Glossary

xxxii

PREFATORY NOTE

Melting points were determined by open glass capillary method on a

Cintex melting point apparatus and are uncorrected. IR spectra were

recorded on a Perkin-Elmer spectrometer using KBr pellets. 1H NMR

spectra were recorded on a Bruker ACF-300 machine and a Varian 300

and 400 MHz spectrometer using CDCl3 or DMSO-d6 with reference to

tetramethylsilane as an internal reference. 13C NMR spectra were

recorded on a 75 and 100 MHz spectrometer. Elemental analyses were

performed by Varian 3LV analyzer series CHN analyzer. Mass spectra

were recorded on a Jeol JMC D-300 instrument by using Electron

Ionization at 70 ev. All reactions were monitored by TLC on pre-coated

silica gel plates 60 F254 (Merck & Co, Germany) visualizing with UV or

iodine spray. Column chromatography was performed on 100-200 mesh

silica gel (SRL, India) using 10-20 times (by weight) of the crude product.

All the chemicals used are commercially available. Dry EtOH was

prepared from reagent grade material by conventional method. Petroleum

ether refers to the fraction of b.p. 60-80 oC.

Chapter-1

A brief review on pharmacological activities

of non steroidal anti-inflammatory drugs

(NSAIDs) and their derivatives

Chapter-1

2

1.1 INTRODUCTION

Non steroidal anti-inflammatory drugs (NSAIDs) are widely used for

the treatment of pain and chronic inflammatory ailments such as

rheumatoid arthritis.1 Inhibition of prostaglandin biosynthesis from

arachidonic acid via inhibition of cyclooxygenase (COX) enzymes is the

mechanism of action of NSAIDs which leads to the anti-inflammatory,

analgesic and pain reducing activities (figure 1.1). COX enzymes exist in

two isoforms COX-1 and COX-2. The prostaglandins involved in

inflammatory processes are produced by COX-2 where as COX-1

catalyses prostaglandins involved in house keeping like gastrointestinal

(GI) and renal function.

Arachidonic acid

COX-2COX-1

Nonselective NSAIDs

Cox-2 selective NSAIDs

Prostaglandins

Inflammation,fever and pain

GI cytoprotection,platelet activity

Prostaglandins

Figure 1.1: Effect of NSAID on arachidonic acid cascade

1.2 NEW BIOLOGICAL ACTIVITIES OF OLD NSAID MOLECULES

Since the last decade, there is a renewed interest in NSAIDs and

surprisingly this does not stem from their traditional properties or uses,

but as a result of new properties, which they may possess (figure 1.2).

Chapter-1

3

Figure 1.2: Off target effect of NSAIDs

1.2.1 Anticancer activity of NSAIDs

Chemopreventive effects of certain NSAIDs appear to be mediated

through both COX-dependent and independent pathways. A number of

molecular mechanisms responsible for this effect have been proposed.

One hypothesis is the obvious involvement of COX-2 inhibition but it is

clear that prostaglandin-independent mechanisms are also involved. It

was an unexpected finding from population-based studies that persistent

use of NSAIDs is coupled with reduced occurrence of colorectal cancer,2,3

esophageal and stomach cancer. Multiple pieces of evidence suggest that

COX-2 plays an important role in cell proliferation by inhibiting

apoptosis. Existing evidence also suggests that COX-2 becomes elevated

in tumour progression. Aspirin,4,5 piroxicam,6,7 sulindac8-10 or COX-2

selective inhibitors8 at doses ranging from 200 ppm and upward can

Chapter-1

4

reduce tumor incidence by 40-95 %. Different examples suggests that

COX independent pathway may also be operative11-14 for example,

NSAIDs and COX-2 selective inhibitors can suppress the growth of tumor

cells that do not express COX-2.14

Additionally, the rank order potency among NSAIDs to inhibit

prostaglandin synthesis does not match the potency to inhibit tumor cell

growth.15 In general, appreciably higher dosages of NSAIDs are required

to inhibit tumor cell growth compared to anti-inflammatory dosages.16

Celecoxib, a COX-2 selective inhibitor, shows strong chemopreventive

activity against mammary carcinoma in rats in some studies. The COX

inhibitor nimesulide is able to suppress the development of 2-amino-1-

methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced mammary gland

carcinogenesis in rats. The molecular structure of nimesulide was used

by Su et al.17 as a starting scaffold to design new sulfonanilide analogs

and examine the structural features that contribute to this anticancer

effect. A series of chemically diverse NSAIDs as listed in table 1.1 which

inhibit human HT29 colon tumor cell growth in vitro and also inhibit

COX-2.

