Antibacterial compounds (procaryotes) Antifungal compounds (eucarytotes) Antiparasitic agents (eucarytotes) Antiviral compounds
Anticancer compounds
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
G+ and G- bacteria
Grampositive bakterier: Gramnegative bakterier:
F. eks.
F. eks.
Streptococcus Staphylococcus Bacillus Clostridium and pseudomembranous colitis - causes anthrax and gastroenteritis - causes botulism, tetanus, gas gangrene,
Spirochetes Neisseria
- causes diphtheria
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.
Gram-negative bacteria have a unique outer membrane, a thinner layer of peptidoglycan, and a periplasmic space between the cell wall and the membrane. In the outer membrane, gram-negative bacteria have lipopolysaccharides (LPS), porin channels,
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
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.
Antibacterial sulfonamides
Azo dyes Bayer etc Late 1800-century, ex.
HO3S N N N HO
O2N
N N
Parardt
(rel. toxisk)
R: Aryl or hetroaryl
- H+
NH2
O HN S O
NH2
O HN S O
NH2
O HN S O
NH2
Nytral sulfonilamid drlig vannlselig. Urine pH ca 6: Crystallization neutral form, kidney damage Modern sulfa drugs pKa 5 7; better solubility
Sulfametoxazol
O O O O N
+
-H
HN
Ar
Ar
Ar
Sulfametoksasol
pKa 6.1
O
O N
HN
NH
2
O N S Ar
Antibact. sulfonamide
H2N O H2N OH O R S NH O
Folic acid
PABA
O OH N H2N N H N N H
Dehydropteridinsyre
O NH N H CO2H Folatereduktase H2N CO2H OH N N N N H N H NH CO2H
CO2H
Tetrahydrofolic acide
Trimetoprim
NH2
Dihydrofolic acid
OCH3
Essential processes bacteria and animals ex. Thymin synthesis (Metab. CH3OH)
N H2N N
OCH3 OCH3
Trimetoprim
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
Essentialt Preferably H Chelater with Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N O
Intramolek. H-bond
O H O O N
Met2+
O O O N
R F R R
O CO2H N R
Ofloksacin Tarivid
O
Levofloxacin, 2x active
CO
2
O
N N
F N N O
CO2H
N O
HN
()
Sparfloxacin
NH2 O F N HN F N H2N CO2H F N F N F
Trovafloxacin
O CO2H
Better effect on G+
Oxazolidones
Linesolid Reg. Norge 2002, 1. antibact. drug with new mechaanism of action in 35 years Inhib. protein synthesis early No cross resist.. G+ and some G-. Resistant strains
CH3 O, CH3SO, Aryl, Hetroaryl, Mettet Hetrosykel Essencial
O
O N N
Zyvoxid
O O
NH F
'R: H, F
'R
O H N O R
R: H, CH 3, OCH3 , CHCl2
New drugs?
O O S N F N O O H N F N HO OH N F O O O N O
(S)-Konfig.
O NH2 OH HN S O O O O S O HN
Linesolid
HN S O O
3'
50S ribosom
3' mRNA
5'
AUG
3'
5' 3'
mRNA
Other antibiotics
NH3 +
Antibiotics
-Lactam-antibiotics
Lactam = cyclic amide
O R N
Penicillines
Gen. struct
7
O R' N N S R H H
CO2H
1 [3.2.0] 4 . 7
(2, 5 , 6 )
[..] .
G+
O O R N H
G-
ala-ala
penicillin ( ala-ala)irreversible binding to trans peptidase Cross linking inhibited enzyme trans peptidase
O HN H H O O R N H N S H R O OH O H O O N H HN S H
enzyme
N H O OH
+
X Y X Y
Semi synthesis
two amide func. Hydrolysis
O O R N H N S H CO2H
Penicillin amidase
O N H2N
CO2H
R'COCl etc.
R'
O O N H N
CO2H
S H
S H
PCl5
R
O Cl
iminochloride
Stability
Basic amide hydrol. - ring strain in
Penicillo syre
H O HN S H R O OH
Penillosyre
O HN H N O S OH
+ CO2
R O
H N
+
O
H2N SH
OH
Penicillamin
Penilloaldehyde
H2O
H2O
O HN
OH O HN
OH
S NH H
HO
O O R N H N S H
HO O NH R
S H
OH
As Alternative. A
Penicillosyre
HO
O O R N H N
OH
Penillinsyre
HO
O O R N H N
Nat. occuring P.
