminoglycoside antibiotics can be inactivated by enzymes which occur in
gram-negative bacteria carrying R-factors.
R-factor genes mediated the formation of aminoglycoside-inactivating
enzymes
1-Aminoglycoside 6'-N-acetyltransferase:
4'
Ad
6'
HO
HO
enzymes make acetylation of NH2 group. (ANT)
3'
Phos
2-O-Phosphoryl transferase: enzymes make
phosphorylation of OH group. (APT)
3- O-Adenyl transferase : enzymes make O-adenylation. (AAT)
Inositol
(Cyclhexanhexaol)
5
NH2
5'
Ac
O
2'
1' H
OH
O
4
Chemical properties:
• Pharmacophoric unit is 1,3-diamino Inositol moiety
“aminocyclitol unit”.
• From this moiety ; we have 3 pharmacophoric groups :
Streptidine
2-deoxy streptamine
H2N
H2N
NH
HN
3
HO
H3C-HN
HO
2
OH
HO
1
OH
NH2
OH
HO
NH2
HO
NH
Spectinamine
OH
NH CH3
HO
OH
NH
(1) Alcoholic functions of these moieties [OH]  make glycosidic bonds
with characteristic amino sugars [aminoglycosides].
(2) They are usually formed of 3 rings, freely soluble in water [why?]
6 They are basic [due to amino group], form acid addition salts.
(3)
[I] Aminoglycosides containing Streptidine
Streptomycin
NH-CH3
OH
H2N
HO
NH
O
HN
HOH2C
O
N-methyl glucosamine
[amino sugar]
HO
CH3
OHC
-CH2-OH
Dihydro Streptomycin
O
NH
HO
OH
NH2
NH
Streptidine
L-Streptose
[neutral sugar]
Streptobiosamine
[Disaccharide]
7
OH
O
[Pharmacophore]
• Produced by Streptomyces griseus.
• Basic, water soluble [available as sesquisulfate salt which
is quite soluble in water].
• With hydrophilic nature  poorly absorbed from GIT
[usually taken I.M.]
M.O.A:
Inhibition of protein synthesis + misreading of mRNA & membrane damage.
Diffuse across outer membrane of T.B.  penetrate
cytoplasmic membrane through electron-dependent
process.
Uses:
(1) Bactericidal [I.M  limit its use in long-course therapy]
(2) Used in combination for T.B. + other infections.
8
SAR:
(1) Reduction of aldehyde to alcohol 
Dihydrostreptomycin [similar activity but with delayed
severe deafness].
(2) Oxidation of aldehyde to carboxyl or conversion to
Schiff's base [oxmie, semicarbazone, phenyl hydrazone]
 inactive
(3) Oxidation of Methyl group in -streptose to methylene
hydroxyl  active but with no advantage over STM.
(4) Demethylation or replacement of amino methyl in
glucosamine part with larger alkyl group   activity.
(5) Removal or modification of either guanidine  
9
activity.
► Produced by fermentation of Sterptomyces griseus & related soil m.o.
► Introduced primarily for treatment of T.B.[ may be due to presence of
two guanido moieties]. But replaced now by other antibiotics as
Rifampin.
Dihydro streptomycin:
Formed by replacing aldehydic group in L-streptose moiety
by alchoholic group [CH2OH]
With greater probability > streptomyces to cause delayed
deafness.
10
[ii] Aminoglycosides containing 2-deoxy Streptamine
[i] 4,6-di-O-glycosyl substitution
Kanamycin
NH2
4'
Ad
6'
HO
HO
3'
HO
HO
NH2
5'
Ac
H
O
1' H
OH
O
4 HN
2
HO
HO
6''
2
3
6
5
1 NH2
O
5''
HO
4'' H2N
11
HO
Kanmycin B
Phos
Kanmycin A
O
NH2
O
2'
OH
1''
O
3''
Glycosidic linkage
OH
2''
O
H
HO
NH2
Kanmycin C
O
■ Isolated from Streptomyces kanamyceticus  mixture of Kanamycin
A, B & C. [according to D-glucose attached to 4-position of 2-deoxy
streptamine].
