FLUROQUINOLINE.pdf

8/14/2019 FLUROQUINOLINE.pdf

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FLUOROQUINOLONES:

from structure to activity and toxicity

F. Van Bambeke, Pharm. D. & P. M. Tulkens, MD, PhDUnit de Pharmacologie Cellulaire et Molculaire

Universit Catholique de Louvain, Brussels, Belgium

SBIMC / BVIKM

www.md.ucl.ac.be/facm www.isap.org

www.sbimc.org - www.bvikm.org

soon...


2/53

Mechanism of action of fluoroquinolones:

the basics...

DNA

PORIN

Gram (-) Gram (+)

Topoisomerase

DNA gyrase


3/53

2 key enzymes in DNA replication:

bacterial DNA is supercoiled

DNA gyrase

topoisomerase IV


4/53

Ternary complex

DNA - enzyme - fluoroquinolone

FLUOROQUINOLON

4 stacked molecules

DNA GYRASEcatalytic subunits

DNA GYRASE

ATP binding subunits

COVALENTLY CLOSED

CIRCULAR DNA

(Shen, inQuinolone Antimicrobial Agents, 1993)


5/53

Resistance to fluoroquinolones: the basics

DNA

Gram (-) Gram (+)

decreased

permeability

mutation ofthe enzymes

efflux pump

Topo

isomeraseDNA gyrase


6/53

Fluoroquinolones are the first entirely

man-made antibiotics:do we understand our molecule ?

NX8

COOH

OR5

R6

R7

R1

Dont panic, we will travel together.


7/53

Chemistry and Activity

This is where all begins...


8/53


9/53

From chloroquine to nalidixic acid...

nalidixic acid

N

HN

Cl

N CH3

CH3

chloroquine

1939

1958

1962N

C

O

C2H5

O-

O

Cl

NN

C

O

O -

H3

C

O

C2H5

7-chloroquinoline(synthesis intermediate

found to display

antibacterial activity)


10/53

Nalidixic acid *

* Belg. pat. 612,258 to Sterling Drugs, 1962

-

typical chemical features of

fluoroquinolones (a, b, c) BUT a naphthridone

(N at position 8: )

limited usefulness as drug

narrow antibacterial spectrum

(Enterobacteriaceaeonly)

short half-life (1.5h)

high protein binding (90%)

a

b

c

NN

C

O

C2H5

O-

O

H3C


11/53

nalidixic acid

1. modify naphthyridone

into quinolone

oxolinic acid *

From nalidixic acid to the

1st fluoroquinolone (1 of 4)

N

C

O

O-

O

C2H5

O

ONN

C

O

C2H5

O-

O

H3C

shows reduced protein binding..

* quinoleine* Ger. pat. to Warner Lambert, 1967


12/53



nalidixic acid2. discovery of

flumequine *

flumequine *

shows weak but broad

Gram(-) activity

NN

C

O

C2H5

O-

O

H3C

* Ger pat. to Rikker Labs, 1973

N

C

O

F

O

-

O

CH3

* benzo-quinolizine


13/53

nalidixic acid

3. introduce a

piperazine *



N

N

N

C

O

C2H5

O-

O

N

HNNN

C

O

C2H5

O-

O

H3C

pipemidic acid *

shows longer half-life...

* pyrido-2-3-pyrimidine* Ger. Pat. to Roger Bellon, 1974


14/53

nalidixic acid

* Belgian patent 863,429, 1978 to Kyorin

NN

C

O

C2H5

O-

O

H3C

N

C

O

FO

-

O

HN

N

CH3

norfloxacin*

1978

2

1

3

combine all 3features *...



broader Gram(-) activity

less protein binding (50%)

longer half-life (3-4h)