Chapter-1

5

Table 1.1 Anti-tumor & COX-2 inhibiting activity of NSAIDs against

human HT29 colon cells

S.No. NSAID Structure Growth

IC50 (µM)

COX-2

IC50 (µM)

1 Aspirin

5000 13.9

2 Celecoxib

50 2.25

3 Diclofenac

160 0.05

4 Flurbiprofen

1800 6.42

5 Ibuprofen

975 >30

6 Indomethacin

180 0.46

7 Piroxicam

900 8.9

8 Sundilac sulfide

60 10.4

Chapter-1

6

1.2.2 Alzheimer’s disease (AD) lowering effect of NSAIDs

An extensive study held and published in the May 28, 2008, online

issue of Neurology, the medical journal of the American Academy of

Neurology says that the various NSAIDs like ibuprofen, naproxen, and

aspirin, all have the effect in reducing the risk of Alzheimer’s disease

(AD). AD is characterized by cerebral deposits of β-amyloid (Aβ) peptides

and neurofibrillary tangles (NFT) which are surrounded by inflammatory

cells. Epidemiological studies have shown that prolonged use of NSAIDs

reduces the risk of developing AD and delays the onset of the disease.18

a) Possible targets of NSAIDs in prevention of AD

Inhibition at doses of 1-10 µm

Inhibition at doses of > 50 µm

Arachidonic acid

COX 1&2 (↑)

Prostanoids

NF-KB (↓) PPAR-γ (↑)

Lipoxygenase( )

Leukotrienes

PPAR-α (↑)

Amyloid precurser pain

β−Secretase

γ−Secretase

Aβ 42 (↓)

COX-2Aβ

Inflammatory cytokines glutamate

b)

ALZHEIMER'S DISEASE

↔

Figure 1.3: Role of COX in Alzheimer’s disease

It has been postulated that some NSAIDs target AD by interacting

with several pathways, including the inhibition of COX and activation of

the peroxisome proliferator-activated receptor (PPAR)-γ (figure 1.3). A

variety of experimental studies indicate that a subset of NSAIDs possess

Aβ-lowering properties. While COX inhibition occurs at low

concentrations in vitro, the Aβ-lowering activity is observed at high

Chapter-1

7

concentrations. Therefore combination of anti-amyloidogenic and anti-

inflammatory activities of certain NSAIDs may produce a profile

potentially relevant to their clinical use as disease-modifying agents for

the treatment of AD.

1.2.3 Antibacterial effect of NSAIDs

Antibiotic resistance arising from the selective pressure generated by

excessive/inappropriate antibiotic use in human and veterinary practices

poses major challenges to the management of infection, particularly with

the scarcity of new antibacterial drugs. For this reason, there is

considerable interest in developing strategies to counteract multidrug

microbial resistance either as an independent pharmaceutical entity or

as an adjunct to existing treatment regimes. During inflammation in

response to infection, PGs of the E/D series elevate cAMP. Elevating

cAMP inhibits two pivotal steps in NADPH oxidase-mediated bacterial

killing, namely the phosphorylation as well as the translocation of the

cytosolic p47phox subunit to cell membrane. As NSAIDs classically

inhibit PG synthesis, it is not surprising that NSAlDs are increasingly

recognised to facilitate leukocyte killing of bacteria. To investigate this, a

series of experiments were carried out in mouse and in humans.19 It was

reported that inhibition of PGs synthesis and signaling enhances

bacterial killing in humans. NSAlDs do not interfere with the mode of

action of antibiotics but exert an additive effect when used in

combination with penicillin, for instance.

Chapter-1

8

NSAID acetaminophen interfere with growth of both Gram positive

and Gram negative bacteria in vitro and has inhibitory effect on E. coli, S.

saprophyticus, P. cepacia, and S. aureus.20 In a trial experiment21 carried

out on the in vitro antimicrobial activity of diclofenac sodium using the

bore-hole method on Mueller-Hinton agar (CM337 Oxoid), diclofenac

sodium was found to possess considerably good antimicrobial properties,

on incubating for 24 h at 37 °C, as shown in table 1.2.

