ANTIBACTERIAL AGENTS

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ANTIBACTERIAL AGENTS Quinolones
Fluoroquinolones Ref Wilson and Gisvolds
Textbook of Organic Medicinal and Pharmaceutical
Chemistry, 10th ed., 1998
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Quinolones and Fluoroquinolones

• The quinolones and fluoroquinolones are
  relatively late arrivals on the antibacterial
  scene. But they are proving to be very useful
  therapeutic agents.
• They are particularly useful in the treatment of
  urinary tract infections and also for the
  treatment of infections which prove resistant to
  the more established antibacterial agents.

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Mechanism of Action

• The quinolones are rapidly bactericidal.
• They inhibit DNA gyrase and topoisomerase IV.
• Thus they inhibit the packing of DNA and the
  further ability of replication and transcription.

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4
SAR

• The pyridone system must be annulated with an
  aromatic ring.
• Introduction of substituents at position 2
  greatly reduces or aboloshes activity. Positions
  5, 6, 7 and 8 of the annulated ring may be
  substituted to good effect.
• Fluorine atom substitution at position 6 is
  associated with significantly enhanced
  antibacterial activity.

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SAR

• Alkyl substitution at the 1-position is essential
  for activity, with lower alkyl (methyl, ethly,
  cyclopropyl) compounds generally having
  progressively greater potency.
• Aryl substitution at the 1-position is also
  consistent with antibacterial activity.

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Quinolone activity/Generations

• Early quinolones, such as nalidixic acid, had
  poor systemic distribution and limited activity
  and were used primarily for gram-negative urinary
  tract infections.
• The fluoroquinolones (i.e., ciprofloxacin,
  ofloxacin, norfloxacin, lomefloxacin, and
  enoxacin), were more readily absorbed and
  displayed increased activity against
  gram-negative bacteria.
• Newer fluoroquinolones (i.e., levofloxacin,
  sparfloxacin, trovafloxacin, and grepafloxacin)
  are broad-spectrum agents with enhanced activity
  against many gram-negative, gram-positive and
  anaerobic organisms.

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Quinolones Fluoroquinolones
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The first generation fluoroquinolones

• The quinolones are divided into generations
  based on their antibacterial spectrum. The
  earlier generation agents are generally more
  narrow spectrum than the later ones.

• Norfloxacin
• Pefloxacin
• Ofloxacin
• Ciprofloxacin
• Levofloxacin

Nalidixic acid Oxolinic acid Flumequine
Pipemidic acid

• Improved anti-Gram (-)

Twice as active as ofloxacin per g
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Ciprofloxacin
http//www.cipro.com/en/home.html

• 19 years ago, Bayer Pharmaceuticals introduced
  the first broad spectrum oral fluoroquinolone,
  Ciprofloxacin (Cipro, Ciproxin). Cipro is
  available in more than 100 countries and has been
  approved for the treatment of 14 types of
  infections, especially urinary tract infections
  (UTIs) such as acute uncomplicated cystitis,
  pyelonephritis, and chronic bacterial
  prostatitis.
• Cipro is considered the "gold standard" therapy
  for many types of Gram Negative infections,
  including Pseudomonas aeruginosa, and has
  maintained a high level of activity against
  Escherichia coli compared to other agents used
  for UTIs.
• Cipro's 19 year history includes
• Extensively studied and documented in over 37,000
  publications
• More than 100,000 patients enrolled in double
  blind trials around the world
• Prescribed for more than 340 million patients
  worldwide
• Extensive and unprecedented safety profile

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The second generation fluoroquinolones

• Temafloxacin a
• Sparfloxacin b
• Grepafloxacin c
• Gatifloxacin d

• anti-Gram (-)
• Improved anti-Gram ()

anti-anaerobe
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a Toyama, 1988 (?) b Dainippon, 1985-1987 c
Otskuda, 1989 d Kyorin, 1988
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The third generation fluoroquinolones

• Trovafloxacin b
• Moxifloxacin c
• Clinafloxacin a
• Gemifloxacin d

• anti-Gram (-)
• anti-Gram ()
• anti-anaerobe

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aKyorin, 1987 b Pfizer, 1993 c Bayer, 1994
d LG Chemical Ltd., S. Korea, 1994-98
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Toxicity

• 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

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SAR of frequent side effects

• Complexation with metallic ions (Fe, Al, Mg, Ca)
• Common to all fluoroquinolones.
• Complexation provides the basis for their
  incompatibilities with antacids, hematinics, and
  mineral supplements containing divalent or
  trivalent metals.
• Phototoxicity
• Quinolones possessing a halogen at the 8-position
  (e.g., lomefloxacin) have the highest incidence
  of phototoxicity.
• Those having an amino (e.g., sparfloxacin) group
  or methoxy group at either the 5- or the
  8-position have the lowest incidence.
• CNS toxicity (binding to GABA receptor)
• The relatively low incidence (lt1) of CNS effects
  associated with quinolones has been attributed to
  antagonism of amino butyric acid (GABA) receptors
  in CNS.
• Only fluoroquinolones having a piperidino, a
  3-amino-1pyrrolidino, or similar basic moiety at
  7-position appear to have this property.

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SAR of frequent side effects
Amino group ? Photoxicity
Spar
piperidino, 3-amino-1pyrrolidino, or similar
basic moiety CNS side effects
Ca, Al, Fe complexation
All FQs
? Photoxicity
flero, lomeflo
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Mechanism of Resistance

• Mutations in the enzymes (DNA Topoisomerase II
  Gyrase) that the drug binds.
• Increase in the bacterial ability to pump the
  drug out of the cell.
• Mutations that cause a change in the outer
  membrane porin proteins of Gram-negative
  organisms which lead to decrease in the ability
  of the drug to get into the cell.

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