Chemotherapeutic Agents / Antibiotics, chapter 34-39
•Antibacterial compounds (procaryotes)
•Antiparasitic agents
(eucarytotes) - Chapt 35
•Antifungal compounds (eucarytotes)
•Antiviral compounds
•Anticancer compounds
Protozoa
Helmints
Insects (Scabies lice etc.)
(Fungi chapt. 36)
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
 Trypano zomas sp: Sleeping sickness
 Entamoeba histolytica: Dysen tery
 Plasmodium sp: Malaria
 Pneumocystis carinii: Oportunistic, AIDS
Treatment of diseases caused by amebia, giardia, trichomonas
Related comp.
treatment of
African sleeping sickness
Metronidazol
Flagyl®, Metronidazol®
N
O2N
CH 3
N
OH
N
O2N
N
CH3
Also effective against anaerobic bacteria
Probably pro-drug -reductive activation
(mech. not fully understood)
Anaerobe org.
e-
O2N
N
O
SO2
N
O2N
N
N
CH3
O2N
OH
N
N
Metabol
O2N
CH3
N
OH
N
O2N
OH
OH
Active metabol.
HO-OH
2 HO
OH
N
O
OH
OH
O O
N
O2
Phase II
conjugation
Formation of toxic
reactive oxygen species
O
OH
O
NH
OH
H2N
O
CH3
Anti - Malaria drugs
Plasmodium sp.
Vektor: Anopheles moskito.
Complex life cyclus.
Mal aria = bad air
40% of world population at risk
300 mil acute illnessess pr year
ca 1 mill deaths pr year
Malaria kills a child every 30 sec.
90% in incidents sub-sahara Africa
De fleste l.m.
aktive her
Historic drugs
-Azodyes and salvarsan (1. synthetic effective drug)
-Quinine fra Cinchona (Kinabark)
HO
N
MeO
Azo dyes
Bayer etc
Late 1800-century, ex.
HO3S
Salvarsan
1. antisyphilis drug 1912
N
N
HO
HO
Quinine
Quinoline
As
As
Pararødt
N
H2N
N
Metylorange
O2N
N
N
OH
MOdern antimalarials
NH2
N
Cinchona pubescens (Kinatre) from South America
Screening of dyes as antibacterials
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)
Quinolines
Mechanism
(DNA Intercalation)
Ferriprotoporphyrin IX:
Binds to FPIX (metabolite from hemoglobine);
tox. form of FPIX, proteinbound FPIX less tox.)
Weak base Hypothesis:
Increase pH in parasite
Quinine
Kinin®
Hydroksyklorokin
Plaquenil®
Klorokin
Klorokinfosfat®
HO
N
HO
N
NH
NH
N
MeO
Cl
Cl
N
N
More active, less tox (comp Quinine)
Resistance!
Dye
Quinine
N
Meflokin
Lariam®
HO
N
H
N
N
H3CO
NH
N
Pamakin, 1926
N
NH
Cl
klorokin
N
CF3
CF3
Also klorokin
resistant
P. palsifarum
Biguanides
Pro-drug
Proguanil (= Chloroguanide)
Inhib. protozoan folate reduktase
Paludrine®
(c.f. Trimetoprim)
Malarone® + atovakvon
taut.
NH
Cl
NH NH
5
1
3
N 2 N 4 N
H
H
H
Liver
6
Cl
NH
NH
- H2
Imine
3
H2N 2 N 4 NH2
1N
N
N
H2N
N
O
H2N
N
OH
N
Folinsyre
OH
OH
N
N
H
Fra folinsyre i kosten
hos mennesker
N
H
Dehydropteridinsyre
PABA
N
H2N
N
H
N
NH
N
H
N
H
CO2H
NH2
OCH 3
N
N
N
H
N
H
Dehydrofolinsyre
Trimetoprim
H2N
N
N
H2N
N
NH
OH
Folatreduktase
CO2H
Tetrahydrofolinsyre
Essensielle prossesser
hos bakterier og dyr
Inkl tymidinsyntese
Other biguanides
Klorhexidine
O
O
OH
N5
CO2H
O
R
S NH
O
O
H2N
enol
N
Antibakt sulfonamid
H2N
keto
Cycloguanil
CO2H
N
H
OH
6
Cl
NH
OH
taut.