Table 1.2 Antibacterial activity of diclofenac against various Gram

positive and Gram negative bacteria

Apart from analgesic, antipyretic, anti-inflammatory action, aspirin

and tylenol have marked antibacterial effect on isolates from urinary

track infection and diabetic foot infection. Aspirin interfere with growth of

both Gram negative and Gram positive bacteria at 500 µg/mL

concentrations while tylenol interferes more effectively at 100 µg/mL

concentration. It is suggested that both drugs can be used with antibiotic

for effective treatment.18 NSAIDs possess antibacterial activity against

Helicobacter pylori at therapeutically achievable doses; an effect that

S.No. Organism Conc of Diclofenac

Sodium /0.1 mL

Zone of

Inhibition (mm)

1 C. albican 2.5 mg 12

2 E. coli 2.5 mg 14

3 P. aeruginosa 2.5 mg 8

4 S. typhi 2.5 mg 13

Chapter-1

9

appears to be independent of COX inhibition. For Helicobacter pylori, >90

% growth inhibition and bactericidal activity were observed consistently

for sulindac sulfide at < or =70 µg/mL and sulindac sulfone at < or =175

µg/mL. The minimal inhibitory concentration (MIC) against Helicobacter

pylori was 125 µg/mL for ibuprofen, 100 µg/mL for indomethacin but

much higher concentration of aspirin (4000 µg/mL) and sulindac

sulfoxide (> or =1250 µg/mL) were required to inhibit the growth of

Helicobacter pylori (table 1.3).22 The decreased prevalence of Helicobacter

pylori from some NSAID users and the chemopreventive effects of NSAIDs

in gastric cancer may be related to inhibition of Helicobacter pylori

growth.

Table 1.3 NSAIDs as antibacterial agents

S.No. NSAIDs Structure IC50 value

1 Aspirin

4000

2 Ibuprofen

125

3 Indomethacin

100

4 Sulindac sulphone

1750

Chapter-1

10

Adverse effects of NSAIDs (figure 1.4) are theorized to be due to

inhibition of COX-1 eg, gastrointestial complications, stomach bleeding,

renal complications and kidney failure.

Physiological stimulus

Inhibition by NSAIDs

COX-1 constitutive

Inflammatory stimulus

Inhibition by NSAIDs

COX-2 induced

Prostaglandin E2, etcinflammatory cells

Inflammation

Anti-inflammatoryeffects of NSAIDs

Thromboxane A2platelets

Prostaglandin I2stomach endothelium

Prostaglandin E2

Kidney

Physiological functions

Adverse effectsof NSAIDs

Figure 1.4: Adverse effects of NSAIDs

1.3 NSAID DERIVATIVES EXPLORED AS A NUMBER OF PROMISING

THERAPEUTIC AGENTS

1.3.1 NSAID derivatives as anti-Inflammatory, analgesic and

antipyretic agents

The NSAID derivatives were reported as anti-inflammatory, analgesic

and antipyretic agents in literature. Some of the representative examples

are depicted in table 1.4.

Chapter-1

11

Table 1.4 NSAID derivatives as anti-inflammatory, analgesic and

antipyretic agents

S.No Drug Drug derivative Ref. No.

1 Aspirin

23

2 Ibuprofen

24

3 Ibuprofen

25

4 Indomethacin

26

5

Ketoprofen

27

6 Mefenamic Acid

NH

Me

Me

O

NH

N Ar

28

7 Naproxen

29

8 Naproxen

30

9 Nimesulide

O

NHSO2Me

O

31

Chapter-1

12

1.3.2 Nitric oxide donating derivatives of NSAIDs

Throughout the human GI track nitric oxides are produced due to

complex mechanism between the host, communal bacteria and dietary

factors. They are bioactive with the potential to affect the processes

locally in the gut.

Figure 1.5: Role of NO in gastric mucosal protection

The nitric oxide-donating NSAIDs (NO-NSAIDs), to which a NO

releasing moiety is covalently attached, may have an important role in

treatment of inflammation with reduced ulcerogenicity (figure 1.5). Some

of the representative examples are depicted in table 1.5.

Table 1.5 NSAID derivatives as nitric oxide donors

S.No Drug Drug derivative Ref. No.

