Chemotherapeutic Agents / Antibiotics, chapter 34-39 Antibacterial compounds (procaryotes) Antiparasitic agents (eucarytotes) - Chapt 35 Antifungal compounds.

Chemotherapeutic Agents / Antibiotics, chapter 34-39

•Antibacterial compounds (procaryotes)•Antiparasitic agents (eucarytotes) - Chapt 35•Antifungal compounds (eucarytotes)•Antiviral compounds•Anticancer compounds

ProtozoaHelmintsInsects (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

ÿ Trichomonas vaginalis: Gelital infections

ÿ Giardia lamblia: Diarea

ÿ Toxoplasma gondii : Toksoplasmosis

ÿ Trypanozomas sp: Sleeping sickness

ÿ Entamoeba histolytica: Dysentery

ÿ Plasmodium sp: Malaria

ÿ Pneumocystis carinii : Oportunistic, AIDS

Treatment of diseases caused by amebia, giardia, trichomonas

Metronidazol

Flagyl®, Metronidazol®

N

N

OH

CH3

O2

NAlso 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

MetabolN

N

OH

O2NOH N

N

OH

O2NOH

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

HON

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

S

O

O

H2NH2N

1932: Prontocil active against Streptoccocces infectionno activity on bacterial cultures

1935: Prontocil metabilized (azoreductase) to Sulfanilamid in vivo

NH2S

O

O

H2N (rel. toxisk)

Modern sulfa drugsr

NH2S

O

OHNR

R: Aryl or hetroaryl

Quinolines

QuinineKinin®

N

MeO

HO

N MeflokinLariam®

N

CF3

CF3

HO

N

H

KlorokinKlorokinfosfat®

N

NH

Cl

N

HydroksyklorokinPlaquenil®

N

NH

Cl

N

HO

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

Biguanides

Proguanil (= Chloroguanide)

Paludrine®

Malarone® + atovakvon

Pro-drug

Inhib. protozoan folate reduktase

(c.f. Trimetoprim)

H2

N

O

OH

PABA

H2

N S

O

O

NH

R

Antibakt sulfonamid

N

N N

H

N

OH

H2

N

N

H

OH

O

Dehydropteridinsyre

N

N N

H

N

OH

H2

N

N

H

NH

O

Dehydrofolinsyre

CO2

H

CO2

H

N

N N

N

OH

H2

N

N

H

NH

O

F olinsyre

CO2

H

CO2

H

Fra folinsyre i kosten

hos mennesker

N

N N

H

H

N

OH

H2

N

N

H

NH

O

Tetrahydrofolinsyre

CO2

H

CO2

H

Folat-

reduktase

Essensielle prossesser

hos bakterier og dyr

Inkl tymidinsyntese

Trimetoprim

N

N

NH2

H2

N 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

N

H

N

H

H

N

NH

N

H

NH

Cl

NH

H

N

H

N

NH

Cl

Other biguanidesKlorhexidine

Atovakvon

Malarone® + proguanil.Also other parasites (P. carinii)Ubiquinone antimetabolite?

Artemeter og Lumefandrin

Riamet®

Others

O

OH

H

OO

H

Artemisinfrom Artemisia annuaChinesee trad. med.

O

O

OH

H

OO

H

MeO

Artemeter

Semisynth. analogImproved solubil.

Mech. involves radicals

No cross resist.

Synth. analogs, active field

O

O

Cl

OH

O

O

CH3

H3CO

H3CO8 Red

ox

Ubiquinone, Q10, Cenzyme Qelectron carriercellular respiration

OH

OH

CH3

H3CO

H3CO

R

Drugs for Helmint infections

Eukaryotes – Invertebrates.

Tropical diseases!

Animal parasites; ex Trichinella spiralis (trikiner).

Mebendazol

Vermox®

N

H

N

NH

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

Permetrin

Nix®

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.

L

PO

OR

R2

OH O POH

L

OR

R1O

HO

PO

OR

R1

Aging

O P

OH

R1O

Pralidoxim

N

N

OH

Me

OH

Pralidoximmotgift

N

N

O

Me

PO OR

R1

Gen structur mustard gasses

PO

O

N

N

Tabun

FP

O

O

Sarin

LP

O

R1

R2

L: Leaving groupR1: alkoksyR2: alkyl, alkoksy, amino

O

O

O

O

SP

S

O

O

Malation

only insects

O

O

O

O

SP

O

O

O

Malaoxon

Act as mustard gassesnot tox.

