Chemotherapeutic Agents, chapter 34-39
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Chemotherapeutic Agents, chapter 34-39 •Antibacterial compounds (procaryotes) •Antifungal compounds (eucarytotes) •Antiparasitic agents (eucarytotes) • •Antiviral compounds •Anticancer compounds
description
Chemotherapeutic Agents, chapter 34-39. Antibacterial compounds (procaryotes) Antifungal compounds (eucarytotes) Antiparasitic agents (eucarytotes) Antiviral compounds Anticancer compounds. Different living organisms. - PowerPoint PPT Presentation
Transcript of 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
Virus
Procaryotes
Eucaryotes
Bakteriea: Monocellular, no nucleus - DNA single strand, cell wall, asex. replic.
Mono or polycellularCell nucleus; DNAMay have cell wallsexual and / or asexual replication
Animals
Plants
Fungi
Protocista: - Protozoea - Algea
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
Grampositive bakterier:
F. eks.
Streptococcus
Staphylococcus
Bacillus - causes anthrax and gastroenteritis
Clostridium - causes botulism, tetanus, gas gangrene,
and pseudomembranous colitis
Corynebacterium - causes diphtheria
Listeria - causes meningitis
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, and a periplasmic space
between the cell wall and the membrane.
In the outer membrane, gram-negative bacteria have
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.
Gramnegative bakterier:
F. eks.
Spirochetes - causes syphilis, lyme disease
Neisseria - causes meningococcus, gonorrhea
G+ and G- bacteria
Synthetic antibacterials (chemotherapeutica)
Antibacterial sulfonamides
Azo dyes Bayer etcLate 1800-century, ex.
NN N
HO3S
Metylorange
NN
O2N
Pararødt
HO
Salvarsan1. antisyphilis drug 1912
AsAs
HOOH
NH2
H2N
Screening of dyes as antibacterials
NN NH2
SO
OH2N
H2N
1932: Prontocil active against Streptoccocces infectionno activity on bacterial cultures
1935: Prontocil metabilized (azoreductase) to Sulfanilamid in vivo
NH2SO
OH2N (rel. toxisk)
Modern sulfa drugsr
NH2SO
OHNR
R: Aryl or hetroaryl
Nøytral sulfonilamid dårlig vannløselig. Urine pH ca 6: Crystallization neutral form, kidney damageModern sulfa drugs pKa 5 – 7; better solubility
ArS
O
O
HN
Sulfametoksasol
pKa 6.1
ArS
O
O
N
- H
+
ArS
O
O
NArS
O
O
N
N
O
N
O
N
O
N
O
ArS
O
O
N
N
O
SulfametoxazolBactrim®, Trimetoprim-Sulfa ® - Urine infectionsCombi. with trimethoprime
NH2
S
O
O
HN
N
O
NH2SO
OH2N
Sulfonamides are acidic
Sulfanilamid pKa 10.4
NH2SO
OHN
- H+
NH2SO
OHN NH2S
O
OHN
TrimetoprimInhib. of folate reductase
H2NO
OH
PABA
H2N SO
ONH
R
Antibact. sulfonamide
N
N NH
NOH
H2N
NH
OH
O
Dehydropteridinsyre
N
N NH
NOH
H2N
NH
NH
O
Dihydrofolic acid
CO2H
CO2H
N
N N
NOH
H2N
NH
NH
O
Folic acid
CO2H
CO2H
From diet, humans
N
N NH
HN
OH
H2N
NH
NH
O
Tetrahydrofolic acide
CO2H
CO2H
Folate-reduktase
Essential processesbacteria and animalsex. Thymin synthesis(Metab. CH3OH)
Trimetoprim
N
N
NH2
H2N OCH3
OCH3
OCH3
Quinolones
Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic..DNA-topoisomerase (humans), anticancer compds. ex. doxorubicinUnique mecanism, no cross resistanceBroad spectrum: G+ and G- ; also mycobactria, clamydia
N N
CO2HO
Parent comp.Nalidixic acid
Urinary tract infect. earliereffect on Gram-negative bacteria (ex. E. coli)
Moderne quinolones
N
OCO2H
R
FR
RR
F increase activity
Essentialt
Preferably HMust have aromatic ringcondenced with the pyridine
must be oxo
Chelater withCa2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
N
O O
O
N
OO
O
Met2+N
O OH
O
Intramolek.H-bond
pKa ca 5.5 - 6.5(Benzoic acid pKa 4.2)
CiprofloksacinCiprox®, Ciprofloxacin®Cilox®
N
CO2
H
O
N
F
HN
OfloksacinTarivid®
N
CO2
H
O
N
F
NO
N
OCO2H
R
FR
RR
(±)N
CO2HO
N
F
N O
Levofloxacin, 2x active
N
CO2HO
N
F
HN
Sparfloxacin
N
CO2HO
N
F
F F F
F
NH2
H2N
Trovafloxacin
Better effect on G+
OxazolidonesLinesolid Zyvoxid®
O N N
O
O
F
NH
O
Reg. Norge 2002, 1. antibact. drug with new mechaanism of action in 35 yearsInhib. protein synthesis early No cross resist.. G+ and some G-. Resistant strains
ON
O
HN
'R
R
O
(S)-Konfig.
