Synthesis and biological evaluation of new 4-carboxyl

quinoline derivatives as cyclooxygenase-2 inhibitors

Bioorganic and Medicinal Chemistry
2009(17)-5312-17
AfshinZarghi, RaziehGhodsi, EbrahimAzizi, Bahram Daraie, Mehdi Hedayati,
Orkideh G.Dadrass

Journal Club Presentation

By

G. Lakshma Reddy
 Introducti
on

1. Arachidonic acid (AA)

2.
3. Cyclooxygenase (COX)
4.
5. Prostaglandins(PGs)
6.
7. Inflammation
 Arachidonic acid (AA)

•
• Arachidonic acid(AA) is a Unsaturated ω-6 fatty acid found in peanut oil.

•
•

 Cyclooxygenase (COX)

Ø An enzyme responsible for the production of prostaglandins

from Arachidonic Acid.
Ø
Ø At present, three COX isoenzymes are known.
Ø
Ø Three forms: COX1 ,COX2 and COX3
Ø
Ø COX-1 and COX-2 are of similar molecular weight,
approximately 70 and 72 kDa respectively.
Ø
Ø COX-1 and COX-2 are having 65% amino acid sequence
homology and near-identical catalytic sites.
Ø
Ø


Ø COX-1 is responsible for the baseline levels of prostaglandins.

Ø
Ø COX-2 produces prostaglandins through stimulation.
Ø
Ø However, while COX-1 and COX-2 are both located in the
blood vessels, stomach and the kidneys, prostaglandin levels
are increased by COX-2 in scenarios of inflammation.
Ø
Ø The most significant difference between the isoenzymes, which
allows for selective inhibition, is the substitution of isoleucine
at position 523 in COX-1 with valine in COX-2 His at
position 513in COX-1 with Arg in COX-2 etc.
Different pathways for Cox 1 and Cox 2
• The enzyme contains two active sites:
• A heme with peroxidase activity, responsible for the reduction of PGG2 to
PGH2, and a cyclooxygenase site, where arachidonic acid is converted
into the hydroperoxy endoperoxide prostaglandin G2 (PGG2). The
reaction proceeds through H atom abstraction from arachidonic acid by
a tyrosine radical generated by the peroxidase active site. Two O2
molecules then react with the arachidonic acid radical, yielding PGG2.
Ø Prostaglandin H2 is the precursor for D,E & F
Ø Production of PGE2is the type of prostaglandin
most associated with inflammation

PGD2 PGE2

PGF2α PGI2
 PROSTAGLANDINS

Ø Like hormones they act as chemical messengers

Ø
Ø Do not move to other sites
Ø
Ø Work right within the cells where they are synthesized
Ø
Ø Control processes including constriction of muscle & blood
 vessels aggregation of platelets


Ø Constriction of uterus during delivery & strengthen pain

signals & induce inflammation
Ø
 Inflammation
Inflammation is a response of a tissue to injury, often injury caused

by invading parasites. It is characterized by

Ø ØIncreased blood flow to the tissue causing
Ø
Ø Increased temperature
Ø
Ø Redness
Ø
Ø Swelling and pain.
 Non Steroidal Anti-Inflammatory Drugs
O OH

Ibuprofen

Naproxen
Research attempts in the discovery of selective COX-2 inhibitors
have produced many classes of compounds such as coxibs
possessing desired selectivity

Celecoxib Rofecoxib Valdecoxib

 The recent market withdrawal of some coxibs such as
rofecoxib(2004) and valdecoxib(2005) due to their adverse
cardiovascular side effects

5-methoxy-2-(4-(methyl sulfonyl) 4-carboxyl quinoline derivatives

phenyl)-1H-indole
Doebner reaction

O NH 2 COOH
O
H + OH EtOH, reflux,
+
12h
MeS O N

16-27 SMe
COOH

oxone , THF/H2O
25 C ,12h
N

SO2 Me

Pfitzinger reaction
COOH
O O
EtOH ,33%KOH
+ O ref lux ,48h
N N
MeO2 S H
43% SO2 Me
 Mechanism
COOH COO-
O O O SO2 Me
OH- OH O O
O OH-
O- NH-
N N NH -
H H

-OOC - COO -
COO
O O H
O
H 2O H H HO-
_ _
OH- N H 2O N
N - SO 2Me
H O SO 2Me OH
H SO2Me
HO-

- OOC
-OOC
O -
OOC O- OH
H 2O OH-
H
_
- OH- -H 2O
N
_ N N
SO 2Me SO2Me
SO2Me

COOH
-
OOC OH COO - 5 4
9
Protic Workup 6 3

N- _
_ OH- N 7
SO 2Me 10 N 2
SO2Me 8 1
SO2Me
 COOH

SO2Me

7, 8, 9,10-tetrahydro-2-(4-(methylsulfonylphenyl)benzo[h]quinoline-4--carboxylic acid
Molecular modeling study
7,8,9,10-tetrahydro-2-(4-(methylsulfonylphenyl)benzo[h]quinoline-
4--carboxylic acid

It was identified as potent and high selective COX-2inhibitor (COX-2

IC50 = 0.043 µM,; selectivity index > 513) that was more potent
than the reference drug clecoxib (COX-2 IC50 = 0.060 µM, SI = 405)

 A molecular modeling study where (9e) was docked in the binding

site of COX-2 showed that the p-MeSO2 substituent on the C-2
phenyl ring is oriented in the vicinity of the COX-2 secondary
pocket (Arg513, Phe518 and Val523) and the carboxyl group can
interact with Arg120. The structure activity data acquired indicate
that the presence of lipophilic substituents on the C-7 and C-8
quinoline ring is important for COX-2 inhibitory activity.
 Conclusions

1.The 4-carboxyl qunoline moiety is a template to design COX-1/-2 inhibitors.

2.
3.
4.In this class of compounds COX-1/-2 inhibition is sensitive to the lipophilic
nature of the C-7 and c-8 quinoline substituents.

3. 7,8,9,10-tetrahydro-2-(4-(methylsulfonylphenyl)benzo[h]quinoline-4--carboxylic
acid exhibited high COX-2 inhibitory potency and selectivity.
1.
 Omega 6 Fatty Omega 3 Fatty
Acid Acids
(Linoleic Acid) (alpha-linolenic acid)

Gamma-linolenic
acid Eicosapentaenoic Acid
(GLA) (EPA)
Evening Primrose Oil
Borage Oil
Black Current Oil
COX

Arachidonic Acid
Prostaglandins Less
PGE1, PGE3 Inflammatory
(Favorable) Leukotrienes

COX Lipoxygenase
Docosahexaenoic acid
Prostaglandins (DHA)
Leukotrien
(PGE2)
Inflammatory
02/11/10 es
THANKS