Fluoroquinolones: from structure to activity and toxicity

St Niklaas, Belgium, December 11th, 1999

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Table of Contents

PPT Slide

Mechanism of action of fluoroquinolones: the basics...

2 key enzymes in DNA replication:

Ternary complex DNA - enzyme - fluoroquinolone

Resistance to fluoroquinolones: the basics

Fluoroquinolones are the first entirely man-made antibiotics: do we understand our molecule ? 

Chemistry and Activity

The pharmacophore common to all fluoroquinolones

From chloroquine to nalidixic acid... 

From nalidixic acid to 1st generation

From nalidixic acid to 1st generation

From nalidixic acid to 1st generation

From nalidixic acid to 1st generation

"1st generation" fluoroquinolones

The "first generation" of fluoroquinolones 

From ofloxacin to levofloxacin...

The "first generation" of fluoroquinolones and beyond... 

From first to second generation of fluoroquinolones 

From second to third generation of fluoroquinolones 

Maintenance of anti - Gram (-) activity

Gram (-) activity (E. coli)

Improving Gram (+) activity (S. pneumoniae)

Activity against S. pneumoniae

Activity against anaerobes ...

Activity against B. fragilis

Is there a SAR for emergence of resistance ?

Is there a SAR for emergence of resistance ?

Fluoroquinolones with a C8-methoxy

Toxicity

Frequent side effects of fluoroquinolones: is there a SAR ?

SAR of frequent side effects

Fluoroquinolones with low or no drug interactions..

Fluoroquinolones with high phototoxicity ...

Rare side effects of fluoroquinolones:

Rare side effects of fluoroquinolones: cardiac toxicity

Cardiac toxicity QT prolongation: is there any SAR ?

Cardiac toxicity QT prolongation: is there any SAR ?

Other severe toxicities

Which part of the molecule is the culprit ?

Pharmacokinetics

SAR of pharmacokinetic parameters

SAR of main pharmacokinetic parameters: how to get a long half life

SAR of main pharmacokinetic parameters: biodisponibility

SAR of main pharmacokinetic parameters: volume of distribution

Resistance: do not forget the correct dosing...

Pharmacokinetic parameters in relation with efficacy

Indications of new fluoroquinolones

Shall we have a very bright future ?

Author: Paul M. Tulkens 

Email: tulkens@facm.ucl.ac.be

Home Page: http://www.md.ucl.ac.be/facm