Download Chemotherapeutic Agents, chapter 34-39

Chemotherapeutic Agents, chapter 34-39
•Antibacterial compounds (procaryotes)
•Antifungal compounds (eucarytotes)
•Antiparasitic agents
(eucarytotes)
•
•Antiviral compounds
•Anticancer compounds
Different living organisms
Eucaryotes
Mono or polycellular
Cell nucleus; DNA
May have cell wall
sexual and / or asexual replication
Animals
Plants
Fungi
Protocista: - Protozoea
- Algea
Procaryotes
Bakteriea:
Monocellular, no nucleus - DNA single strand,
cell wall, asex. replic.
Virus
RNA or DNA + protein coating (not really a cell)
Use other oramisms ribosomes for protein synth
Antibacterial compounds, chapter 34 (- antimycobacterials)
•Synthitic antibacterials (chemotherapeutica)
•Antibiotics
Antibiotics
Product from metabolism (natural product)
(also applies if compd is prepared synthetically,
or is a synthetic analog of a naturally occuring antibiotic/ semisynthetic compd)
Inhibit growth (bacteriostatic) or kill (bacteriocide) microorg.
Effective in low conc.
Antimicrobial chemotherapeutics: Antimicrobial comp ≠ Antibiotics
G+ and G- bacteria
Grampositive bakterier:
Gramnegative bakterier:
F. eks.
F. eks.
Streptococcus
Staphylococcus
Bacillus - causes anthrax and gastroenteritis
Clostridium - causes botulism, tetanus, gas gangrene,
and pseudomembranous colitis
Corynebacterium - causes diphtheria
Listeria - causes meningitis
Spirochetes - causes syphilis, lyme disease
Neisseria- causes meningococcus, gonorrhea
The cell walls of gram-positive bacteria are made up
of twenty times as much murein or peptidoglycan than
gram-negative bacteria. These complex polymers of
sugars and amino acids cross-link and layer the
cell wall.
The thick outer matrix of peptidoglycan, teichoic acid,
polysaccharides, and other proteins serve a number of
purposes, including membrane transport regulation, cell
expansion, and shape formation
Gram-negative bacteria have a unique outer membrane,
a thinner layer of peptidoglycan, an d a periplasmic space
between the cell wall and the membrane.
In the outer membrane, gram-negative b acte ria ha ve
lipopolysaccharides (LPS), porin channels,
and murein lipoprotein all of which gram-positive bacteria lack.
The gram-negative outer membrane which contains LPS,
an endotoxin, blocks antibiotics, dyes, and detergents protecting
the sensitive inner membrane and cell wall.
Synthetic antibacterials (chemotherapeutica)
Salvarsan
1. antisyphilis drug 1912
Antibacterial sulfonamides
H2N
HO
Azo dyes
Bayer etc
Late 1800-century, ex.
HO3S
As
N
N
Metylorange
HO
Pararødt
OH
NH2
N
O2N
As
Screening of dyes as antibacterials
N
N
1932: Prontocil active against Streptoccocces infection
no activity on bacterial cultures
O
H2N S
O
H2N
N
N
NH2
1935: Prontocil metabilized (azoreductase) to Sulfanilamid in vivo
O
H2N S
O
NH2
Modern sulfa drugsr
O
H
R N S
O
NH2
R: Aryl or hetroaryl
(rel. toxisk)
Sulfonamides are acidic
O
H2N S
O
- H+
O
HN S
O
NH2
NH2
O
HN S
O
NH2
O
HN S
O
NH2
Sulfanilamid
pKa 10.4
Nøytral sulfonilamid dårlig vannløselig.