EWG R; Olessnukleofilic
Ampicillin Pentrexyl,
NH
2
Amoxicillin
O O OH O O N H O OH N N S N H H O N O O N
S N H H
Amoxicillin,
O HO
O O
Pivampicillin
O
S N
O H N O O NH
2
Pondocillin,
NH
2
S N H H
O O O R N H N S H R OH OH HN S H
O O N H
Kloksacillin Ekvacillin
O OH
Cl
N O
S N H H
CH
3
; ( )
Dikloksacillin Diclocil
O OH
Cl Cl O
S N N H H O
Meticillin
O OH O
CH
3
OCH
3
S N H H
OCH
Meticillinam Selexid
O OH O
Pivmeticillinam Selexid
O O O N O N O
S S N N H N N H
No nucleophilic cabronyl
-Lactamase Inhibitors
Combination with penicillines Clavulanic acid
Enzyme
OH O N X H O OH R' R
Tazobaktam
O OH O
Enzyme
O O N
OH
O
O OH
R' R
X H H
N O OH S
H O
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
O N O H OH O OH
Carbapenems / Carbapenins
O N R H H
Tienamycin from Streptomyces cattleya 1976 Broad spectrum Not substr. for
HO
O N H H
CO2H S R'
NH2
, ( )
No S in 5-membered ring
Meropenem Meronem
O N CO O H NH
N S
HO H H R'
HO
Cephalosporins
Cefalosporin C from Cephalosporium acremonium 1945
CO2H O HO NH2 O O H N N H H S O O CO2H O 6 5 4 R'' R' N 3 N 2 R 7 8 S H H 1
6- membered ring; Less ring strain than penicillins Subst in 3-pos., important for hydrolyttic stability
OH
CO2H O N RHN H H S O
O HO2C RHN HN
CO2H
+
S O
Metabolism
CO2H O N RHN H H S O O O OH O N RHN H H S OH RHN H H S N O O O
Esterase
Inactive lactone
7-ACA
HO2C H O R O N N H S H CO2H
mCPBA
R
O N N H
CO2H C H H H
O N N H S H OH CO2H O R O N N H H S
S H O
Pummerer omleiring
1. generation:
CO2H O H N O N H H S O
2. generation:
Cefoxitin Mefoxitin
CO2H H N S O O N O H S O NH2 O
O N
H N O
O N H H
Steric hindrance
3. generation:
Very broad spectrum, also Pseudomonas sp Not cleaved by -Lactamase Acid labile
Ceftazidim Fortum
CO2H O O
N HO2C O N H2N S O H N O N H H S N
H N
CO2
Monobactams
O SO3H R' N N R R'' R'''
HO
O N H
N O H
NH2
NH
2
Aztreonam Azactam
HO
O SO H N N
3
Bare effekt p GH
Aminoglycosides
Broad spectrum Toxic Inhib. protein synthesis
O H
2
O NH3 O
Basic, water solubile salts phys. pH -Glykosides (= acetals) stabile acidic media because of protonated amino subst.
NH3 +
mRNA
NH3 +
NH
H
2
NH
NH
OH H
2
Streptidin
N HN
HO
OH
(sykloheksander.)
O O
L-Streptose
HO OH O HO
Streptomycin
O HO
N-Metylglucosamin
NH
Neomycin Streptomyces fradia (1949). Maxitrol , eyedrops Less tox. than streptomycin
NH2 O NH2 HO HO O O O H2 N OH OH NH2 HO O OH NH2 OH O
NH2
NH2
HO O OH NH2
NH2 O HO O OH N H R NH2
HO HN
Neomycin C
R = R' = -CH3: Gentamicin C1 R = CH3, R' = -H: Gentamicin C 2 R = R' = -H: Gentamicin C 1a
NH2 O NH2 HO O
HO HN
NH2
HO HO
HO O OH NH2
O H2 N
Tobramycin
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
N O
R NH HO
R'
OH
O S OH
Tetrasyclines
OH O HO
10 9 8 7 11 12
OH O
1 2 3
O NHR2 OH
Mechanism: Bindes to 30S part of ribosome, inhibits protein synth.; komplexing Mg2+ involved. Binds also to 30S-rib. mammals, but bacteria cells also have active transport mech. for T uptake. The most broad spctrum antibiotic known to date.
D
6
C
R6
H5 H 4 R5 N
D
6a
C
6 5a
B
5 4a
A
4
2 3
Bakteriostatic, not baktericid. Attacks natural bacteria flora in GI tract (oportunistic candida infect.)
Naftacene
Chelate
N HO R2HN N H R5 H R6 O O OH O O
n+
R5
R6
HO R2HN O O
OH O HO
10 9 8 11 12
OH O
1 2 3
Metn+
OH O OH OH
Met
OH O
OH O HO
OH O
1 2 3
O NHR2 O
-2H
O O OH O NHR2 H
Chelate: Chelos = Claw, Klo (greek) Metn+ Ca2+ (milk) Fen+ (iron prep.) Al3+ (antacida.)
