•Antibacterial compounds (procaryotes ... · Antibakt sulfonamid N N H N OH H2N H OH O...
26
Chemotherapeutic Agents / Antibiotics, chapter 38-43 •Antibacterial compounds (procaryotes)-Antimycobacterials chapt. 41 •Antiparasitic agents (eucarytotes) •Antifungal compounds (eucarytotes) •Antiviral compounds •Anticancer compounds G+ G- Mycobacteria
Transcript of •Antibacterial compounds (procaryotes ... · Antibakt sulfonamid N N H N OH H2N H OH O...
Chemotherapeutic Agents / Antibiotics, chapter 38-43
•Antibacterial compounds (procaryotes)-Antimycobacterials chapt. 41•Antiparasitic agents (eucarytotes) •Antifungal compounds (eucarytotes) •Antiviral compounds•Anticancer compounds
G + G - Mycobacteria
Pathogenic mycobacteria:M. tuberculosis (tuberculosis)M. Leprae (Leprosy)M. Avium (Opportunistic infection in AIDS patients)M. bovis (mainly cattle infect, infected milk USA)
TUBERCULOSIS (TB)High lipid / wax content in cell wall (mycolic acid)Slow growing organismsAerobe bacteriaResistant to chemicals and dryingEasily 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
30 million people will die from TB the next 10 years
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
WHO (1993): TB a "global emergency"
HOO
NHMeHO
HO HO
O
HOOH
OH
HN
NH
NHH2N
NHH2N
Inhibits protein synthesisToxic!
First effective drug: Streptomycin 1946
Treatment•Long time ≥6 mnds•Combination of drugs Different stages of bacterial growth
DOT: Directly observed therapy
First-line drugs
IsoniazidIsoniazid®
N
O NHNH2
N
ONH2
NADH co-enzymein enzyme involved in cell wallcomponent synth
H H
NO
HN NH2
IsoniazideAntituberculosis drug
NO
Mn2+ /O
Active acyl radical formed in vivo
N
ONH2
HO
N
Inactive der. of co-enz
Mycolic acid
Long Chain ACP-Enoyl Fatty Acid Reductase (inhA)
R
ACPO
APC: Acyl carrier protein)
N
ONH2
H H
NADH co-enzymeinhA
1,4 hydride add.
R
ACPO
N
ONH2
NAD+
CH3(CH2)1'7 14 CO2H17
OH ((CH2)23CH3
15CO2H17
OH((CH2)23CH3
α-mycolates
O
CH3(CH2)17
ketomycolates
15CO2H17
OH((CH2)23CH3CH3(CH2)17
methoxymycolates
H3CO
First-line drugs
OH OH
OH
N
N
NH
O
OOHOH
HO
MeCO2
MeO
O
O
Rifampicin
Inhib. RNA-synth.
RifampicinRimactan® Broad spectrum antibiotic
From Streptomyces spInhib bacterial RNA polymerase(π−π intract. naphtalene rings aromatic AA?)Induce CYP2C; increased metabol. of certain anti AIDS drugs
Pyrazinamide
N
O NHNH2
IsoniazideN
N
O NHNH2
Mechanism not known
Ethambutol
NH
HN
OH
HO
Mechanism not fully knownSynth of cell wall comp.:Inhib. arabinocyl transferase?Arabinose, Arabinomannan and Lipoarabinomannan
Second-line drugs
Ethionamide p-Aminosalicylic acid CycloserineIsolated Spreptomyces sp
N
O NHNH2
Isoniazide
N
S NH2
Mech. ≈ Isoniazide
CO2HOH
NH2
PABA antimetabolite
Folic acid synth (≈antibact. sulfa)
ONH
H2N O
Inhib. alanine racemaseand alanine ligase;Inhib. peptidoglycan synth
HO
O
O
NH2
NH2
O
R
NH2
O
OHH2N
HO
HOHO
R=OH: Kanamycin AR=NH2: Kanamycin B
Kanamycin(aminoglycoside antibiotics)
Others
Quinolones
N
OCO2H
R
FR
RR
O N NO
O
F NH
O
Oxazolidinones
Treatment of MAC infections
O
O
O
MeOO
ON
HOHOHO
O
OO
OH
Clarithromycin(Macrolide)
Other macrolidesEthambutolQuinolonesRifabutin (Rifamycin)
Chemotherapeutic Agents / Antibiotics, chapter 38-43
•Antibacterial compounds (procaryotes)•Antiparasitic agents (eucarytotes) - Chapt 39•Antifungal compounds (eucarytotes)•Antiviral compounds•Anticancer compounds
ProtozoaHelmintsInsects (Scabies lice etc.)