O
Proguanil (chloroguanide)
O
enamine
N
N
H
N
H
NH2
OCH 3
OCH 3
CO2H
Cl
NH
CO2H
N
H
N
H
NH
N
H
H
N
H
N
NH
H
N
NH
Cl
Others
O
Cl
OH
H3CO
8
O
H3CO
CH3
O
O
ox
Malarone® + proguanil.
Also other parasites (P. carinii)
Ubiquinone antimetabolite?
H
O
O
O O
O
H
H
Artemisin
from Artemisia annua
Chinesee trad. med.
H
O
MeO
O O
O
H
Mech. involves radicals
H
Artemeter
No cross resist.
Synth. analogs, active field
Semisynth. analog
Improved solubil.
Artemeter og Lumefandrin
Riamet®
R
H3CO
Ubiquinone, Q10, Cenzyme Q
electron carrier
cellular respiration
OH
Atovakvon
Red
H3CO
CH3
OH
Drugs for Helmint infections
Eukaryotes – Invertebrates.
Tropical diseases!
Animal parasites; ex Trichinella spiralis (trikiner).
Benzimidazoles
Many active analogs known
Binds to tubulin - prevents formation of microtubules
inhib. mitosis (c.f. certain anticancer drugs)
May also inhib. fumarate reductase
Mebendazol
Vermox®
O
N
NH
N
H
OMe
O
Drugs against Ectoparasites (insects)
Lice, scabies etc
Pyretrines
Insecticides from Crysantemum sp
O
R'
R
Cl


O
O
O
Chlorinated pesticides:
Lindane
Block GABA CNS neurtransmittor
(Also neurotox. effects on humans)
Cl
Cl
Cl
Cl
Cl
Cl
Cl
O
Synth. analog, more stabile
Mixt. of 4 stereoisomers
Permetrin
Nix®
Irreversible Inhibitors
Acetylcholine esterase
Not drugs, nerve gasses, insecticides etc.
Malation
Prioderm® lice
Gen structur mustard gasses
L
R2
P
R1
N
O
N
L: Leaving group
R1: alkoksy
R2: alkyl, alkoksy, amino
P
F
O
P
O
O
O
O
O
O
Sarin
Tabun
O
OH
O
Aging
OH
R2
Pralidoxim
P
O
R1
OR
L
P
O
OR
O
P
R1
O
OH
HO
OH
N
L
R1
N Me
Pralidoxim
motgift
OH
OR
O
P
R1
O
N
N Me
O
O
S
P
O S
P
OR
O
only insects
O
P
O O
S
O
O
O
Malation
Malaoxon
not tox.