R6 H R5 N
R6
H5 H 4 R5 N
OH
R6 Basic amine
OH
H 4 R5 N H
O NHR2 OH
A
H
Base
H N H
OH
Protonated tetracycline
H
O OH O NHR2 H N H OH H
Epitetracycline inactive
D
6
C
H HO
H H 2O
- H2O
Base
H
taut.
D
6
C
O
O H
Base
H O
5-ring lactone
Isotetracycline inactive
R2 -H -H -H
9 8
OH O HO
10 11 12
OH O
1 2 3
O NHR2 OH
D
7 6
C
R6
H5 H 4 R5 N
-CH2NHCH2NH(CH2)4CH(NH2)CO2H
Tetracyclin Isolation from Streptomyces sp, Semisynth from chlorotetracycline more effective (low bioavailability)
HO OH O HO O O OH O HO O
HO
NH
H
2
/ kat.
NH
OH H Cl HO H N HO H H N
OH
Klortetracyclin
etracyclin
fra fermenter. av
Streptomyces
arte
HO
CH in vivo
O NH N H N H OH OH H H HO H N HO N H
2 2
O
2
NH OH H N
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 NH2 H HO H OH N OH O Cl N O OH O OH O Cl OH O NH2 OH O OH O OH O H H OH N O NH2 OH
Cl
Oxytetracyclin
H HO
H OH N
OH
Hemiacetal HF
- H2O
OH O HO OH O O NH2 H OH N OH
OH O HO
OH O
O NH2
OH O
O Cl
NaHSO3
O OH
O NH2
H OH N
OH H H OH N
OH
H2 / kat.
OH OH OH O O OH O HO OH O O NH2 H H OH N OH
H OH N
OH
Anhydrotetracyclin
Makrolides
O O O O Amino sugar
Isolated from soil-bakteria, Streptomyces sp. Reletively narrow spectrum, mainly G+. Low tox. Bindes to 50S part of ribosome, inhib. Protein synth.
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
O O N HO HO HO O O O O O OH O HO O HO HO O HO O O O O O OH O O N O O O
H
HO HO HO O O O
hemiketal
O
HO HO O O O O O O
O R'
-H2O
O
Erytromycin
inactive spiroketal
Spiroforbindelse
Azitromycin
Erythromycin H
O HO HO HO O O O R
HO HO MeO O O O O O OH O HO O
Klaritromycin
N
O N
N HO O HO O
HO HO
O O
O O O OH
O R'
Telitromycin
N N N
Increased stabil., bioavailability, less side effects Somewhat more broad spectrum
O N N O O O O O O O O R MeO O HO O O O
No ketone
O N OH O O HO O HO
Increased stability acidic media No intramolec. hemikatalisation Improved ribosome binding, less resistans Increased ribosome affinity
In N. 2002. Ketolide.
Polypeptides
Low oral avail.; local admin. or. infusion/injektion. Often high tox (kidneys).
D-amino acids and other rare AA.
H H2N R CO2H R H2N H CO2H
D-Amino acid
L-AA
Vancomycin
HO
NH2
HO OH O OH O O O O OH Cl Cl
Teicoplanin
R:
HO OH HO O OH O O O O HN HO2C N H Cl H N O O N H H N O O O N H NH2 O HO HO O NH O N O H O R Cl
HO O O HN HO2C HO N H
H N
O N H O H2N O
H N O
O N H
H N
OH OH
heptapeptide fragment
HO O OH O
HO
heptapeptide fragment
OH OH
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
HO
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
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
D-Glu
HO
2
HO
C NH
2
HN O
NH
Asp
N H
His
HN
HN
D-Phe
Lys 4
O O
NH
O HN HN
Ile
N H O
Ile
NH
Orn
SH NH OH
2
C NH H N O N O NH
2
S HO NH
2
NH
Cys
Ile
CH
CH
CH
2
CH
2
NH
2
CO
NH CH
2 2
CH
2
CH
2
NH
CH
2
NH
2
NH
CO H O C O C H N H C O CH N H C O C H N H C
CH
3
(H
3
C)
2
HCH
2
CH
HC
C H
2
C H
2
C H
2
C H
2
C H
CH
2
CH
3
OC
CH
2
CHOHCH
3
NH
CH
2
H
2
NH
2
CH
2
CH
NH
R=-CH(CH
CO CO
3
)
2
: Colisin A / Polymyxin E
1
R=Ph: Polymyxin B
1
NH
CH
CHOHCH
3
H
2
NH
2
CH
2
CH C O
NH
Others
Chloroamfenikol
Cl
O Cl O
2
H NH
OH
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 anemiea, leukemi), seldom used systhemically. Simple structure total synthesis.
Stereoid
CO
2
H HO
OCOMe
Fusidinic acid
HO H
Narrow spectrum: G+; Sta fylloc cocus aureus, Strepto cus sp.(weak effec coc t). I nhib. Protein syn th. No cros res s ist.
corynebakt ria e