* 6-fluoro-7-pyrimidino-quinoleine


15/53

From norfloxacin to the other 1st generation

fluoroquinolones: pefloxacin

-

H3C

N

pefloxacin *

Add a methyl

to still increasehalf-life

* Ger. pat. 2,840,910 toRoger Bellon/Dainippon,197

O O

norfloxacin

N

CF O-

HN

N

CH3

O O

N

CF O-

N

CH3


16/53

-

H3C

OCH3

N

C

O

O-

O

N

N

CH3

-

H3C

N

C

O

O-

O

N

N

F

F

ofloxacin** Eur. pat. Appl. 47,005 to Daiichi, 1982

pefloxacin

tricyclic compound(as in flumequine but

morpholine ring)

From norfloxacin to the other 1st generation

fluoroquinolones: ofloxacin

O O

norfloxacin

N

CFO

-

HN

N

CH3


17/53


18/53

"1st generation" fluoroquinolones

N

C

O

F O-

O

HN

N

-

H3C

piperazine

N

C

O

O-

O

HN

N

N

C

O

O-

O

N

N

CH3

CH3

F

F

norfloxacin ciprofloxacin

pefloxacin

OCH3

-

H3C

N

C

O

O-

O

N

N

F

ofloxacin

methyl

cyclo

propyl

morpho


19/53

The " first generation" of fluoroquinolones

1960 1970 1980

Nalidixic acid

Oxolinic acid

CinoxacinPipemidic acid

Norfloxacin

Pefloxacin

Ofloxacin

Ciprofloxacin

Fleroxacin

Rufloxacin

improvedanti Gram (-)

activity

t1/2 activity3-4 h ++

11 h +

6 h ++

3-4 h +++


20/53

From ofloxacin to levofloxacin...

OCH3

-

H3C

N

C

O

O-

O

N

N

F

Ofloxacin is a racemic mixture

N

O

CH3

H

The active form of ofloxacin is the (-) S isomer

Levofloxacin is the

pure (-) S isomer *

* Eur. pat. 206,283 to Daiichi, 1987


21/53

The present " first generation" of fluoroquinolones ...

1960 1970 1980

Nalidixic acid

Oxolinic acid

Flumequine

Pipemidic acid

Norfloxacin

Pefloxacin

Ofloxacin

Ciprofloxacin

Fleroxacin

Rufloxacin

improvedanti Gram (-)

activity

t1/2 activity3-4 h ++

11 h +

6 h ++

3-4 h +++

Levofloxacin 6 h ++++

twice

as active asofloxacin per g


22/53


23/53

1960 1970 1980 1990 2000

Temafloxacin a

Sparfloxacin b

Grepafloxacin c

Gatifloxacin d

The second generation fluoroquinolones

Gram (-);

improvedGram (+)

anti-anaerobe

a: Toyama, 1988 (?) ; b: Dainippon, 1985-1987; c: Otskuda, 1989; d: Kyorin, 1988


24/53

1960 1970 1980 1990 2000

The third generation fluoroquinolones

Trovafloxacin b

Moxifloxacin c

Clinafloxacin a

Gemifloxacin d

anti-Gram (-)

anti-Gram (+)anti-anaerobe

a:Kyorin, 1987; b: Pfizer, 1993; c: Bayer, 1994; d: LG Chemical Ltd., S. Korea, 1994-98


25/53

1. maintenance of anti - Gram (-) activity

NC

COOH

OR5

F

R7

R1

Cl, F halogen

O-CH3 methoxy

NH2

N

N

R

piperazine

bulky group

MIC

M

Gram (-)

Gram (-)


26/53

Gram (-) activity (E. coli)

N

C

O

FO-

O

HN

N

ciprofloxacin0.125 - 0.5

grepafloxacin0.06 - 2

gatifloxacin0.06

N

C

O

F

N

O-

OCH3

HN

H3C

H CO3

N

C

O

F

N

O

OCH3

HN

H3C

I II


27/53

2. improving Gram (+) activity (S. pneumoniae)

NX8

COOH

OR5

F

R7

R1

if X8 = C

Cl, F halogen

O-CH3 methoxy

N

N

H 2N

F

F

CH3

pyrimidine

naphthyridone

bulky group

MIC

Gram (+)

Gram (+)

Gram (+)