Act as mustard gasses
Chemotherapeutic Agents / Antibiotics, chapter 34-39
•Antibacterial compounds (procaryotes)
•Antiparasitic agents
(eucarytotes) •Antifungal compounds (eucarytotes) - Chapt 36
•Antiviral compounds
•Anticancer compounds
Fungicides / Fungistatika / Antimykotika
Chemotherapeutics / Antibiotics
Synthetic Antifungals
N
Azoles
N
N
H
Azol / Pyrrol
N
H
1,2-Diazol
1,3-Diazol / Imidazol
Squalen
epoksidsyklase
Squalen
epoksidase
HO
O
Squalen
N
H
Antimycotic allylic amines
H
Lanosterol
Lanosterol
14a-demetylase
Antimycotic azoles
Component of
fungus cell walls
HO
HO
Ergosterol
H
H
HO
H
Kolesterol
H
N
N
N
H
1,2,4-Triazol
Lanosterol
CH2OH
CH3
HO
HO
H
O
N
N
Fe
N
N
H
C(OH)3
HO
H
HCO2H
14a-demethylase heme
(CYP450 fungi)
N R
N
N
N
Fe
N
N
Antimyc. azole
HO
H
Klotrimazol:
Canesten®, Klotrimazol® utvortes
Canesten®, vaginal behandlig
Ekonazol:
Pevaryl®, utvortes
Pevaryl®, vaginal behandlig
Miconazol:
Daktar®, utvortes
Daktar®, vaginal behandlig
Cl
N
N
Cl
Cl
N
N
Cl
O
X=H: Ekonazol
X=Cl: Mikonazol
X
Ketokonazol:
Cl
O
N
N
Cl
SAR:
O
O
N
N
O
-Weakly basic azole ring, imidazol / 1,2,4-triazol
"cis", [±]
F
N
Vorikonazol
F
OH
N (R)
N
(less tox. humans), pKa 6.5-6.8
Flukonazol
N
-2 or 3 other aromatic rings
(Racemate)
-Cl (or F) on at least one aromatic ring
N
(s) F
(F i flukonazol)
Cl
Itrakonazol:
O
N
N
N
O
Cl
O
N
N
N
O
N
N
-Lipophilic structures (as lanosterol)
Squalen
epoksidsyklase
Squalen
epoksidase
Allylic amines
Terbinafin
Lamicil®
HO
O
Squalen
Antimycotic allylic amines
H
Lanosterol
Lanosterol
14a-demetylase
Antimycotic azoles
N
HO
Prevents formation of cell wall comp.
Accumulation of toxic squalene
HO
H
Ergosterol
H
H
Kolesterol
H
HO
Enzyme-Nu
Enz--Nu
Squalene
epoxide
cyclase B
Squalene
epoxidase
H
H
H
HO
O
H
HO
H
H
Lanosterol
(Animals
Fungi)
Antimycotic Antibiotics
OH
n
n
Polyenes
O
O
O
Aminosukker
Proad spectrum. Some effect on certain protozoa.
Isolated, Streptomyces sp.
Binds to sterols in fungal cell membrane; cell leaks K+, small org. molecules
SAR:
•Macrolaktone [26 eor 38-ring, Larger than macrolides ( erytromycin etc)]
•Polyene (Macrolides not polyenes)
•Several OH-groups
•amino sugar, mykosamin
•Bad water sol.
OH
O
HO
O HO
HO HO
HO
OH
O
O
OH
N
CO2H
HO
HO
HO
Nystatin A
O
OH
NH2
OH
O
O
O
O
O HO
O
O
O
OH
Erytromycin
Nystatin A
Amfotericin B
toxic, bad oral avail;
Local treatment, mouth, GI tract
Systhemic infect (infusion)
Somewhat less tox.
OH
OH
O
OH
O
HO
O HO
HO HO
HO
OH
O
HO
OH
O HO
OH
HO HO
O
CO 2H
O
Amfotericin B
Nystatin A
O
O
OH
O
OH
CO 2H
OH
OH
NH 2
OH
NH 2
Amfotær struktur
OH
OH
OH
O
CO 2H
O
Hemiacetal
OH
OH
O
OH
CO 2
O
HO
O
O
OH
NH 2
OH
O
O
OH
NH 3
CO 2H
CO 2H
OH
O
O
OH
NH 2
OH
O
O
OH
OH
NH 2
OH
Peptides
Caspofungin
Serious systhemic infect.