Urine pH ca 6: Crystallization neutral form, kidney damage
Modern sulfa drugs pKa 5 – 7; better solubility
Sulfametoxazol
O
N
O
O
- H+
HN S Ar
O
Sulfametoksasol
pKa 6.1
N
O
N S Ar
O
O
O
N
O
N S Ar
O
N
O
N S Ar
O
Bactrim®, Trimetoprim-Sulfa ® Urine infections
Combi. with trimethoprime
O
O
N
N
O
N S Ar
O
O
HN S
O
NH 2
O
NH
OH
N
N
H2N
N
CO2H
N
H
N
CO2H
Antibact. sulfonamide
O
R
S NH
O
H2N
H2N
H2N
OH
OH
OH
N
N
O
Folic acid
O
N
N
H
From diet, humans
N
H
Dehydropteridinsyre
PABA
O
O
OH
N
H2N
N
H
N
NH
N
H
N
H
H2N
NH2
Essential processes
bacteria and animals
ex. Thymin synthesis
(Metab. CH3OH)
Inhib. of folate reductase
H2N
OCH3
OCH3
N
OCH3
Trimetoprim
N
N
H
N
H
Dihydrofolic acid
Trimetoprim
N
N
N
CO2H
Tetrahydrofolic acide
NH
OH
CO2H Folatereduktase
CO2H
CO2H
Quinolones
Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic..
DNA-topoisomerase (humans), anticancer compds. ex. doxorubicin
Unique mecanism, no cross resistance
Broad spectrum: G+ and G- ; also mycobactria, clamydia
Parent comp.
Nalidixic acid
Moderne quinolones
must be oxo
O
F increase activity
CO2H
N
R
O
F
N
CO2H
R
Urinary tract infect. earlier
effect on Gram-negative bacteria (ex. E. coli)
R
N
R
Essentialt
Preferably H
Must have aromatic ring
condenced with the pyridine
Intramolek.
H-bond
O
H
Chelater with
Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N
O
O
O
O
N
pKa ca 5.5 - 6.5
(Benzoic acid pKa 4.2)
O
Met2+
O
O
O
N
R
O
F
CO2H
R
N
R
R
Ciprofloksacin
Ofloksacin
Ciprox®, Ciprofloxacin®
Tarivid®
Cilox®
O
F
O
F
O
CO2H
N
N
Trovafloxacin
NH2 O
F
O
F
CO2H
N
F
CO2H
N
N
H2N
N
F
F
F
Better effect on G+
CO2H
O
(±)
Sparfloxacin
F
N
N
N
HN
HN
Levofloxacin, 2x active
CO2H
N
N
N
O
Oxazolidones
Linesolid
Reg. Norge 2002,
Zyvoxid®
1. antibact. drug with new mechaanism of action in 35 years
O
Inhib. protein synthesis early
O
No cross resist.. G+ and some G-.
N
N
F
Resistant strains
O
NH
O
CH3 O, CH3SO,
Aryl, Hetroaryl,
Mettet Hetrosykel
Essencial
O
'R: H, F
'R
N
O
H
N
R
O
New drugs?
(S)-Konfig.