M


28/53


29/53


30/53

Activity against B. fragilis

N

C

O

FO-

O

HN

N

ciprofloxacin

2 - 128

gemifloxacin0.5 - 64

moxifloxacin

0.25 - 8

I II

H

NN

C

O

F

N

O

F

F

H

H3N

+

trovafloxacin

0.125 - 8

O O

N

CFO

H CO3

HNN

2

NN

C

O

FO-

O

N

CH2

N

H3CO

H N

H CO3

N

C

O

F

N

O-

OCH3

HN

H3C

gatifloxacin

0.25 - 8

III


31/53

Is there a SAR for emergence of resistance ?

The "Mutant Prevention Concentration" *

"When Mycobacterium bovis BCG and Staphylococcus aureus were

plated on agar containing increasing concentrations of fluoroquinolone,

colony numbers exhibited a sharp drop, followed by a plateau and a second

sharp drop.

The plateau region correlated,vith the presence of first-step resistant

mutants. Mutants were not recovered at concentrations above those

required for the second sharp drop, thereby defining a mutant prevention

concentration (MPC).

A C8-methoxy grouplowered the MPC for an N-1-cyclopropyl

fluoroquinolone"


32/53

Fl i l ith C8 th


33/53

Fluoroquinolones with a C8-methoxy

N

C

O

FO-

O

HNN

ciprofloxacin moxifloxacin

I II

N

C

O

FO

O

H CO3

HN N

H CO3

N

C

O

F

N

O-

OCH3

HN

H3C

gatifloxacin

III


34/53

Toxicity

This is where all may fail...

Frequent side effects of fluoroquinolones:


35/53

Frequent side effects of fluoroquinolones:

is there a SAR ?

COMPLEXATION WITH METALLIC IONS (Fe, Al, Mg, Ca)

PHOTOTOXICITY

DRUG INTERACTIONS: INHIBITION OF cyt P450 (1A2)

CNS TOXICITY (BINDING TO GABA RECEPTOR)

GASTRO-INTESTINAL DISCOMFORT

CARTILAGE and MUSCULOSQUELETAL TOXICITY

?

??

SAR f f t id ff t


36/53

SAR of frequent side effects

NX8

COO-

OR5

F

R7

R 1

Phototoxicity

C

F Inhibit ion of P450

Inhibit ion of P450

N

Binding to

GABA receptorPenetration

in CNS

HN

N

R

HN

NR

R

R

sparflo,

flero,lomeflo

Ca++, Al+++, Fe++

complexation

cipro,

grepa ...

All FQs

Fluoroquinolones with low or no drug


37/53

Fluoroquinolones with low or no drug

interactions..

N

C

O

F

N

O-

OCH3

HN

H3C

NN

C

O

F

N

O-

O

F

F

H

H

H3N

+

Trova

N

C

O

F

O-

O

HN

N

H3C

Gati

N

C

O

F O-

O

HNN

Mox

Grepa

3

H CO

H CO

3

Fl i l ith hi h h t t i it


38/53

Fluoroquinolones with high phototoxicity ...

Bay 3118 c

N

C

O

FO-

O

HN

N

NH2

F

H3C

H3C

O

N

F

Cl

HNN

N

C

O

F

CH2CH2F

O-

O

N

N

H3C F

N

C

O

FO-

O

HN

N

F CH3

H3C

Lomefloxacin b

Fleroxacin a

Sparfloxacin a: Kyorin, 1981; b: Hokuriku, 1985; c: Bayer, 1994


39/53

Rare side effects of fluoroquinolones:


40/53

q

cardiac toxicity

Torsade de pointes: paroxysm of ventricular tachycardia in which the

electrocardiogram shows a steady undulation in the QRS axis in runs of 5 to

20 beats with progressive changes in direction. It is a most severe type of

arythmia which may cause death. It is most often associated with andpreceeded by a prolongation of the QT interval.