■ Commercially available Kanamycin is pure Kanamycin A [the least
toxic of them].
■ Chemically stable within pH of 2-11, very stable to heat [sterilized by
autoclaving].
■ Unstable to R-factor enzymes: [giving INACTIVE compounds]
3'-OH  Phosphorylation.
4'-OH  Adenylation.
6'-NH2  Acetylation.
■ To improve its activity  SEMI-SYNTHETIC PRODUCTS by:
(1) Adding functional group that prevents enzymatic attack.
(2) Removal of susceptible functional groups which are not important for
activity.
12
Semi-synthetic aminoglycosides
Amikacin [Amikin®]
4'
X
Ad
Phos
6'
HO
X
HO
3'
NH2
5'
O
2'
1' H
OH
O
4 H N
2
HO
6
5
1 NH
O
1''
HO
O
HO
H2N
13
2
3
OH
2''
O
OH
C
CH
CH2 CH2 NH2
L-AHBA
The side chain protects
amikacin from attack by
steric hindrance or folding
L--Amino-α-Hydroxy Butyric Acid
Semi-synthetic analogue of Kanamycin A  produced by
acylation of 1-amino group with L-AHBA [L--Amino-α-Hydroxy
Butyric Acid].
Advantages:
(1) Less toxic than Kanamycin or Gentamicin.
(2) L-AHBA   binding to R-factor mediated enzymes 
prevent adenylation at C4' are phosphorylation at C3‘ 
potency & broaden spectrum.
Amikacin is resistant to many R-factor mediated enzymes
due to the presence of L-AHBA [L--Amino-α-Hydroxy Butyric Acid].
Uses: serious infections by bacteria those are resistant to other
aminoglycosides
14
Gentamicin [Garamycin®]
H3C
Ad
X
Phos
4'
X
NH
CH3
CH 6'
4'
Ac
5'
3'
NH2
H2C 6'
1' H
NH2
O
4 H N
2
HO
3'
2
3
6
5
4'
5'
O
2'
H3C
CH 6'
5'
O
2'
NH2
1 NH
2
NH2
1' H
O
Gentamicin C1a
3'
O
2'
NH2
1' H
O
Gentamicin C2
O
Gentamicin C1
1''
O
3HC
HO
HN
OH
2''
CH3
Garosamine Suger: specific for all Gentamicins
 Produced by fermentation of Micromonspora purpurea & other related
soil m.o. [mixture of compounds]
15
Uses:
1- Has significant activity ≠ Pseudomonas aeroginosa infections [in
burns, pneumonias & UTI], also, prevent fouling of soft contact lenses.
2- It is not effective for gonorrhea or chlamydia infections.
3- Gentamicin is also used in molecular biology research as an
antibacterial agent in tissue and cell culture, to prevent contamination of
sterile cultures. Gentamicin is one of the few heat-stable antibiotics that
remain active even after autoclaving ,which makes it particularly
useful in the preparation of some microbiological growth media
16
[iii] Aminoglycosides with Spectinamine
Spectinomycin
Spectinamine Ring
Spectinamine Ring
OH
CH3
OH
O
O
HN
OH
O
O
CH3
H3C
O
NHCH3
OH
O
OH
O
NH CH3
O
OH
NH
CH3
 Produced by fermentation of Streptomyces spectabilis.
Composed of Spectinomine moiety + bicyclic moiety fused at 4-OH &
5-OH. [with only one sugar].
 The interaction of Spectinomycin with the 30S-ribosomal subunit is
reversible.
 Spectinomycin is an aminocyclitol antibiotic that is structurally
related to aminoglycosides. It lacks amino sugars.
17
M.O.A:
Interfere with binding t-RNA to ribosomes  interfere
with initiation of protein synthesis [as Streptomycin],
BUT, NOT cause misreading of messenger [≠
Streptomycin]  Bacteriostatic NOT Bactericidal
effect.
Uses:
(1) Alternative to penicllins, that it not cause serious otoor nephrotoxicity.
(2) It's the drug of choice in treatment of GONORRHEA
cause by penicillinase-producing N. gonorrhea.
18