O
O
HO
S
N
F
N
F
OH
O
O
N
F
O
H
N
PNU 177553
(Pharmacia&Upjohn)
S
N
AZD 2563
(AstraZeneca)
O
O
N
O
R: H, CH3, OCH3 , CHCl2
AA'-O
NHCHO
O-AA-FMet
AA-O
O-fMet
5'
3'
50S
NH3 +
70S
Protein
30S
CO2-
mRNA
Other
antibiotics
b-Lactam-antibiotics
Antibiotics
b-Laktam
Lactam = cyclic amide
O
R
N
O
R
N

Penicillins
CO2H
O
R'
N
R
b-Laktamase-
Karbapenems
inhibitors
O
CO2H
O
N
N
R''
N
S
R
S
H H
H H
R'
b
Cefalosporines
O
R'
N
R
N
H H
CO2H
R''
S
Monobaktames
O
SO3H
R'
N
N
R
H H
+ Cilastatin
Penicillines
Gen. struct
7
CO2H
O
R'
N
R
N
6
1
2
N
5
1-Aza-4-tiabicykco[3.2.0]heptane
3
S
4
S
N
S
tot. 7atoms in ring
H H
b-lactam
(2S, 5R, 6R)
X atomsr
[x.y.z]alkane
z atomsr
tot no. of atomes
y atoms
Mechanism
Peptidoglycane detail
HInhib. cell wall synth. - peptidoglycane
- ala-ala
CO2H
O
R
N
H
O
N
H
X
Y
Y
S
H
Pentapeptide:
gly-gly-gly-gly-gly
CO2H
O
R
X
N
O
G+
X: N-acetylglucosamin
Y: N-acetylmuraminsyre
X
N
H
Y
X
Y
Tetrapeptide:
L-alaD-gluL-lysL-ala
ala-ala
G-
Peptidoglycane synth. -cross linking
X
penicillin (- ala-ala)irreversible binding to trans peptidase
Cross linking inhibited
Y
X
Y
enzyme
enzyme
trans peptidase
HN H
O
+
X
Y
X
H
Y
O
O
O
R
OH
N
H
HN
O
S
H
O
O
N
O
N H
H
R
N
H
S
H
OH
Semi synthesis
two amide func.
Hydrolysis
CO2H
O
N
O
R
Penicillin
amidase
R'COCl
etc.
N
S
N
H
CO2H
O
H
N
O
R'
S
H2N
CO2H
O
H
S
N
H
H
6-aminopenicillansyre
R=Ph: Benzylpenicillin
R=OPh: Fenoksymetylpenicillin
from fermentation
Mild acidic hydrol
taut.
CO2H
O
R
PCl5
N
OH
N
Cl
R
S
N
CO2H
O
N
H
S
H
iminochloride
Stability
Basic amide hydrol. - ring strain in b-lactame
OH
O
O
O
N
O
R
OH
N
H
O
S
H
R
N
H
O
OH
N
H
O
O
S
H
OH
R
N
H
O
OH
HN
S
H
stabile pH•7
OH
Penicillo
syre
Acidic hydrolysis
Alternative A
Penicillo
syre
H2O
H
O
OH
O
R
HO
N
O
OH
O
S
N
H
R
H
O
N
H
O
O
N
O
S
H
R
OH
HN
HN
O
H
N
R
S
N
H
OH
O
H
OH
Penillosyre
S
+
CO2
H
O
labilem acidic media
H
O
+
H
N
R
OH
H2N
Penicillamin
H 2N
H 2N
H
N
R
O
SH
O
Penilloaldehyde
H
N
R
OH
OH
O
±H
SH
O
O
OH
O
OH
H2N
S
OH2
H
N
R
O
O
S
H2 O
Acidic hydrolysis
Alternative B
O
OH
O
N
O
R
H
O
H
S
H
OH
HN
HO
S
O
H
NH
R
R
N
N
H
O
S
NH
OH
O
OH
HN
O
HO
O
O
O
S
N
H
R
H2O
Penicillosyre
As Alternative. A
Acidic hydrolysis
Alternative C
O
OH
O
O
N
O
R
O
HN
S
N
H
H
NH
O
±H
O
S
H H
O
N
R
OH
O
R
O
HS
N
H
R
N
H
O
S
O
H
CO2H
R
N
N
S
CO2H
Penillinsyre
H
O
O
H
OH
O
N
O
N
R
N
OH
HN
N
O
R
H
OH
HN
O
S
O
HO
O
OH
HS
N H
R
HS
OH
Structure acide stabile pennicillines
O
O
O
N
O
R
O
S
N
H
H
O
HO
O
R
N
H
N
H
OH
H
BensylP. acid labile
HN
S
O
OH
NH
H
Nat. occuring P.