(Fungi chapt. 40)
ProtozoaEucaryotes, unicellular (may exist in colonies)Protozoa and algae (protocista)Complex replication (sexual and asexual) Patogenic P. most common tropical area3. world diseasesMany diseases can be prevented by clean drinking waterCertain 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
MetronidazolFlagyl®, Metronidazol®
N
N
OH
CH3O2N Also effective against anaerobic bacteriaProbably pro-drug -reductive activation(mech. not fully understood)
N
N
OH
CH3O2N
Anaerobe org.e-
N
N
OH
CH3O2N
O2O O
HO-OH
2 HO
Metabol N
N
OH
O2N OH N
N
OH
O2N OH
O
Active metabol.
Phase II conjugation
OH
NH
OH
O
H2N
O CH3
O
N
N
OH
CH3O2N
Formation of toxic reactive oxygen species
Related comp.treatment of African sleeping sickness
OO2NN N
SO2
Anti - Malaria drugsPlasmodium sp. Vektor: Anopheles moskito. Complex life cyclus.
De fleste l.m.aktive her
Mal aria = bad air
40% of world population at risk300 mil acute illnessess pr yearca 1 mill deaths pr yearMalaria kills a child every 30 sec.90% in incidents sub-sahara Africa
Historic drugs-Azodyes and salvarsan (1. synthetic effective drug)-Quinine fra Cinchona (Kinabark)
Cinchona pubescens (Kinatre) from South America
N
MeO
HO N
QuinineN
Quinoline
MOdern antimalarials
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
Quinolines
QuinineKinin®
N
MeO
HO N MeflokinLariam®
NCF3
CF3
HO NH
KlorokinKlorokinfosfat®
N
NH
Cl
N
HydroksyklorokinPlaquenil®
N
NH
Cl
NHO
More active, less tox (comp Quinine)Resistance!
Also klorokin resistantP. palsifarum
N
NH
Cl
N
klorokin
N
NH
H3CO
N
Pamakin, 1926
Dye
Quinine
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
BiguanidesProguanil (= Chloroguanide)Paludrine®Malarone® + atovakvon
Pro-drugInhib. protozoan folate reduktase(c.f. Trimetoprim)
H2NO
OH
PABA
H2N SO
ONH
RAntibakt sulfonamid
N
N NH
NOH
H2N
NH
OHO
Dehydropteridinsyre
N
N NH
NOH
H2N
NH
NHO
Dehydrofolinsyre
CO2H
CO2H
N
N N
NOH
H2N
NH
NHO
Folinsyre
CO2H
CO2H
Fra folinsyre i kostenhos mennesker
N
N NH
HN
OH
H2N
NH
NHO
Tetrahydrofolinsyre
CO2H
CO2H
Folat-reduktase
Essensielle prossesser hos bakterier og dyrInkl tymidinsyntese
Trimetoprim
N
N
NH2
H2N OCH3
OCH3
OCH3
NH2
enamine
NH
Imine
taut.
OH
enol
O
keto
taut.
Cl
NH
NH
NH
NH NH
Proguanil (chloroguanide)
Liver
N N
NH2N NH2
Cl
1
1
2
2
3
3
4
4
5
5
6
6
Cycloguanil
- H2
Cl
NH
NH
N
NH NH
NH N
H
HN
NH
NH
NHCl
NH
HN
HN
NH Cl
Other biguanidesKlorhexidine
AtovakvonMalarone® + proguanil.Also other parasites (P. carinii)Ubiquinone antimetabolite?
Artemeter og LumefandrinRiamet®
Others
O
O H
H
OO
H
Artemisinfrom Artemisia annuaChinesee trad. med.
O
O
O H
H
OO
H
MeO
Artemeter
Semisynth. analogImproved solubil.
Mech. involves radicalsNo cross resist.Synth. analogs, active field
O
O
Cl
OH
O
OCH3
H3CO
H3CO8 Red
oxUbiquinone, Q10, Cenzyme Qelectron carriercellular respiration
OH
OHCH3
H3CO
H3CO
R
Drugs for Helmint infectionsEukaryotes – Invertebrates. Tropical diseases! Animal parasites; ex Trichinella spiralis (trikiner).
MebendazolVermox®
NH
NNH
O
O
OMe
BenzimidazolesMany active analogs knownBinds to tubulin - prevents formation of microtubulesinhib. mitosis (c.f. certain anticancer drugs)May also inhib. fumarate reductase
Drugs against Ectoparasites (insects)
Lice, scabies etc
PermetrinNix®
PyretrinesInsecticides from Crysantemum sp
R
OO
R'∗
Cl
Cl ∗
OO
O
Synth. analog, more stabileMixt. of 4 stereoisomers
ClCl
ClCl
ClCl
Chlorinated pesticides:LindaneBlock GABA CNS neurtransmittor(Also neurotox. effects on humans)
Irreversible InhibitorsAcetylcholine esterase
Not drugs, nerve gasses, insecticides etc.
