Medicinal Chemistry of Quinolones

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Medicinal Chemistry of Quinolones
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First Generation of Quinolones (FGQs)

• Synthetic compounds consisted of an N1 alkylated
  1,4-dihydro-4-oxo-3-pyridinecarboxylic acid fused
  to a substituted aromatic ring.
• The first quinolone introduced to clinic in 1962
  to fight against G(-) urinary infections

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• Other FGQs after 1962 were stronger, with broader
  spectrum of activity with Oxolinic acid and
  Cinoxacin as examples

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Mechanism of action of quinolones

• The bactericidal action of nalidixic acid and its
  congener is the result of the inhibition of DNA
  synthesis. It is due to the inhibition of
  bacterial DNA gyrase (topoisomerase).
• DNA gyrase is responsible for introducing
  negative supercoil into circular duplex DNA.
• Negative supercoiling relieves the torsional
  strain of helical DNA, facilitating unwinding,
  and thereby, allows transcription and replication
  to occur.

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SAR of Quinolones

• 1,4-dihydro-4-oxo-3-pyridinecarboxylic acid
  portion is necessary for the antibacterial
  activity.
• The pyridone ring must be attached to an aromatic
  ring, in which isosteric substitution of carbon
  with nitrogen still remaines the activity.

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SAR continued

• Isosteric substitution of carbon with nitrogen
  still remains the activity.

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SAR continued

• N1-Substitution is necessary for antibacterial
  activity. Small alkyl or cycloalkyl groups
  increase it cyclopropylgtethylgtmethyl

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SAR continued

• N1- Aryl substitution still remains the activity,
  sometimes optimises it.

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SAR continued

• Substitution at C2 position decreases the
  activity remarkably or changes the antibacterial
  characters.
• Substitution at C5 , C6 , C7 and especially at C8
  has good effects on the activity.
• C6 fluorine substitution increases the activity
  prominently, Thats why quinolones are also
  called fluoroquinolones.
• Substituted or unsubstituted piperazinyl or
  pyrolidinyl groups at C7 increase the activity
  against p.aeroginosa

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SAR continued

• Ring fusion at C1and C8 C5 and C6 C6 and C7 or
  C7and C8 introduces active compounds

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Why Fluoroquinolones cause CNS toxicity?

• Tremor, sleep disorders, anxiety, and convulsions
  because of GABA antagonism at the receptor.
• Because of low penetration to brain this toxicity
  is rare.

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How Fluoroquinolones cause metal comlexation?

• This occurs with cations such as Ca2, Zn2,
  Fe2, Fe3, Bi3. Thats why there is an
  interaction between quinolones and mineral
  containing drugs.
• Since this complexes are water insoluble, and
  there are bivalent metal ions in the urine,
  fluoroquinolones cause crystalluria.

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