O
R
N
O
N
O
OH
N
O
O
S
N
H
H
H
PhenoxymethylP.acid stabile
Indictive electron withdrawing effect
EWG R; Olessnukleofilic
Semisynthetic, increased acid stability
Ampicillin
O
Pentrexyl®,
N
O
NH 2
Amoxicillin
OH
O
N
H
H
O
Pivampicillin
O
N
O
Pondocillin®,
NH 2
N
H
H
O
N
O
O
O
S
O
NH 2
N
H
H
O
O
Amoxicillin®,
S
HO
O
Piperacillin
Tazocin®
O
N
OH
H
N
N
O
S
O
N
O
N
H
S
H
OH
Resistant strains
O
OH
O
R
b-Lactamase
N
O
N
H
O
O
S
H
R
N
H
OH
HN
S
Kloksacillin
Ekvacillin®
H
O
O
O
OH
N
H
N
H
N
O
N
O
R
Cl O
O
S
OH
N
H
S
CH 3
H
Dikloksacillin
Diclocil®
Larger R; effect on b-lactamase resistant bacteria (starical hindrance)
O
Cl O
O
Cl
Meticillin
CH 3
O
O
OH
N
OCH 3 O
N
H
OCH 3
N
H
N
O
S
H
Acid labile, last resort drug resist. strains
N
H
S
OH
Semisynthetic, Broad spectrum, Imines
Meticillinam
Selexid®
Pivmeticillinam
Selexid®
O
O
O
OH
O
N
N
N
N
H
S
No nucleophilic
cabronyl
N
N
H
O
O
S
O
b-Lactamase Inhibitors
Combination with penicillines
Clavulanic acid
Enzyme
O
OH
O
X
O
O
R'
N
No subst,
less steric hindrance
Enzyme
OH
O
R
H
H
O
OH
N
R'
X
H H
R
O
Tazobaktam
O
OH
N
N
O
H
OH
O
N
N N
S
HO O
OH
•Mechanism based irreversible enzyme inactivators
Suicide substrate - kcat inhibitors - Trojan horse inhib. - latent alkylating agent
≈ Pro-drug, must be activated by the enzyme
Clavulanic acid irreversibly inhibits b-lactamase
OH
O
O
OH
N
O
O
H
Nu
O
O
H
O
H
H
O
O
HN
H
OH
OH
OH
O
OH
HN
H
O
OH
Nu
Nu
O
O
O
OH
HN
HH
O
Nu
OH
Carbapenems / Carbapenins
CO2H
O
R''
N
R
H H
Tienamycin from
Streptomyces cattleya
1976
S
R'
N
HO
Broad spectrum
No S in
5-membered ring
NH2
CO2H
O
H H
Not substr. for blactamase
S
Labile, acidic and basic media
Cleaved in vivo av DHP-I
(dehydropeptidase I)
R'
Meropenem
Meronem®
Imipenem + cilastan
Tienam®
O
NH
CO2H
O
N
HO
H H
HN
N
NH2
S
Not nucleophilicm
R'
Imipenem
CO 2H
O
HO
O
HN
S
O
Cilastatin
DHP-I inhib.
HO
H H
N
NH
S
R'
OH
O
2. Gen.
Not cleaved by
DHP-1
Cephalosporins
Cefalosporin C from Cephalosporium acremonium 1945
O
CO2H
O
H
N
O
HO
NH2
O
N
H H
O
CO2H
O 6 5 4 R''
R'
N
3
N
2
R 7 8 S
H H
1
S
6- membered ring; Less ring strain than penicillins
Subst in 3-pos., important for hydrolyttic stability
OH
O
CO2H
O
CO2H
HO2C
O
N
RHN
H H
HN
S
RHN
S
O
+
O
Good leaving group
Metabolism
O
O
N
RHN
H H
S
O
O
CO2H
Esterase
O
OH
O
O
O
N
OH
N
RHN
RHN
H H
S
H H
S
Inactive lactone
Isolation from Cephalosporium sp
or semisynth from 7-aminocefalosporic acid (7-ACA)
O
CO2H
O
O
N
H2N
H H
7-ACA
S
Semisynth from penicillins
HO2C H
O
R
CO2H
O
mCPBA
N
N
H
R
S
H
O
(ox. av sulfid
til sulfoksid)
CO2H
O

N
N
H
S
H
O
C
H
H
H
O
R
O
N
N
H
S
H
OH
Pummerer
omleiring
CO2H
O
R
O
N
N
H
H
S
1. generation:
Relatively broad spectrum (G+, some G-)
Cleaved by b-Lactamase
Cephalexin
Cefalex® Keflex®
CO2H
H2N
O
H
N
O
N
H H
Cefalotin
Cefalotin® Keflin®
O
CO2H
O
H
N
S
S
O
O
N
H H
S
Realtively diff. to hydrolyze
Only oral Ceph.
