Anda di halaman 1dari 38

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 Clostridium and pseudomembranous colitis - causes anthrax and gastroenteritis - causes botulism, tetanus, gas gangrene,

Spirochetes Neisseria

- causes syphilis, lyme disease - causes meningococcus, gonorrhea

Corynebacterium Listeria - causes meningitis

- 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.

Synthetic antibacterials (chemotherapeutica)

Antibacterial sulfonamides
Azo dyes Bayer etc Late 1800-century, ex.
HO3S N N N HO

Salvarsan 1. antisyphilis drug 1912


H2N HO As As OH NH2

Metylorange Screening of dyes as antibacterials

O2N

N N

Parardt

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

(rel. toxisk)

Modern sulfa drugsr


O H R N S O NH2

R: Aryl or hetroaryl

Sulfonamides are acidic


O H2N S O

- H+
NH2

O HN S O

NH2

O HN S O

NH2

O HN S O

NH2

Sulfanilamid pKa 10.4

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

Bactrim, Trimetoprim-Sulfa Urine infections Combi. with trimethoprime


Ar O

HN

Ar

Ar

Ar

Sulfametoksasol

pKa 6.1
O

O N

HN

NH
2

O N S Ar

O OH N H2N N N N CO2H O OH N H2N N N N H N H OH N H NH CO2H

Antibact. sulfonamide
H2N O H2N OH O R S NH O

Folic acid

From diet, humans

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

Inhib. of folate reductase

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

Parent comp. Nalidixic acid


O CO2H N N

Moderne quinolones must be oxo F increase activity


F R N R R O CO2H

Urinary tract infect. earlier effect on Gram-negative bacteria (ex. E. coli)

Essentialt Preferably H Chelater with Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N O

Intramolek. H-bond
O H O O N

Must have aromatic ring condenced with the pyridine

Met2+
O O O N

pKa ca 5.5 - 6.5 (Benzoic acid pKa 4.2)

R F R R

O CO2H N R

Ciprofloksacin Ciprox, Ciprofloxacin Cilox


O F F CO
2

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.

PNU 177553 (Pharmacia&Upjohn)

AZD 2563 (AstraZeneca)

O NH2 OH HN S O O O O S O HN

Linesolid
HN S O O

3'

mRNA 30S ribosom

50S ribosom

5' initiator tRNA tRNA-Met tRNA-fMet

AUG 30S initiator kompleks

3' mRNA

5'

AUG

3'

AA'-O NHCHO O-AA-FMet AA-O O-fMet

5' 3'

mRNA

Other antibiotics

50S 70S Protein 30S


CO2-

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 )

[..] .

Mechanism HInhib. cell wall synth. - peptidoglycane ala-ala


O O R N H N S H CO2H N H X Y X Y CO2H X Y

Peptidoglycane detail X: N-acetylglucosamin Y: N-acetylmuraminsyre Pentapeptide: gly-gly-gly-gly-gly Tetrapeptide: L-alaD-gluL-lysL-ala

G+

O O R N H

G-

ala-ala

Peptidoglycane synth. -cross linking


X Y X Y

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

R=Ph: Benzylpenicillin R=OPh: Fenoksymetylpenicillin from fermentation taut.


O OH R N N S H CO2H

6-aminopenicillansyre Mild acidic hydrol


CO2H N N S H

PCl5
R

O Cl

iminochloride

Stability
Basic amide hydrol. - ring strain in

Acidic hydrolysis Alternative A H2O H


O O R N H N S H R O OH HO O N H OH N S H R O N H O OH O

Penicillo syre
H O HN S H R O OH

Penillosyre
O HN H N O S OH

labilem acidic media H


O OH O H2N R O H N SH OH R O OH O OH O H2N H N S OH2 H2N R O H N

+ CO2

R O

H N

+
O

H2N SH

OH

Penicillamin

Penilloaldehyde

H2O

Acidic hydrolysis Alternative B


O O O R N H N S H O OH

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

Acidic hydrolysis Alternative C


O O O R N H N S H O NH H OH O HN S O OH O HN S H H N R H O N R O S H R N N S CO2H CO2H R O O N H HS N O OH O N H R O N HS OH O OH O HN HS O OH

HO
O O R N H N

OH

Penillinsyre

Structure acide stabile pennicillines


O O O R N H N S H O HN S NH R O S H N H H H O O N O OH O OH O OH O N H N H

BensylP. acid labile

HO
O O R N H N

Nat. occuring P.

EWG R; Olessnukleofilic

PhenoxymethylP.acid stabile Indictive electron withdrawing effect

Semisynthetic, increased acid stability Piperacillin Tazocin


O OH O

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

Acid labile, last resort drug resist. strains


3

OCH

Semisynthetic, Broad spectrum, Imines

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

No subst, less steric hindrance

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

CO2H R'' S R'

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

Imipenem + cilastan Tienam


NH O N HO H H R' CO2H S HN NH2 HN S O O OH O

Meropenem Meronem
O N CO O H NH

N S

HO H H R'

Not nucleophilicm Imipenem

HO

Cilastatin DHP-I inhib.

