Chemotherapeutic Agents / Antibiotics, chapter 38-43 •Antibacterial

26 Pages·2008·2.45 MB·English

Chemotherapeutic Agents / Antibiotics, chapter 38-43
•Antibacterial compounds (procaryotes)-Antimycobacterials
chapt. 41
•Antiparasitic agents (eucarytotes)
•Antifungal compounds (eucarytotes)
•Antiviral compounds
•Anticancer compounds
G -
Mycobacteria
G +
Pathogenic mycobacteria:
M. tuberculosis (tuberculosis)
M. Leprae (Leprosy)
M. Avium (Opportunistic infection in AIDS patients)
M. bovis (mainly cattle infect, infected milk USA)
30 million people will die from TB the next 10 years
8 million new cases each year
TUBERCULOSIS (TB)
ca. 1/3 of the world population are infected
(incl. dormant infections)
High lipid / wax content in cell wall (mycolic acid)
ca. 95% of the cases in developing countries
Slow growing organisms
Aerobe bacteria
no new drugs on the marked for the last 25 - 30 years
Resistant to chemicals and drying
Easily killed by heat
Until ca. 1950; 50 % of all infected died
Infection by inhalation of the bacteria
Pulmonary TB most common
May also attack other organs including CNS
WHO (1993): TB a "global emergency"
First effective drug: Streptomycin 1946
H N NH
2
O HN
OH
HO NH
HO HO OH NH
O H2N
HO NHMe Inhibits protein synthesis
HO
Toxic!
Treatment
•Long time ≥6 mnds
•Combination of drugs Different stages of bacterial growth
DOT: Directly observed therapy
First-line drugs
Isoniazide
Isoniazid
N Antituberculosis drug
O
Isoniazid®
HN
NH
2
O NHNH
2 Mn2+ /O
N
N Active acyl radical
O formed in vivo
N H H O H O
O
NH NH
2 2
N N
NADH co-enzyme Inactive der. of co-enz
in enzyme involved in cell wall
component synth
Long Chain ACP-Enoyl
Fatty Acid Reductase (inhA)
APC: Acyl carrier protein)
O O
ACP ACP
OH
((CH ) CH
223 3
CH3(CH2)1'7 14 17 CO2H Mycolic acid R R
α-mycolates
O OH((CH ) CH H H O O
223 3
CH3(CH2)17 15 17 CO2H NH2 1,4 hydride add. NH2
N N
ketomycolates
NADH co-enzyme NAD+
H3CO OH((CH2)23CH3 inhA
CH3(CH2)17 15 17 CO2H
methoxymycolates
First-line drugs
Ethambutol
Pyrazinamide
OH
O NHNH
2 H
O NHNH2 N
N
H
N HO
N
N
Isoniazide
Mechanism not fully known
Synth of cell wall comp.:
Mechanism not known Inhib. arabinocyl transferase?
Arabinose,
Arabinomannan
and Lipoarabinomannan
Rifampicin
Rimactan®
Broad spectrum antibiotic
From Streptomyces sp
HO
MeCO2 OH OH O Rifampicin Inhib bacterial RNA polymerase
OH OH
MeO NH Inhib. RNA-synth. (π−π intract. naphtalene rings aromatic AA?)
N
O Induce CYP2C; increased metabol. of certain anti AIDS drugs
O
OH N
O
Second-line drugs
Cycloserine
Ethionamide p-Aminosalicylic acid
Isolated Spreptomyces sp
S NH CO H H N O
2 2 2
OH
NH
O
N
NH
2
Inhib. alanine racemase
Mech. ≈ Isoniazide
and alanine ligase;
PABA antimetabolite
Inhib. peptidoglycan synth
)
Folic acid synth (≈antibact. sulfa
O NHNH
2
N
Isoniazide
Kanamycin
(aminoglycoside antibiotics)
NH O
2
R
HO O
NH
2
HO
HO
HO
NH
2
O
O
H N
2
OH
R=OH: Kanamycin A
R=NH : Kanamycin B
2
Others
Oxazolidinones
Quinolones
R O
O
F CO H
2
O
O N N
R N
NH
R R F
O
Treatment of MAC infections
Clarithromycin
(Macrolide)
O
N
O HO Other macrolides
HO MeO O
HO
Ethambutol
O
O
O Quinolones
O O
OH Rifabutin (Rifamycin)
Chemotherapeutic Agents / Antibiotics, chapter 38-43
•Antibacterial compounds (procaryotes)
•Antiparasitic agents (eucarytotes) - Chapt 39
•Antifungal compounds (eucarytotes)
•Antiviral compounds
•Anticancer compounds
Protozoa
Helmints
Insects (Scabies lice etc.)
(Fungi chapt. 40)
Protozoa
Eucaryotes, unicellular (may exist in colonies)
Protozoa and algae (protocista)
Complex replication (sexual and asexual)
Patogenic P. most common tropical area
3. world diseases
Many diseases can be prevented by clean drinking water
Certain protozal diseases spread by insects
Ex. patogenic protozoa
 Trichomonas vaginalis: Gelital infections
 Giardia lamblia: Diarea
 Toxoplasma gondii: Toksoplasmosis
 Trypanozomas sp: Sleeping sickness
 Entamoeba histolytica: Dysentery
 Plasmodium sp: Malaria
 Pneumocystis carinii: Oportunistic, AIDS
Treatment of diseases caused by amebia, giardia, trichomonas
Related comp.
Metronidazol
treatment of
Flagyl®, Metronidazol®
African sleeping sickness
N
Also effective against anaerobic bacteria
O N CH N
2 N 3 Probably pro-drug -reductive activation O2N O N
SO
2
(mech. not fully understood)
OH
N Anaerobe org.
N
e-
O2N N CH3 O2N N CH3 N Metabol N OH N
O2N N CH3 O2N N O2N N OH
OH O
OH
OH OH
OH
Active metabol.
O
O O 2
Phase II
HO-OH Formation of toxic conjugation
O
reactive oxygen species OH H2N
2 HO
O NH O CH3
OH