2. generation:
More broad spectrum
Not cleaved by b-Lactamase
Cefoxitin
Mefoxitin®
Cefuroxim
Cefuroxim® Zinacef®
O
CO2H
H
N
S
O
Syn isomer, steric hindrance b-L
Anti cleaved byb-L
O
O
N
O H
NH2
S
Increased stability
compared to cephalotin
N
H
N
O
Steric hindrance b-L
O
CO2H
O
O
O
O
N
H H
S
NH2
3. generation:
Very broad spectrum, also Pseudomonas sp
Not cleaved by b-Lactamase
Acid labile
Cefotaxim
Cefotaxime®
Claforan®
O
N
O
CO2H
H
N
N
O
H2N
Ceftazidim
Fortum®
Good leaving group
Steric hindrance
G-
HO2C
O
CO2
O
N
O
N
H H
S
H
N
N
O
H2N
S
O
N
N
H H
S
S
Oral 3. gen (not in N):
Ceftriaxon
Rohephalin®
R'
O
O
H
N
N
N
CO2H
O
N
H
N
N
H2N
O
S
N
H H
O
H2N
O
N
O
H H
S
S
S
S
N
CO2H
R
N
N
OH
R: -H, -CH=CH2, -CH2OCH3
Monobactams
From Sulfacetin;
weak antibacterial
Not substrate forr b-lactamase
O
SO3H
R'
N
N
R
R'' R'''
O
O
H
N
O
HO
Only 4 membered ring
N
H
NH2
O
N
SO3H
O H
NH 2
S
Aztreonam
Azactam®
N
O
HO
N
O
O
O
H
N
N
H
SO 3H
Mer stabil enn Sulfacetin
Bare effekt på G-
Aminoglycosides
 Broad spectrum
 Toxic
H2N
 Inhib. protein synthesis
O
 -N o absorb. from GI, local treatment infect. GI tract.
O
 Systhemic infections – parenteral adm.
O
H
NH3
O
 Basic, water solubile salts phys. pH
 -Glykosides (= acetals) stabile acidic media because of protonated
amino subst.
Bind to
mRNA read wrong
Transloc. blocked
NH3 +
3'
5'
mRNA
NH3 +
50S
Protein
30S
Ribosom
70S
CO2-
NH
H2N
NH
H2N
NH
HN
O
OH
OH
HO
Streptidin
(sykloheksander.)
 First aminoglyc.: Streptomycin (ca 1944) from Streptomy
O
O
griseus
L-Streptose
HO
HO
HO
OH
 Toxic!
O
N-Metylglucosamin
NH
Neomycin
Gentamicin
Garamycin®
From Micromonospora purpurea.
Streptomyces fradia (1949).
Maxitrol®, eyedrops
Less tox. than streptomycin
R
NH2 O
HO
HO
O
O
O
NH2
H2 N
OH
OH
O
O
OH
NH2
HO
O
OH
Neomycin C
Netilmicin
Netilyn® injek.
Semisynth from Sisomicin
(Micromonospora inyoensis)
O
NH2
OH NH2
O
R'
NH
NH2
NH2
HO
 First antituberculosis drug.