2. Gen. Not cleaved by DHP-1

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

Good leaving group

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

Isolation from Cephalosporium sp or semisynth from 7-aminocefalosporic acid (7-ACA)


CO2H O N H2N H H S O O

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

(ox. av sulfid til sulfoksid)

Pummerer omleiring

1. generation:

Relatively broad spectrum (G+, some G-) Cleaved by -Lactamase


CO2H H2N O H N O N H H S

Cephalexin Cefalex Keflex

Cefalotin Cefalotin Keflin


S

CO2H O H N O N H H S O

Realtively diff. to hydrolyze Only oral Ceph.

2. generation:

More broad spectrum Not cleaved by -Lactamase


Cefuroxim Cefuroxim Zinacef

Cefoxitin Mefoxitin
CO2H H N S O O N O H S O NH2 O

Syn isomer, steric hindrance


CO2H O O S NH2

Increased stability compared to cephalotin


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

Cefotaxim Cefotaxime Claforan


O N N H2N S O O N H H S

Good leaving group Steric hindrance G-

H N

CO2

Oral 3. gen (not in N):


Ceftriaxon Rohephalin
CO2H O N N H2N O S H N O N H H S O N S N N OH N H2N S O R' O O H N N N H H CO2H R S

R: -H, -CH=CH2, -CH2OCH3

Monobactams
O SO3H R' N N R R'' R'''
HO

From Sulfacetin; weak antibacterial Not substrate forr


O O H N O SO3H

O N H

N O H

Only 4 membered ring

NH2

NH
2

Aztreonam Azactam
HO

O SO H N N
3

Mer stabil enn Sulfacetin

Bare effekt p GH

Aminoglycosides
Broad spectrum Toxic Inhib. protein synthesis
O H
2

No absorb. from GI, local treatment infect. GI tract.


Systhemic infections parenteral adm.

O 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


5' 3'

NH3 +

mRNA

50S Protein 30S Ribosom 70S


CO2-

NH3 +

NH

H
2

NH

NH

OH H
2

Streptidin

N HN

HO

OH

(sykloheksander.)

First aminoglyc.: Streptomycin (ca 1944) from Streptom griseus

O O

L-Streptose

HO OH O HO

Streptomycin

First antituberculosis drug. Toxic!

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

Gentamicin Garamycin From Micromonospora purpurea.


R' NH O NH2 O

Netilmicin Netilyn injek. Semisynth from Sisomicin (Micromonospora inyoensis)


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

R = -Et: Netilmicin (R = -H: Sisomicin)

Tobramycin Nebcina Tobi , Tobrex Streptomyces tenebrarius.

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

Klindamycin Dalactin Dalactin C lindamycin. Semisynth from linkomycin

N O

R NH HO

R'

R= H, R'=Cl: Klindamycin R=OH, R'=H: Linkomycin,

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

Tetracyclines: Gen. struct. (reg. in N.)


10 9 8 7 11 12 1 10a 11a 12a

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

Acid - Base prop.


Acidic phenol Acidic enol Zwitter ion (high water sol.) neutral pH
OH

HO R2HN O O

OH O HO
10 9 8 11 12

OH O
1 2 3

O NHR2 Acidic enol

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

Stability; acid / base


pH 2 - 6: Epimerisation C-4 O OH O NHR2 OH N H H O OH O NHR2 O OH O NHR2 H N H OH H N H O OH O NHR2 OH H N H O OH

O NHR2 OH

A
H

Base

H N H

OH

Protonated tetracycline

H
O OH O NHR2 H N H OH H

Epitetracycline inactive

pH 2: Dehydratisation; Aromatisation C-ring (R6=OH) OH O OH OH O OH OH O OH OH O OH OH OH O

D
6

C
H HO

H H 2O

- H2O

Base
H

taut.

Benzylic cation (resonanse stab.)


pH 7.5: Rearrangement to isotetracyclines (R6=OH) OH O OH OH O OH OH O O H H O H OH O O H H O OH O O

D
6

C
O

O H

Base

H O

5-ring lactone

Isotetracycline inactive

R5 Tetracycline -H -OH -H Oxytetracycline -OH Doxycycline Lymecycline

R6 -OH -OH -H -OH

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

Lymecyclin More water sol., pro-drug. Semisynth from tetracycline


HO HO OH OH O HO O O NH
2

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

OH T Lymecyclin etracyclin Lysin

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

NCS Electrophil chrorination reag. - H2O

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

exocyclic double bond


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

Degradation acidic media H


O HO HO HO O O O R

H
HO HO HO O O O

hemiketal
O

HO HO O O O O O O

Ester hydrol. in vivo

O R'

-H2O
O

Erytromycin

Erytromycin ethylsuksinate Pro-drug (masks bad tast)

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'

Increased stability acidic media No intramolec. hemikatalisation

Increased stability acidic media No intramolec. hemikatalisation

Telitromycin
N N N

Increased stabil., bioavailability, less side effects Somewhat more broad spectrum

Increased stabil., bioavail. More active G- less active G+ Spiramycin


OH OH

O N N O O O O O O O O R MeO O HO O O O

IsolatedStreptomyces ambofaciens. G+.


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

R= H: Spiramycin I R=COCH3: Spiramycin II R=COCH2CH3: Spiramycin III

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

Leu Cys / Ile

Colistin (Polymyxin E1) Polymixin B


HN CO R H
2

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