STRUCTURE–ACTIVITY RELATIONSHIP
OF quinolones
1
The essential pharmacophore for activity is the carboxy-4-pyridone
nucleus. The pyridone system must be annulated with an aromatic
ring. Apparently, the carboxylic acid and the ketone are involved in
binding to the DNA/ DNA-gyrase enzyme system.
2
Reduction of the 2,3-double bond or the 4-keto
group inactivates the molecule,
O
5
R6 6 3 COOH
4
7
1 2
R7 X N
8
R1
GENERAL STRUCTURE
3
substitution at C-2 interferes with enzyme–substrate
complexation.
O
5
R6 6 3 COOH
4
7
1 2
R7 X N
8
R1
GENERAL STRUCTURE
4
Fluoro substitution at the C-6 position greatly improves antimicrobial
activity by increasing the lipophilicity of the molecule, which in turn
improves the drug’s penetration through the bacterial cell wall. C-6
fluoro also increases the DNA gyrase/topoisomerase IV inhibitory
action.
O
F COOH
HN N N
CIPROFLOXACIN
5
An additional fluoro group at C-8 further improves
drug absorption and half-life, but also increases
drug-induced photosensitivity.
O
F COOH
H3C
HN N C N
F
H3C SPARFLOXACIN
6
Substitution of a methoxy group at C-8 reduces the
photosensitivity (moxifloxacin and gatifloxacin).
O
F COOH
HN N C N
OCH3
H3 C
GATIFLOXACIN
7
Heterocyclic substitution at C-7 improves the spectrum of activity especially against gram
negative organisms. The piperazinyl (ciprofloxacin) and pyrrolidinyl (moxifloxacin)
represent the most significant antimicrobial improvement. Unfortunately, the piperazinyl
group at C-7 also increases binding to central nervous system (CNS) γ-aminobutyric acid
(GABA) receptors, which accounts for CNS side effects. Alkyl substitution on the
piperazine nitrogen (ofloxacin and levofloxacin) is reported to decrease binding to GABA.
O
F COOH
O
HN N N F COOH
H
N
N N
CIPROFLOXACIN
OCH3
MOXIFLOXACIN
8
O
F COOH
HN N N
CIPROFLOXACIN
O
F COOH
H 3C N N N
O
CH3
OFLOXACIN
9
Alkyl substitution at the 1-position is essential for
activity, with lower alkyl (methyl, ethyl,
cyclopropyl) compounds generally having
progressively greater potency.
O O
F COOH F COOH
HN N N HN N N
C2H5
CIPROFLOXACIN NORFLOXACIN
10
The cyclopropyl substitution at N-1 appears to
broaden activity of the quinolones to include
activity against atypical bacteria including
Mycoplasma, Chlamydia, and Legionella species.
O
F COOH
HN N N
CIPROFLOXACIN
11
Substitution of a 2,4-difluorophenyl at N-1 also improves
antimicrobial potency, but agents with this substitution (trovafloxacin
and temafloxacin) have been withdrawn from the market due to
serious adverse effects.
O
5
R6 6 3 COOH
4
7
1 2
R7 X N
8
R1
GENERAL STRUCTURE
12
The introduction of a third ring to the nucleus of the quinolones gives
rise to ofloxacin. Additionally, ofloxacin has an asymmetric carbon at
the C-3′ position. The S-(−)- isomer (levofloxacin) is twice as active
as ofloxacin and 8 to 128 times more potent than the R-(+)-isomer
resulting from increased binding to the DNA gyrase.
O
F COOH
H3C N N N
O
CH3
OFLOXACIN
13
Thank you
14