Streptomycin
O
HO
HN
O
O
NH2
NH2
O
HO
OH
R = R' = -CH3: Gentamicin C 1
R = CH3, R' = -H: G entamicin C 2
R = R' = -H: Gentamicin C 1a
HO
HN
O
O
OH
NH2 O
NH2
HO
Tobramycin
Nebcina® Tobi®, Tobrex
Streptomyces tenebrarius.
NH2
HO
O
NH2
HO
HO
O
H2 N
O
NH2
OH Tobramycin
N
H
R
R = -Et: Netilmicin
(R = -H: Sisomicin )
Lincomycines
 Sulfur cont. antibiotics from Streptomyces lincolnensis;
 Naturally occuring: Linkomycin (not in N), more active semisynth
der.
 Inhib protein synth, binds to 50S part of ribosome
Klindamycin
Dalactin® Dalactin® Clindamy cin®.
N
R
O
Semisynth from linkomycin
R= H, R'=Cl: Klindamycin
R'
R=OH, R'=H: Linkomycin,
NH
HO
OH
O
S
OH
Tetrasyclines
OH O HO
10
9
12
11
D
6
7
1
B
C
8
OH
O
A
NHR2
3
H5 H 4
R5 N
R6
 Mechanism: Bindes to 30S part of ribosome, inhibits protein
O
2
synth.; komplexing Mg2+ involv ed.
OH
 Binds also to 30S-rib. mammals, but bacteria cells also have active
transport mech. for T uptake.
Tetracyclines: Gen. struct. (reg. in N.)
 The most broad spctrum antibiotic known to date.
10
9
11 12
1
10a 11a 12a
D
8
7
6a
6
A
B
C
5a
5
4a
2
 Bakteriostatic, not baktericid.
3
 Attacks natural bacteria flora in GI tract (oportunistic candida
4
infect.)
Naftacene
Chelate
N
HO
H
R5
Acid - Base prop.
R6
H
Acidic enol
Acidic phenol
Zwitter ion (high water sol.)
neutral pH
R2HN
N
HO
2
H
R5
H
O
R6
O OH
O
Metn+
R2HN
O
O
OH O
OH
OH
-2H
OH
O
OH
10
Metn+
9
O
8
O
OHO
Chelate: Chelos = Claw, Klo (greek)
Metn+
O
NHR2
Ca2+
(milk)
Fen+ (iron prep.)
Al3+ (antacida.)
OH O HO
H
R6
H
R5 N
11
12
OH
O
1
O
2
3
7
6
R6
H5 H 4
R5 N
OH O HO
1
NHR2
OH
Basic amine
O
2
NHR2
3
Acidic enol
R6
OH
OH
O
H 4
R5 N
H
O
Stability; acid / base
pH 2 - 6: Epimerisation C-4
OHO
OHO
O
NHR2
A
OH
H
N
H
O
OHO
NHR2
OH
H
N
H
H
OHO
Epitetracycline
- inactive
OH
H
N
H
N
H
Protonated tetracycline
O
NHR2
OH
H
N
H
O
NHR2
OH
H
OHO
O
NHR2
Base
H
OHO
O
NHR2
H
N
H
OH
H
pH Š2: Dehydratisation; Aromatisation C-ring (R6=OH)
OH O
D
OH
OH O
OH
OH O
OH
OH O
OH OH O
OH
C
6
H
H
H
HO
Base
- H2O
H 2O
taut.
H
Benzylic cation
(resonanse stab.)
pH •7.5: Rearrangement to isotetracyclines (R6=OH)
OH O
D
OH
OH O
OH
6
H
H
O
Base
H
O
H
OH O
O
H
OH O
H
O
O
C
O
OH O
H
5-ring lactone
O
O
H
Isotetracycline
inactive
Tetracycline
R5
R6
R2
-H
-OH
-H
-OH
-H
Oxytetracycline -OH
OH O HO
10
9
11
D
8
7
C
6
R6
OH
O
12
B
1
O
2
A
H5 H 4
R5 N
NHR2
3
OH
Doxycycline
-OH
-H
-H
Lymecycline
-H
-OH
-CH2NHCH2NH(CH2)4CH(NH2)CO2H
Tetracyclin
Isolation from Streptomyces sp,
Semisynth from chlorotetracycline more effective
(low bioavailability)
HO
OH O HO
O
HO
OH O HO
O
O
NH 2
Cl HO
H
H
O
H2 / kat.