0 50change in QTc prolongation (msec)

20 msec: population risk

fluoxetine: 2

moxifloxacin: 7

grepafloxacin: 10

sparfloxacin: 15

cisapride + clari: 25 terfenadine: 46

Cardiac toxicity QT prolongation:


41/53


is there any SAR ?

FO(H 2C)

3NHN

H3CO

O

OCH3

Cl

H2N

cisapride

astemizole

terfenadinC(CH3)3C(H 2C) 3

H

OH

NCHO

OCH3

C(H2C)

2

H

OHN

H

N

N

N

CH2

F



42/53


is there any SAR ?

FO(H

2C)

3NHN

H3CO

O

OCH3

Cl

H2N cisapride

N NH

F

F CH3

CH3

H2N

N

O

C

-O

O

sparfloxacin

N NH

F CH3H3C

N

O

C

-O

O

grepafloxacin

???

Oth t i iti


43/53

Other severe toxicities

1992:

The temafloxacin syndrome:

hemolytic uraemic anemia

discoloured urine, fever

jaundice, nausea, vomiting

abdominal pain

coagulopathy

hepatic and renal dysfunction

0.056% incidence

2 deaths

withdrawn in June 1992

1999:

The trovafloxacin syndrome:

serious hepatic events

laboratory abnormallities

ALT, bil irubin,

encephalopathies

necrotic inf lammation

0.0056% incidence

5 transplants

6 deaths (multifactorial)

withdrawn / limited in June 1999


44/53


45/53


46/53

SAR of main pharmacokinetic parameters:

h t t l h lf lif


47/53

how to get a long half life

t 1/2(h) no. of dailyadministrations

oflo 5 - 7 2 x*peflo 10 2 x*flero 9 - 13 1 x

grepa 10 - 12 1 xgati 13 1 x

gemi 8 1 xtrova 10 1 xmoxi 12 1 x

other FQ 3 - 6 2 x* higher MIC

N

HN

H3C

H3CN

N

NH

H

H3N+ HN

N

N

CH2

N

H3CO

H2N

SAR of main pharmacokinetic parameters:

bi di ibilit


48/53

biodisponibility

biodisponibility

trovafloxacin 90 %

no data available for gemifloxacin

other FQ 60-90 %

N

C

O

FO-

O

N


49/53

Resistance: do not forget the correct


50/53

Resistance: do not forget the correct

dosing...

Inadequate dosing of antibiotics is probably an important reason fomisuse and subsequent risk of resistance. A recommendation on

proper dosing regimens for different infections would be an

important part of a comprehensive strategy. The possibi lity to

produce such a dose recommendation based on pharmacokineticand pharmacodynamicconsiderations wil l be further investigated in

one of the CPMP working parties

European Agency of the Evaluation ofMedicinal Products(London)

EMEA discussion paper

on Antimicrobial resistance3 January 1999 EMEA/9880/99

Pharmacokinetic parameters in relation with efficacy


51/53

p y

Dose Cmax MIC for AUC MIC for

(mg) (mg/l) pk/MIC=10 (mg.h/l) AUIC=125

norflo 400 (X2) 1.6 0.2 14 0.1

peflo 400 (X2) 4.6 0.4 108 1.0

cipro 500 (X2) 1.5 0.2 17 0.1

oflo 200 (X2) 3.1 0.4 66 0.4

levoflo 500 8.7 0.8 73 0.4

grepa 600 1.4 0.1 20 0.2

gati 400 4.5 0.4 28 0.2

trova 200 2.3 0.2 25 0.2

moxi 400 2.5 0.2 30 0.2gemi 600 4 0.4 24 0.2

I di ti f fl i l


52/53

Consider local epidemiology, and do not believe it is

always a first choice

The use of the FQ should focus on infections in which

there is a differential benefit over conventional agentsin terms of efficacy, safety, or cost;

in infections for which few alternative treatments exist,

or against organisms towards wich they are sufficiently

active to prevent the rapid emergence of resistance.

Indications of new fluoroquinolones

Sh ll h b i ht f t ?


53/53

Shall we have a very bright future ?

or some

problems ?

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