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1.
Synthetic antibacterial agents
Chloramphenicol
 First, isolated from streptomyces bacteria in 1947.
 Due to its simple structure, nowadays it is widely
produced in large scale by chemical synthesis from Pnitroacetophenone.
 It has a bacteriostatic action, inhibiting bacterial
protein biosynthesis…. Believed to be through
inhibiting the elongation step.
 It has a broad spectrum of activity, but because of its
serious systemic toxicity (aplastic anemia), it is mainly
used topically for skin and eye infections.
Chloramphenicol
 Active on both gram +ve and gram –ve bacteria, even
on penicillin resistant strains such as H.influenza, N.
meningititis and S. pneumonia.
 It has a good penetration to CNS… used in meningitis.
 Not recommended in UTI (why?)… only 5-10% of the
unmetabolized chloramphenicol is excreted in urine.
 Bacteria became resistant to chloramphenicol through
the production of chloramphenicol acyltransferase
which acylate the OH group at C1 and C3 to the
inactive esters.
Metabolism of Chloramphenicol
SAR of Chloramphenicol
 P-nitro group can be replaced by other aryl ring or
oxygenated functional group without great loss in
activity.
 Phenyl ring can accept multi-substitutions.
 Conversions of 1-OH to keto group causes appreciable
loss inactivity.
Chloramphenicol esters
 They have better physicochemical properties than
Chloramphenicol which has both bitter taste and bad
water solubility.
Quinolones antibacterial agents
 Nalidixic acid is the lead compound for this group.
 According to the heterocyclic core can be divided into:
 Naphthyridines: nalidixic acid and enoxacin.
 Quinolines: norfloxacin, ciprofloxacin, ofloxacin,
lemofloxacin.
 Cinnolines: Cinoxacin
Quinolones antibacterial agents
 Spectrum of activity:
 Highly active against urinary tract pathogens such as E.
coli, Klebsiella, Citrobacter, proteus as well as salmonella
and shigella.
 Most except fluoroquinolones are not active on P.
aeruginosa and H. influenza.
 Inactive on anaerobic and gram +ve bacteria.
 Pharmacokinetics:
 They have good oral bioavailability.
 They reach urine in enough concentration to be effective
in UTI (>40%).
Quinolones antibacterial agents
 Mechanism of action:
Inhibit DNA synthesis by inhibiting DNA gyrase
(topoisomerase-II) which is important for DNA
supercoiling.
 Transport into bacterial cell: mainly through the porin
channels of the gram –ve bacteria.
 Mechanisms of bacterial resistance:
 Mutation in porin channels.
 Energy dependant efflux mechanism.
SAR of Quinolones
 The carboxylic acid at C3 is essential for activity.
 Pyridone ring must be annulated with aromatic ring
such as in Naphthyridine, Quinolines and Cinnolines.
 Isosteric replacement of nitrogen for C2, C5, C6 or C8
resulted in retained activity.
 Substitution at C2 greatly reduces or abolishes activity.
 Positions 5,6,7 and 8 can be substituted for better
efficacy
SAR of Quinolones
 Positions 5,6,7 and 8 can be substituted for better
efficacy:
 Piperazine ring and 3-aminopyrrolidine at C7 enhances
activity, mainly against P. aeruginosa.
 Fluorine atom at C6 also improved activity
(Fluoroquinolones).
 Alkyl substitution on C1 improves activity (but small
alkyl or aryl group).
 Ring condensation at 1-8, 5-6, 6-7 and 7-8 also lead to
better activity.
Fluoroquinolones
 They are 6-fluoro-7-piperazinoquinolones derivatives.
 They exhibit extended spectrum of activity that covers
most of gram +ve and gram –ve bacteria especially P.
aeruginosa.
 Members:
 Ciprofloxacin.
 Norfloxacin.
 Ofloxacin.
 Pefloxacin.
 Lomefloxacin.
 Enofloxacin.
 Levofloxacin.
Chemical structure of
Fluoroquinolones
 Have an acidic (3-carboxylic acid) and basic
(piperazinyl) group, this makes these compounds
present as zwitterionic species at physiological pH.
 Like tetracyclines, they have chelating properties due
to the presence of β-diketo structure. They can form
stable, insoluble metal complexes with di and trivalent
metal ions:
 They should not be given along with antacids
and mineral supplements.
 formation of this chelate will reduce the
oral availability of these agents.
Chemical structure of
Fluoroquinolones
 Fluorine atom at C6 increases potency against gram –
ve bacteria.
 The piperazinyl group at C7 improves antipsuedomonal activity of Fluoroquinolones.
 Chelation also has another –ve effect: the possibility to
chelate with urine ions (Mg++ and Ca++) which leads to
crystalluria
Renal failure sometimes.
Enoxacin
 Well absorbed following oral administration (90%).
 Well distributed through the body… reaches kidney,
prostate and cervix.
 Used mainly in prostatitis.
Ciprofloxacin
 40-50% excreted unchanged in urine.
 Highly distributed to all body fluids including CS fluid.
 Highly potent against gram –ve especially P. aeruginosa
(why?).
 Used in gastroenteritis, skin, soft tissues (bone and joints)
infections and UTI.
Ofloxacin
 Has 1,4-oxazine ring.
 Has better penetration to CNS than ciprofloxacin
(why?).
 The structure has asymmetric carbon atom, normally
ofloxacin is given as racemate, although the 3S(-)
isomer is 125x more active than the 3R(+) isomer.
 Recently the 3S(-) isomer (Levofloxacin)
has been prepared and now marketed
instead of ofloxacin which is more potent
(Chiral switching phenomenon)
Lomefloxacin
 Has longer duration of action (t1/2 =7-8hrs), this is believed
to be due to:
 Excellent tissue distribution.
 Efficient renal reabsorption.




The only one that is given once daily.
It has an excellent oral bioavailability (98%).
Mainly used in acute bronchitis.
High incidence of phototoxicity due to the presence of two
fluorine atoms.
 Phototoxicity: is the formation of highly reactive oxygen
radicals due to the exposure to light.
Sparfloxacillin
 Higher potency against gram +ve
Staphylococcus and streptococcus bacteria.
 More active on anaerobic bacteria and Chlamydia.
 Long t1/2 (= 18hrs)
 Has the lowest incidence for phototoxicity.
New generation fluoroquinolones
 Gemifloxacin:
 is an oral broad-spectrum
quinolone antibacterial agent.
 Active against both gram +ve and gram –ve
bacteria except P. aeruginosa.
 used in the treatment of chronic bronchitis and mild-tomoderate pneumonia.
 Has a protein binding of 60-70%.
 Only 5-10% of the drug will be metabolized in the body
to give the N-acetyl and the glucuronide conjugate.
New generation fluoroquinolones
 Moxifloxacin:
 Considered a fourth generation quinolones.
 Given orally, parenterally and as eye
drops for treatment of conjunctivitis
(Bayer).
 Uses:




Chronic bronchitis.
Acute bacterial sinusitis.
Pneumonia.
Skin infections.
 20% excreted unchanged in urine and 25% in feces.
 More than 50% of the drug metabolized to the sulfate and
glucuronide conjugates.