Essencial
R: H, CH3, OCH3, CHCl2'R: H, F
CH3O, CH3SO, Aryl, Hetroaryl, Mettet Hetrosykel
ON
O
HN
N
PNU 177553(Pharmacia&Upjohn)
F
S
SO
ON
O
OAZD 2563(AstraZeneca)
F
NO
FNHO
O
OH
New drugs?
initiator tRNA
OH 3'
tRNA-Met
OS
O
NH2
tRNA-fMet
OS
O
HN
O
mRNA30S ribosom
OS
O
HN
O
3'mRNA
5'
30S initiator kompleks
AUG
50S ribosom
OS
O
HN
O
3'5' AUG
Linesolid
NHCHO
3'
NH3+
5'
CO2-
mRNA
50S
O-fMet
30S
AA-OO-AA-FMet
Protein
AA'-O
70S
Other antibiotics
Antibiotics
Penicillines
-Lactam-antibioticsLactam = cyclic amide
NO R
-Laktam
NO R
a
N
S
OCO2H
H H
NR
R '
Penicillins
NO
-Laktam ase-inhiitors
NO
CO2H
H
Karapenem s
R
H R '
SR ''
Cefalosporines
N
S
OCO2H
R ''
HH
NR '
R
NO
H H
NR
R '
Monoaktam es
SO3H
+ Cilastatin
N
S
OCO2H
H H
NR
R'
Gen. struct
-lactam
N
S
1-Aza-4-tiaicykco[3.2.0]heptane1 2
3
456
7
tot. 7atom s in ring
(2S, 5R , 6R )[x.y.z]alkane
tot no. of atom es
X atom sr
y atom s
z atom sr
N S
G-
G+N
S
CO2H
H
O
NH
R
O
HN
CO2HO
NH
R
O
HInhib. cell wall synth. - peptidoglycane≈ ala-ala
ala-ala
YX
YX
YX
YX X: N-acetylglucosaminY: N-acetylmuraminsyre
Pentapeptide:gly-gly-gly-gly-gly
Tetrapeptide:L-ala-D-glu-L-lys-L-ala
Peptidoglycane detail
Mechanism
N
SH
O
NH
R
O
YX
YX YX
YX
+
Peptidoglycane synth. -cross linking
trans peptidase
penicillin (≈ ala-ala)irreversible binding to trans peptidaseCross linking inhibited
enzyme
HNOH
H
O OH
HN
SH
O
NH
R
O
enzyme
NOH
HO OH
Semi synthesis
Stability
N
S
CO2H
H
O
NH
OR
R=Ph: BenzylpenicillinR=OPh: Fenoksymetylpenicillinfrom fermentation
Penicillin amidase
N
S
CO2H
H
O
H2N
6-aminopenicillansyre
R'COCletc. N
S
CO2H
H
O
NH
R'
O
N
S
CO2H
H
O
N
OHR
taut.
N
S
CO2H
H
O
N
ClR
Mild acidic hydrol
two amide func.Hydrolysis
iminochloride
PCl5
Basic amide hydrol. - ring strain in -lactam e
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OHOHHN
SH
O
NH
R
O
O OHOH
Penicillosyre
staile pH≥7
OH
H
Acidic hydrolysisAlternative A
O
HNR
OPenilloaldehyde
+SH
H2N
O OH
Penicillamin
N
SH
O
NH
R
O
O OH
N
SH
HO
NH
R
O
O OHOH
HN
SH
O
NH
R
O
O OHO
Penicillosyre
labilem acidic media
H
SHN
O OH
HNR
O
Penillosyre
SH2N
O OH
HNR
O
SH2N
O OH
HNR
OOH2
+ CO2
±H
SHH2N
O OH
HNR
OOH
H
H2O
H
H2O
Acidic hydrolysisAlternative B
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
HN
SH
O OH
ONH
O
R
HO
PenicillosyreAs Alternative. AH
H2O
Acidic hydrolysisAlternative C
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
±H
HN
SHH
O OH
ON
O
R H
HN
HS
O OH
ON
O
R
N
HS
O OH
ON
O
RH
N
HS
O OH
N
O H
O
R
SN
N
CO2H
CO2H
R
Penillinsyre
H
H
Structure acide stabile pennicillines
N
SH
O
NH
R
O
O OH
N
SH
O
NH
R
O
O OH
HN
SH
O OH
ONH
O
R
EWG R; Olessnukleofilic
N
H
O
NH
O
BensylP. acid labile
N
H
O
NH
OO
PhenoxymethylP.acid stabileIndictive electron withdrawing effect
H Nat. occuring P.