Semisynth. from prod. of fermentation ( Glarea lozoyensis)
Inhib. synth of b-1,3-D-glucan; cell wall comp. certain fungi
Few good inhib. of fungi cell wall comp.
compared to antibacterials
Chemotherapeutic Agents / Antibiotics, chapter 34-39
•Antibacterial compounds (procaryotes)-Antimycobacterials
•Antiparasitic agents
(eucarytotes)
•Antifungal compounds
(eucarytotes)
•Antiviral compounds
•Anticancer compounds
G+
G-
Mycobacteria
chapt. 37
Pathog enic mycoba cteria:
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 T B the next 10 years
TUBERCULOSIS (TB)
High lipid / wax content in cell wall (myco lic acid)
Slow growing orga nisms
Aerobe bacteria
Resistant to chemicals and drying
Easily killed by heat
8 million new cases each year
ca. 1/3 of the world population are infected
(incl. dormant infections)
ca. 95% of the cases in developing countries
no new drugs on the marked for the last 25 - 30 years
Until ca. 1950 ; 50 % o f all infected died
Infection by inhalation of the bacteria
Pulmonary TB mo st co mmon
May also attack other orga ns including CNS
WHO (1993): TB a "global emergency"
First effective drug: Streptomycin 1946
H2 N
HN
O
HO
HO
HO
O
HO
HO
NH
OH
NH
NH
OH
H2 N
NHMe
Inhibits protein synthesis
Toxic!
Treatment
•Long time ≥6 mnds
•Combination of drugs
Different stages of bacterial growth
DOT: Directly observed therapy
First-line drugs
Isoniazid
N
O
Isoniazid®
O
HN
NHNH 2
Isoniazide
Antituberculosis drug
NH 2
Mn 2+ /O
N
O
H H O
N
N
Active acyl radical
formed in vivo
H O
O
NH2
NH2
N
N
NADH co-enzyme
in enzyme involved in cell wall
component synth
Inactive der. of co-enz
Long Chain ACP-Enoyl
Fatty Acid Reductase (inhA)
APC: Acyl carrier protein)
O
OH ((CH ) CH
2 23
3
CH3(CH2)1'7
14
17
CO2H
-mycolates
OH ((CH ) CH
2 23
3
O
CH3(CH2)17
15
17
CH3(CH2)17
ACP
R
R
H H O
O
NH2
1,4 hydride add.
N
OH ((CH ) CH
2 23
3
15
Mycolic acid
CO2H
ketomycolates
H3CO
O
ACP
17
methoxymycolates
CO2H
NADH co-enzyme
inhA
NH2
N
NAD+
First-line drugs
Ethambutol
Pyrazinamide
O
OH
NHNH2
O
NHNH2
N
H
N
HO
N
N
H
N
Isoniazide
Mechanism not fully known
Synth of cell wall comp.:
Inhib. arabinocyl transferase?
Mechanism not known
Arabinose,
Arabinomannan
and Lipoarabinomannan
Rifampicin
Rimactan®
Broad spectrum antibiotic
From Streptomyces sp
HO
MeCO 2
OH OH
OH
MeO
O
O
Rifampicin
Inhib bacterial RNA polymerase
Inhib. RNA-synth.
(p-p intract. naphtalene rings aromatic AA?)
OH
NH
N
O
OH
O
N
Induce CYP2C; increased metabol. of certain anti AIDS drugs
Second-line drugs
Ethionamide
NH2
S
Cycloserine
Isolated Spreptomyces sp
p-Aminosalicylic acid
CO2H
OH
H 2N
O
O
N
NH2
Mech. ≈ Isoniazide
PABA antimetabolite
NHNH2
O
NH
Folic acid synth (≈antibact. sulfa
)
N
Isoniazide
Kanamycin
(aminoglycoside antibiotics)
NH2 O
R
O
HO
HO
NH2
HO
HO
O
O
H2N
OH
R=OH: Kanamycin A
R=NH2: Kanamycin B
NH2
Inhib. alanine racemase
and alanine ligase;
Inhib. peptidoglycan synth
Others
Oxazolidinones
Quinolones
O
R
F
O
CO2H
O
R
N
R
R
N
N
F
O
NH
O
Treatment of MAC infections
Clarithromycin
(Macrolide)
O
N
HO
HO
O HO
MeO
O
Ethambutol
O
O
Quinolones
O
O
Other macrolides
O
OH
Rifabutin (Rifamycin)