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Antibacterial activity of quinolones is determined by:
- Activity
against DNA gyrase and topoisomerase IV targets.
- Susceptibility
to efflux pumps.
- The
route(s) by which the molecule penetrates into the cell,
particularly whether it is porin dependent.
Much
is known about the structure activity relationships of the
quinolones:
- Quinolones
bind to DNA gyrase via the carboxy group at C3 in the
4-quinolone ring so these are essential for activity.
- This
carboxy group may also be responsible for chondrotoxicity
as the same part of the molecule chelates cations like
Mg2+.
- A
methoxy group at C8 increases lethality particularly in
Gram-positive bacteria.
- Substituents
at other positions, such as C7, affect Gram-negative potency,
pharmacokinetics, CNS effects and drug interaction.
- Quinlolones
with fluorine at the C6 position are the most potent by
1-2 orders of magnitude, but also associated with chondrotoxicity.
However,
the structure activity relationships are very complex and
not fully understood.
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