Semisynthetic, increased acid stability
N
S
H
O
N
H
O
O
OH
H
NN
O
N
O
O
PiperacillinTazocin®
N
S
H
O
N
H
O
O
OH
NH2
HO
Amoxicillin
Amoxicillin®,
N
S
H
O
N
H
O
O
O
NH2
OO
Pivampicillin
Pondocillin®,
N
S
H
O
N
H
O
O
OH
NH2
Ampicillin
Pentrexyl®,
HN
SH
O
NH
R
O
OHN
SH
O
NH
R
O
O OH
-Lactam ase
Larger R ; effect on -lactam ase resistant acteria (starical hindrance)
R esistant strains
N
SH
O
NH
R
O
O OHN
S
H
O
N
H
O
OOH
N
O
Cl
CH3
KloksacillinEkvacillin®
N
S
H
O
N
H
O
OOH
N
O
Cl
CH3
Cl
DikloksacillinDiclocil®
N
S
H
O
N
H
O
O
OH
OCH3
OCH3
Meticillin
Acid labile, last resort drug resist. strains
N
S
H
O
NN
O
OH
N
S
H
O
NN
O
O
O O
Semisynthetic, Broad spectrum, Imines
MeticillinamSelexid®
PivmeticillinamSelexid®
No nucleophiliccabronyl
-Lactamase Inhibitors
Combination with penicillines
N
O
H
O
O
OH
OH
N
S
H
O
O
OH
N
N NO
O
Clavulanic acid Tazobaktam
N
X
R'
HR
OO OH
No subst, less steric hindrance
EnzymeOH
N
X
R'
HR
O OH
H
OO
Enzyme
H
N
OH
OO OH
OH
Clavulanic acid irreversibly inhibits -lactam ase
OH
HN
OH
O
O OH
OHHH
H HN
O
O
O OH
OH
O
Nu
Nu
O
Nu
H
HN
O
O
O OH
OH
O
HHNu
•Mechanism based irreversible enzyme inactivators Suicide substrate - kcat inhibitors - Trojan horse inhib. - latent alkylating agent ≈ Pro-drug, must be activated by the enzyme
Carbapenems / Carbapenins
N
O
CO2
H
HHR'
S
HO
NH
NO
MeropenemMeronem®
2. Gen.Not cleaved byDHP-1
Imipenem + cilastanTienam®
NO CO2H
H
R
H R'
SR''
No S in 5-membered ring
NO
CO2H
HH R'
SHO
NH2Tienamycin fromStreptomyces cattleya1976Broad spectrumNot substr. for −lactam ase
Laile , acidic and asic m edia
Cleaved in vivo av DHP-I(dehydropeptidase I)
NO
CO2H
HH R'
SHO
HNNH
Not nucleophilicm
Imipenem
HO S OH
O
NH2
O
HN O
CilastatinDHP-I inhib.
Cephalosporins
Cefalosporin C from Cephalosporium acremonium 1945
N
S
OCO2H
HH
HN
HOONH2
O O
O N
S
OCO2H
R''
HH
NR'
R
6- membered ring; Less ring strain than penicillins
Subst in 3-pos., important for hydrolyttic stability
123
456
7 8
N
S
OCO2H
HH
RHNO
OOH
HN
S
CO2H
HO2C
RHNO
O+
Good leaving group
N
S
OCO2H
HH
RHNO
O
Metabolism
Esterase N
S
O
HH
RHNOH
O OH
N
S
O
HH
RHN
O O
Inactive lactone
N
S
CO2H
H
O
NH
R
O mCPBA N
S
CO2H
HC
O
NH
R
O
(ox. av sulfidtil sulfoksid) Pummerer
omleiring
H
HH
O
N
S
HO2C
H
O
NH
R
O
OH
N
H
O
NH
R
O
S
CO2H
H
D
Sem isynth from penicillins
Isolation from Cephalosporium sp
or semisynth from 7-aminocefalosporic acid (7-ACA)
N
S
OCO2H
HH
H2NO
O
7-ACA
1. generation: Relatively broad spectrum (G+, some G-)Cleaved by -Lactamase
CephalexinCefalex® Keflex® N
S
OCO2H
HH
HN
O
H2N
Realtively diff. to hydrolyzeOnly oral Ceph.
