1. FLUOROQUINOLONES
Quinolones comprise of synthetic anti-bacterial agent, naphthyridine derivative introduced in the treatment of UTI.
Clinical usefulness of quinolones is due to good oral absorption, activity against gram negative urinary pathogens and comparatively higher concentration in urine than that of plasma or tissue conc.
Nalidixic acid is the first member quinolone class drugs.
Quinolone comprise of synthetic N-1 alkylated -3-carboxy-prid-4-one ring.
Discovery of fluoro group at C6 position of basic nucleus greatly increase the biological activity.
The agents that possess C6 F group are referred as fluoroquinolones.
Nalidixic acid shows antibacterial activity against gram negative bacteria whereas new members of this class possessing 6-fluoro-7- piperazinyl ring substitution are active against both gram positive and gram negative bacteria.

3. Classification Nalidixic acid Ciprofloxacin Lomefloxacin Levofloxacin
First generation
Nalidixic acid
Second generation
Ciprofloxacin
Lomefloxacin
Levofloxacin
Norfloxacin
Third generation
Gatifloxacin
sparfloxacin

5. MECHANISM OF ACTION
Bactericidal action is result of inhibition of DNA synthesis.
This is due to inhibition of bacterial DNA Gyrase enzyme responsible for introducing negative supercoil into circular DNA.
Negative supercoiling relieve torsional stress of unwinding helical DNA thereby allow transcription and replication.
DNA gyrase is a tetrameric structure which in turn have two subunits each, i.e. 2A and 2B subunits. The A and B subunits together bind to DNA, hydrolyze ATP, and introduce negative supertwists.
The A subunit carries out nicking of DNA, B subunit introduces negative supercoils, and then A subunit reseals the strands.
Fluoroquinolones bind to the A subunit and interfere with its strand cutting and resealing function.

10. STRUCTURE ACTIVITY RELATIONSHIP
1,4-dihydro-4-oxo-3-pyridine carboxylic acid is essential for activity.
Pyridone system must be annulated with aromatic ring.
Isosteric replacement of carbon atom with nitrogen at postion 2,5,6,8 retain the activity.
Substitution at C2 position greatly reduce or abolish the activity

11. Position 5,6,7,8 of annulated ring greatly retain activity.
Piperazinyl or 3-aminopyrrolidinyl substitution at 7 position enhance activity against P. aeruginosa.
Fluorine substiution at 6 position significantly enhance the activity.
Alkyl group substitution at N1 position is essential for the activity, only lower alkyl group have greater potency (methyl, ethyl, cyclopropyl).
Aryl substitution also consistent with anti-bacterial activity. 2,4-difluoro phenyl group provide optimum potency.
Ring condensation at 1,8-, 5,6-, 6,7-, 7,8- position also lead to active compound.(1,8-levofloxacin)

12. RESISTANCE
Highly polar fluoroquinolones enter the bacterial cell through charged porin channel in outer membrane.
Mutation lead to alter porin protein which lead to decrease in uptake of fluoroquinolnes and resistance develops.

13. ADVERSE EFFECT
It antagonise to the GABA causing irritaility, sleep disorder, vertigo, anxiety, aggitation, convulsions. Only fluoroquinolones having 1piperidino, 3-amino-pyrrolidinoo ring or basic moety at 7 position shows this property.
Phototoxicity/ extreme sensitivity to sulight shown by fluoroquinolones possessing halogen atom at 8 position. While fluoroquinolones which have amino or methoxy moiety eiher at 5 or 8 position have lowest incidence of phototoxicity.
First class Nalidixic acid possess only C3 carboxylic acid as ionisable group. Its Pka fall in the range of due to acid weakening effect by H-bonding with C4 carbonyl group.
Second class quinolones have Pka range because of presence of basic piperazino group at 7 position and F at 6 position.

14. Quinolones possess exellent chelating property so are incompatible with antacids, hematinics and mineral supplement containing divalent or trivalent metals. It form 1:1, 1:2, 1:3 chelate with metals are reduce its bioavailability.