Malation

Prioderm® lice

Chemotherapeutic Agents / Antibiotics, chapter 34-39

•Antibacterial compounds (procaryotes)•Antiparasitic agents (eucarytotes) -•Antifungal compounds (eucarytotes) - Chapt 36•Antiviral compounds•Anticancer compounds

Fungicides / Fungistatika / AntimykotikaChemotherapeutics / Antibiotics

Synthetic Antifungals

AzolesN

H

Azol / Pyrrol

N

N

H

1,2-Diazol

N

N

H

1,3-Diazol / Imidazol

N

N

N

H

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

Kolesterol

H

H

H

Antimycotic allylic amines

HO

Lanosterol

H

CH3

Fe

O

N

N N

N

14a-demethylase heme(CYP450 fungi)

HOH

CH2OH

HOH

C(OH)3

HCO2H

HOH

FeN

N 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

Cl

X=H: Ekonazol

X=Cl: Mikonazol

Ketokonazol:

N

N

Cl

Cl

O

O

O N N

O

"cis", [±]

Itrakonazol:

N

N

N

Cl

Cl

O

O

O N N N

N

N

O

Flukonazol

(Racemate)

Vorikonazol

N

N

N

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

Terbinafin

Lamicil®

N

Squalen

Squalen epoksidase

O

Squalen epoksid-syklase

HOLanosterol

Lanosterol14a-demetylase

Antimycotic azoles

HOErgosterol

HO

H

H

HO

Kolesterol

H

H

H

Antimycotic allylic amines

Prevents formation of cell wall comp.Accumulation of toxic squalene

O

HO LanosterolH

Squaleneepoxidase

Enzyme-Nu

H

HOH

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 eor 38-ring, Larger than macrolides ( erytromycin etc)]

•Polyene (Macrolides not polyenes)

•Several OH-groups

•amino sugar, mykosamin

•Bad water sol.

O

OO

Aminosukker

n

OH

n

O

O

OOH

CO2H

OH

HO

OH

HOHOHOOHO

O

OHNH2

OHNystatin A

O

O

O

HOO

O

NHO

Erytromycin

HO

HO

O

O

O

OH

O

O

O

OH

CO2

H

OH

HOOHHOO

HO

O

OH

NH2

OHAmfotericin B

HO

OH

O

O

O

OH

CO2

H

OH

HO

OH

HOHOHOOHO

O

OH

NH2

OHNystatin A

Nystatin A

toxic, bad oral avail; Local treatment, mouth, GI tract

Amfotericin B

Systhemic infect (infusion)

Somewhat less tox.

O

O

OH

CO2

H

OH

O

OH

NH2

OH

Amfotær struktur

O

O

OH

CO2

OH

O

OH

NH3

OH

O

HO

CO2

H

OH

O

OH

NH2

OH

O

Hemiacetal

O

O

OH

CO2

H

OH

O

OH

NH2

OH

Peptides

Caspofungin

Serious systhemic infect.

Semisynth. from prod. of fermentation ( Glarea lozoyensis)

Inhib. synth of -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 chapt. 37

•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

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

HOHO

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

Isoniazid

Isoniazid®

N

O NHNH2

N

O

NH2

NADH co-enzymein enzyme involved in cell wallcomponent synth

H H

NO

HNNH2

IsoniazideAntituberculosis drug

NO

Mn2+ /O

Active acyl radical formed in vivo

N

O

NH2

HO

N

Inactive der. of co-enz

Mycolic acid

Long Chain ACP-Enoyl Fatty Acid Reductase (inhA)

R

ACPO

APC: Acyl carrier protein)

N

O

NH2

H H

NADH co-enzymeinhA

1,4 hydride add.

R

ACPO

N

O

NH2

NAD+

CH3(CH2)1'7 14CO2H

17

OH ((CH2)23CH3

15CO2H

17

OH((CH2)23CH3

α-mycolates

O

CH3(CH2)17

ketomycolates

15CO2H17

OH((CH2)23CH3

CH3(CH2)17

methoxymycolates

H3CO

First-line drugs

OH OH

OH

N

N

NH

O

OOHOH

HO

MeCO2

MeO

O

O

Rifampicin

Inhib. RNA-synth.

Rifampicin

Rimactan®Broad spectrum antibiotic

From Streptomyces sp

Inhib bacterial RNA polymerase

( intract. naphtalene rings aromatic AA?)

Induce CYP2C; increased metabol. of certain anti AIDS drugs

Pyrazinamide

N

O NHNH2

Isoniazide

NN

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

CO2H

OH

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

HO

HO

R=OH: Kanamycin AR=NH2: Kanamycin B

Kanamycin(aminoglycoside antibiotics)

Others

Quinolones

N

O

CO2H

R

FR

R

RO N N

O

O

F

NH

O

Oxazolidinones

Treatment of MAC infections

O

O

O

MeOO

O

NHO

HO

HO

O

O

O

OH

Clarithromycin(Macrolide)

Other macrolides

Ethambutol

Quinolones

Rifabutin (Rifamycin)