LPOOR
R2
OH O P OH
L
OR
R1O
HOPOOR
R1
AgingO P
OH
R1O
Pralidoxim
N
NOH
Me
OH
Pralidoximmotgift
N
NO
Me
PO OR
R1
Gen structur mustard gasses
POO
N
N
Tabun
FPOO
Sarin
LPOR1
R2L: Leaving groupR1: alkoksyR2: alkyl, alkoksy, amino
O
O
O
OS P S
O
O
Malation
only insects
O
O
O
OS P O
O
O
Malaoxon
Act as mustard gassesnot tox.
Malation Prioderm® lice
Chemotherapeutic Agents / Antibiotics, chapter 38-43
•Antibacterial compounds (procaryotes)•Antiparasitic agents (eucarytotes) -•Antifungal compounds (eucarytotes) - Chapt 40•Antiviral compounds•Anticancer compounds
Fungicides / Fungistatika / AntimykotikaChemotherapeutics / Antibiotics
Synthetic Antifungals
AzolesNH
Azol / Pyrrol
NNH
1,2-Diazol
N
NH
1,3-Diazol / Imidazol
NNNH
1,2,4-Triazol
Component of fungus cell walls
Squalen
Squalen epoksidase
O
Squalen epoksid-syklase
HOLanosterol
Lanosterol14a-demetylase
Antimycotic azoles
HOErgosterol
HO
H
H
HO
KolesterolH
H
H
Antimycotic allylic amines
HO
Lanosterol
H
CH3
FeO
NN N
N
14a-demethylase heme(CYP450 fungi)
HO H
CH2OH
HO H
C(OH)3
HCO2H
HO H
FeNN N
N
NN R Antimyc. azole
Klotrimazol: Canesten®, Klotrimazol® utvortesCanesten®, vaginal behandlig
N N
Cl
Ekonazol: Pevaryl®, utvortesPevaryl®, vaginal behandlig
Miconazol: Daktar®, utvortesDaktar®, vaginal behandlig
N N O
Cl
Cl
X
ClX=H: EkonazolX=Cl: Mikonazol
Ketokonazol:
N N
Cl
Cl
O
O O N NO
"cis", [±]
Itrakonazol:
N NN
Cl
Cl
O
O O N N NNN
O
Flukonazol(Racemate)
Vorikonazol
N NN
F
F
OH
N
N
F(s)
(R)
SAR:
-Weakly basic azole ring, imidazol / 1,2,4-triazol
(less tox. humans), pKa 6.5-6.8
-2 or 3 other aromatic rings
-Cl (or F) on at least one aromatic ring
(F i flukonazol)
-Lipophilic structures (as lanosterol)
Allylic amines
TerbinafinLamicil®
N
Squalen
Squalen epoksidase
O
Squalen epoksid-syklase
HOLanosterol
Lanosterol14a-demetylase
Antimycotic azoles
HOErgosterol
HO
H
H
HO
KolesterolH
H
H
Antimycotic allylic amines
Prevents formation of cell wall comp.Accumulation of toxic squalene
O
HO LanosterolH
Squaleneepoxidase
Enzyme-Nu
H
HO H
H
Enz--Nu
H
Squalene epoxide cyclase
(AnimalsFungi)
H
B
Antimycotic AntibioticsPolyenes
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 or 38-ring, Larger than macrolides ( erytromycin etc)]•Polyene (Macrolides not polyenes)•Several OH-groups•amino sugar, mykosamin•Bad water sol.
O
OO Aminosukker
nOH
n
O
O
O OH
CO2H
OH
HO
OH
HOHOHOOHO
O
OHNH2
OHNystatin AO
O
O
HOO
ON
HO
Erytromycin
HOHO
O
OO
OH
O
O
O OH
CO2H
OH
HOOHHOOHO
O
OHNH2
OHAmfotericin B
HO
OH
O
O
O OH
CO2H
OH
HO
OH
HOHOHOOHO
O
OHNH2
OHNystatin A
Nystatin Atoxic, bad oral avail; Local treatment, mouth, GI tract
Amfotericin BSysthemic infect (infusion)Somewhat less tox.
O
O
OH
CO2H
OH
O
OHNH2
OH
Amfotær struktur
O
O
OH
CO2
OH
O
OHNH3
OHO
HOCO2H
OH
O
OHNH2
OH
O
Hemiacetal
O
O
OH
CO2H
OH
O
OHNH2
OH
Peptides
CaspofunginSerious systhemic infect.Semisynth. from prod. of fermentation ( Glarea lozoyensis)Inhib. synth of β-1,3-D-glucan; cell wall comp. certain fungi
Few good inhib. of fungi cell wall comp. compared to antibacterials