N
S
OCO2H
HH
HN
O
O
O
S
CefalotinCefalotin® Keflin®
2. generation: More broad spectrumNot cleaved by -Lactamase
CefoxitinMefoxitin®
CefuroximCefuroxim® Zinacef®
N
S
OCO2H
HO
HN
O
O
O
NH2
S
Increased stabilitycompared to cephalotin
Steric hindrance -L
N
S
OCO2H
HH
HN
O
O
O
NH2
O
NO
Syn isomer, steric hindrance -LAnti cleaved y -L
3. generation: Very broad spectrum, also Pseudomonas sp Not cleaved by -LactamaseAcid labile
CefotaximCefotaxime®Claforan®
CeftazidimFortum®
CeftriaxonRohephalin®
Good leaving groupSteric hindranceG-
N
S
OCO2H
HH
HN
O
O
O
N
S
N
H2N
O
N
S
OCO2H
HH
HN
O
S
N
S
N
H2NN
NN
OHO
O
Oral 3. gen (not in N):
N
S
OCO2
HH
HN
O
N
N
S
N
H2N
O
HO2C
N
S
OCO2H
HH
HN
R
ON
S
N
H2N
OR'
R: -H, -CH=CH2, -CH2OCH3
Monobactams
N
O
H
N
SO3
H
H
N
O
N
S
NH2
O
HO
O
Mer stabil enn Sulfacetin
Bare effekt på G-
AztreonamAzactam®
NO
H
HN
SO3H
ONH
HO
O
O
NH2
O
From Sulfacetin; weak antibacterialNot substrate forr -lactam ase
NO
R'' R'''
NR
R' SO3H
Only 4 membered ring
Aminoglycosides
H2
N
O
O
ÿ Broad spectrum
ÿ Toxic
ÿ Inhib. protein synthesis
ÿ ≈No absorb. from GI, local treatment infect. GI tract.
ÿ Systhemic infections – parenteral adm.
ÿ Basic, water solubile salts phys. pH
ÿ -Glykosides (= acetals) stabile acidic media because of protonated
amino subst.O
O
NH3
H
5' 3' mRNA
50S
30S
Ribosom
Protein
NH3+
NH3+
CO2-
70S
Bind to mRNA read wrongTransloc. blocked
O
OH
O
OO
HN
OH
OHHO
NH
H2
N
NH
H2
N
NH
HO
O
NH
HO
HO
Streptomycin
N-Metylglucosamin
L-Streptose
Streptidin
(sykloheksander.)ÿ First aminoglyc.: Streptomycin (ca 1944) from Streptomyces
griseus
ÿ First antituberculosis drug.
ÿ Toxic!
Neomycin
Streptomyces fradia (1949).Maxitrol®, eyedropsLess tox. than streptomycin
GentamicinGaramycin®From Micromonospora purpurea.
TobramycinNebcina® Tobi®, TobrexStreptomyces tenebrarius.
NetilmicinNetilyn® injek.Semisynth from Sisomicin(Micromonospora inyoensis)
O
OHO
OHO
O
OH
NH2
NH2
HO
O
HO
NH2
NH2
OH
O
OH
NH2
H2N
Neomycin C
HO
O
O
NH2
NH2
O
NH2
NHR
R'
O
OHHN
HO
R = R' = -CH3: Gentamicin C1R = CH3, R' = -H: Gentamicin C2R = R' = -H: Gentamicin C1a
HO
O
O
NH2
NH2
O
NH2
NH2
O
OHH2N
HO
HO
HO
Tobramycin
HO
O
O
NH2
NH
O
OHHN
HO
O
NH2
OH
R
R = -Et: Netilmicin(R = -H: Sisomicin)
Lincomycines
ÿ Sulfur cont. antibiotics from Streptomyces lincolnensis;
ÿ Naturally occuring: Linkomycin (not in N), more active semisynth
der.
ÿ Inhib protein synth, binds to 50S part of ribosome
KlindamycinDalactin® Dalactin® Clindamycin®.
Semisynth from linkomycinNH
R'R
O
SOH
HOOH
N
O
R= H, R'=Cl: Klindamycin
R=OH, R'=H: Linkomycin,