NH 2
OH
N
Klortetracyclin
fra fermenter. av Streptomyces arter
HO
H
H
OH
N
Tetracyclin
Lymecyclin
More water sol., pro-drug.
Semisynth from tetracycline
OH
HO
O HO
O
H
HO
H
O
N
H
OH
N
Lymecyclin
HO
OH O HO
O
NH 2
N
H
O
in vivo
O
CH 2O
NH 2
OH
HO
H
H
NH 2
OH
N
Tetracyclin
O
H2N
Lysin
OH
Doxycyclin
Not OH i 6-pos. More stabile in water solution (also mixture).
Longer t 1/2, good oral absorb.
Semisynth oxytetracyclin.
OH O HO
OH
O
O
O
Cl
N
OH O
O
OH
O
OH
Cl
O
HO
H
OH N
OH
Oxytetracyclin
- H2O
NCS
Electrophil
chrorination reag.
H
HO
OH
O
H
H
OH N
OH
O
O
OH O
NH2
H
OH
exocyclic
double bond
H
OH N
O
NH2
H
OH N
OH O HO
OH
O
Anhydrotetracyclin
H
H
OH N
OHO
O
OH
O
NH2
H
NH2
OH
NaHSO3
O
Cl
OH
H2 / kat.
OH
O
O
OH
HF
NH2
H
OH N
NH2
Hemiacetal
OH O HO
O
O
O
OH
H
OH N
O
OH
- H2O
OH O HO
OH OH
OH
Cl
NH2
NH2
H
OH O
H
OH N
OH
Makrolides
O
O
 Isolated from soil-ba kteria, Streptomyces sp.
Amino sugar
 Reletively narrow spectrum, mainly G+. Low tox.
O
 Bindes to 50S part of ribosome, inhib. Protein synth.
O
Structure / Activity:
 Macrolaktone (14-16-ring, smaller than antimycotic polyenes)
 Keto function
 No unsat. in lactone ring (spiramycin - dien) ° an timycotic
polyenes
 Amino sugar
Erytromycin
Degradation acidic media
O
O
O
N
HO
HO
O HO
HO
O
O
O
O
Ester hydrol.
in vivo
O
OH
Erytromycin
H
O
O
HO
HO
O
O
HO
N
O
O
O
O
O
O
HO
HO
HO
HO
OH
Erytromycin ethylsuksinate
Pro-drug (masks bad tast)
O
R
O R'
O
O
hemiketal
H
O
O
HO
HO
HO
O
O
HO
O
O
O
-H2O
O
O
O
O
O
O
inactive spiroketal
Spiroforbindelse
Azitromycin
Klaritromycin
Erythromycin
N
H
N
O
HO
HO
HO
HO
N
O
O
HO
HO
HO
R
MeO
O
OH
Increased stability acidic media
No intramolec. hemikatalisation
OH
Increased stabil., bioavail.
More active G- less active G+
Increased stabil., bioavailability,
less side effects
Somewhat more broad spectrum
N
O
O
O
Increased stability acidic media
No intramolec. hemikatalisation
Telitromycin
O
O
O
O
O
O
O
HO
O
O
O R'
O
O HO
O HO
Spira mycin
N
N
OH
OH
IsolatedStreptomyces ambofaciens.
G+.
O
N
N
O
O HO
MeO
O
O
O
O
No ketone
O
O
O
O
O
Increased stability acidic media
No intramolec. hemikatalisation
Improved ribosome binding, less resistans
Increased ribosome affinity
In N. 2002. Ketolide.
