The document discusses urinary tract anti-infective agents, specifically fluoroquinolone antibiotics. It notes that these broad-spectrum antibiotics are often used to treat urinary tract infections (UTIs) and hospital-acquired infections associated with urinary catheters. The document provides details on the four generations of fluoroquinolones and their mechanisms of action, inhibiting bacterial DNA replication through effects on DNA gyrase or topoisomerase IV enzymes. It also discusses the structure-activity relationships of fluoroquinolones and summarizes clinical uses and dosages for treating various bacterial infections.

1. UrinaryTractAnti-infectiveagents

2. Synthetic anti- bacterial agents used
mainly for urinary tract infections.
Many drugs are used to control urinary
tract infections because of their
ability to develop concentration in
urinary bladder, adequate to inhibit
the growth of infective organisms.

3. • Fluoroquinolones are broad-spectrum antibiotics
(effective for both gram-negative and gram-
positive bacteria)
• They play an important role in treatment of
serious bacterial infections, especially hospital-
acquired infections and others in which
resistance to older antibacterial classes is
suspected.
• Fluoroquinolones are often used for
genitourinary infections, and are widely used in
the treatment of hospital-acquired infections
associated with urinary catheters .

6. FIRST GENERATION
SECOND GENERATION
THIRD GENERATION
FOURTH GENERATION

7. • Nalidixic acid ,Cinoxacin ,Rosoxacin
FIRST GENERATION
• Norfloxacin, Ciprofloxacin, Ofloxacin , Sparfloxacin , Enoxacin
SECOND GENERATION
• Balofloxacin Levofloxacin Temafloxacin
THIRD GENERATION
• Clinafloxacin Gatifloxacin Gemifloxacin Moxifloxacin
FOURTH GENERATION

8. • Eg- Nitrofurantion, Nitrofurazone
• Eg- Methenamine

10.  Quinolones exert their antibacterial effect by preventing bacterial DNA from
replication and transcription.
 Quinolones inhibit the bacterial DNA gyrase or the topoisomerase IV enzyme,
thereby inhibiting DNA replication and transcription.
 For many gram-negative bacteria DNA gyrase is the target, whereas
topoisomerase IV is the target for many gram-positive bacteria.
 The majority of quinolones in clinical use belong to the subset fluoroquinolones,
which have a fluorine atom attached to the central ring system, typically at the 6-
position or C-7 position are effective against both gram –ve and +ve bacteria.

13. • General pharmacophore required
are
• 4- pyridine-3- carboxylic acid
• Ring attachment at C5 and C6
• Reduction of 2,3 double bond
reduces activity
• Fluorine at C6 is essential for
DNA topoisomerase enzyme of
bacteria

14.  Pyridone system must be annulated with an aromatic ring.
 Isosteric replacement of Nitrogen for carbon atoms at some positions are
consistent and retain the anti- bacterial activity.
a) at position 2- cinnolines [cinoxacin]
b) at position 5- 1,5 naphthyridines
c) at position 6- 1,6 naphthyridines
d) at position 8- 1,8 naphthyridines
 Substituents at position 2 greatly reduces or abolishes activity.
 Substituents at positions 5,6,7 & 8 of the annulated ring produce good
effects.
 Substitution at position 6 with fluorine atom significantly enhances the
activity.
 Alkyl substitution at position 1 [one] is essential for activity and lower
alkyl grps have greater potency.

15. SAR
Position 1:
• Side chain attached to Ring N affects activity
• Initially short chain alkyl substuents were used like
ethyl,latter cyclopropyl,ethyl fluro, oxetane improved
the activity against gram possitive bacteria.
• Connecting N-1 and C8 displayed increased activity as
well as good bioavailability and increased half life .eg
Ofloxacin

16. SAR
Position 2,3
• Not much changes were made in carboxylic acid as
it binds to DNA gyrase of bacterial cell.
• Any change reduces activity
• Replacement of 3-carboxylic acid with isothiazole
produced more potent drug but had poor solubility

17. SAR
Position 5
• Bulky substituents reduces activity , whereas methyl and
amino substituents increases activity,eg, grepafloxacin,
sparfloxacin

18. SAR
Postiion 7
• Attachment of hetrocyiclic ( piperazine,3,4 dimethyl piperazine, , amino
pyrolidines)with nitrogen improves activity agt gram –ve baceria. Also
pharmacokinectic properties.
Eg:grepafloxacin, sparfloxacin
• Bicylic substituents also retain acitivity eg Trovafloxacin

19. SAR
Position 8
• Fluorine /chlorine substituents increase activity
• Methoxy group at C8 shows good activity
Eg gatifloxacin and moxifloxacin.
• Replacing C with N at this position retains activity

22. • Old quinolones … Nalidixic acid (1962)
– No systemic antibacterial level
– Effective against gram –ve bacteria that cause
urinary tract infection.(E.Coli,P
enterobacter,Klebsiellbactericidala,)
– These are bactericidal
– They inhibit DNA gyrase enzyme.
– These are 1,8 napthyridine derivative

23. Orally active antibacterial agents
Al similarity to
Structurally similarity to nalidixic acid
63% is bound to plasma protiens

24. Treatment for urinary tract infections caused
by E-coli
1-ethyl-6 fluro-4-oxo-7-piperazin-1-yl-1H-
qinoline-3-carboxylic acid

29. Adverse effects
• Nausea, vomiting, abdominal pain, headache, vertigo, visual
disturbance, hallucination,urticaria,

30. 1-(5-nitrofurfurylidene)amino] hydantoin.

32. SYNTHESIS
5- Nitro-2-furfuraldehyde
+
1-amino hydantoin
Condensation
-H2O

33. Adverse effects:
Nuasea, stomach upset epigastric
distress
Crystalluria.
Contraindicated in renal
insufficiency

34. Clinical uses
• UTI
– norfloxacin 400 mg bid, ciprofloxacin 250-500
mg bid, ofloxacin 200-400 mg bid,
levofloxacin 250 mg OD, lomefloxacin 400 mg
OD, gatifloxacin 400 mg single dose
• Bacterial diarrhea
– norfloxacin 400 mg bid, ciprofloxacin 500 mg
bid
• Gonococcal infection
– norfloxacin 800 mg single dose, ofloxacin 300
mg bid, ciprofloxacin 500 mg single dose,
lomefloxacin 400 mg single dose, gatifloxacin
400 mg single dose