O
O
O
R
N
OH
O
O
HO
O
HO
R= H: Spiramycin I
R=COCH3: Spiramycin II
R=COCH2CH3: Spiramycin III
Polypeptides
 Low oral avail.; lo cal admin. or. infusion/injektion.
H
 Often high tox (kidneys).
H2N
 D-amino acids and other rare AA.
Vancomycin
NH2
HO OH
OH
OH
Cl
N
H
O
N
H
O
H2N
O
H
N
O
N
H
H
N
OH OH
O
O
Cl
NH
O
O
O
N
H
O
HO
N
H
O
O OH
HO
O
H
N
heptapeptide fragment
Isol. Streptomyces orientalis (= Amycolatopsis orientalis).
G+bakteria, Neisseria sp (G-).
Inhib. Synth of mucopeptide polymer in cell wall.
No oral uptake,
Minimal degrad. In Gi, local treatment GI infect.
Rel. tox., little resisence
Severe infections few other alternatives
O
O
HN
HO2C
O
HO
HO
HO
R
Cl
O
OH
O
L-AA
O
N
O H
O
O
HN
HO2C
HO
Cl
O
H
N
CO2H
Teicoplanin
O
O
H2N
CO2H
H
R:
O
O
HO
R
D-Amino acid
HO OH
HO
R
HO
O
H
N
N
H
O
NH2
O
heptapeptide fragment
OH
OH
OH
Isol. Actinoplanes teichomyceticus.
Only G+.
Mech as vanoc.m..
More lipid sol. than vancomycin, better distrib. In fat tissue
Little resistance tox. Less than vancomycin;
Severe infect., few alternatives
D-Asp
O
HO 2C
Bacitracin
Isol. Baccilus subtilis.
Mixt of struct
(Bacitracin A, A1, B, C, D, E, F1, F2, F3 and G)
Bacitracin A main comp. Bacimycin.
Mainly G+.
Inhib. Synth. mukopeptide in cell wall.
Requires Zn2+ for activity
NH 2
HN
N
O
NH
O
Asp
His
N
H
O
HN
HN
D-Phe
O
Lys
4
O
O
NH
O
HN
HN
Ile
N
H
O
D-Glu O
Ile
Orn
NH
SH
NH 2
HO 2C
NH
O
S
H
N
N
O
Leu
HO
NH 2
O
NH 2
Cys / Ile
Colistin (Polymyxin E1)
Polymixin B
HN
CO
R-H2C CH CH CH 2CH 2NH 2
CO NH
CH 2CH 2NH 2
CH 2CH 2NH 2
NH CO
CH 3
H O
O
(H3C) 2HCH 2C CH HC
N C C N C CH N C C N C C C C C C CH 2CH 3
H H O
H O H H
H2 H2 H2 H2 H
OC
CH 2
CHOHCH 3
NH CH 2
H2NH 2CH 2C CH NH
R=-CH(CH 3)2: Colisin A / Polymyxin E 1
CO CO
R=Ph: Polymyxin B 1
NH CH CHOHCH 3
H2NH 2CH 2C CH NH
C
O
Cys
OH
O
NH 2
Ile
Others
Chloroamfenikol
Cl
O
O2N
H
H OH
Cl
NH
OH
 Isol. 1.time Streptomyces venezuelae (1947), later found in several
microorg.
 Broad spectrum. Inhib. Protein synth., mech. Not fully
understood.
 Rel. tox. (daqmage bone marrow – an emiea, leukemi), seldom
used systhemically.
 Simple structure – total synthesis.
Stereoid
H
HO
CO 2H
OCOMe
Fusidinic acid
 Narrow spectrum: G+; Stafylloccocus
Streptococcus sp.(weak effect).
 Inhib. Protein synth.
 No cross resist.
H
HO
aureus,
H
corynebakteria