1 Aspirin

32

2 Aspirin

33

Chapter-1

13

3 Diclofenac

34

4 Ibuprofen

35

5 Ibuprofen

33

6 Indomethacin

33

1.3.3 NSAID derivatives as antioxidant

Derivatives of NSAIDs (table 1.6) have radical scavenging activity.

Table 1.6 NSAID derivatives as antioxidant

S.No. Drug Drug derivative Ref. No.

1 Ibuprofen

36

2 Ketoprofen

36

3 Naproxen

37

Chapter-1

14

4 Indomethacin

37

5 Naproxen Me

HO

Me

Me

(CH2)n

(CH2)nO

X

OMeO

Me

Me

38

1.3.4 NSAID derivatives as prodrugs NSAIDs, commonly used for the treatment of chronic inflammatory

diseases suffer from several undesired side effects, the most important

being GI irritation and ulceration. The prodrug designing (table 1.7) is

one of the several strategies used to overcome this drawback. The

rationale behind the prodrug concept is to achieve temporary blockade of

the free carboxylic group present in the NSAIDs till their systemic

absorption.

Table 1.7 NSAID derivatives as prodrugs

S.No. Drug Drug derivative Ref. No.

1 Aspirin

38

2 Aspirin,

salicylamide

40

3 Diclofenac

41

Chapter-1

15

4 Ibuprofen Me

Me

MeHN

OS

R= H, COCH3,N

ON

O

Me

Me

Or

NHRO

O

42

5 Ibuprofen

43

6 Indomethacin

44

7 Indomethacin

OCl

Me

MeO

N

HN

ON

S

45

8 Ketorolac

46

9 Naproxen

29

10 Naproxen

47

11 Tolmetin and

paracetamol

48

12 a=Aspirin

b=Naproxen

c=Indomethacin

d=Ibuprofen

49

Chapter-1

16

1.3.5 NSAID derivatives as selective COX-2 inhibitors

COX-2 plays an important role in inflammation. Its preferential

inhibition by anti-inflammatory drugs not only relieves symptoms of

inflammation but reduces unwanted side effects related to gastric ulcer,

renal impairment and platelet function. Many NSAIDs in clinical use

have been converted to selective COX-2 inhibitors. Only slight

modification of existing NSAIDs has drastically changed its COX binding

characteristics. Few examples of these are listed in table 1.8.

Table 1.8 NSAID derivatives as selective COX-2 inhibitors

S.No. Drug Drug derivative Ref. No.

1 Flurbiprofen F

Me

HO

O

EtO

EtO

50

2 Indomethacin

O

Cl

Me

MeO

N

N

S

R

51

3 Indomethacin

52

4 Meclofenamic acid

X= ORNRR'

HN

Me

Me

O X

53

Chapter-1

17

5 Nimesulide NHSO2Me

OPh

O

O

NHCHO

54

6 Nimesulide

55

1.3.6 NSAID derivatives as antibacterial agents

Syntheses of derivatives derived from NSAIDs were reported and the

synthesized molecules were tested in vitro and in vivo against various

Gram negative and Gram positive bacteria (table 1.9).

Table 1.9 NSAID derivatives as antibacterial agents

S.No. Drug Drug derivative Ref. No.

1 Diclofenac

56

2 Naproxen

57

3 NS-398

58

4 Pyroxicam

59

Chapter-1

18

1.3.7 NSAID derivatives with anticancer activity

Cancer is the second leading cause of death worldwide after

cardiovascular disease according to W.H.O whereas colon or colorectal

cancer is wide spread in the Western world. In spite of availability of

various therapies to treat different types of cancer, deaths due to cancer

are projected to continue to rise to over 11 millions by 2030 according to

W.H.O. Thus there is an urgent need to identify new agents. Several

published studies suggest that NSAIDs are promising anticancer agents

(table 1.10).

Table 1.10 NSAID derivatives as anticancer agents

S.No. Drug Drug derivative Ref. No.

1 Ibuprofen

60

2 Ibuprofen

61

3 Indomethacin

62

4 Indomethacin

O

Cl

CH2COOH

MeO

N

63

5 Mefenamic Acid

NH

Me

Me

O

NH

N

OH

64

Chapter-1

19

6 Naproxen

61

7 Nimesulide

65

8 Nimesulide

66

1.3.8 Miscellaneous activities of NSAID derivatives

A number of new derivatives of NSAIDs were synthesized and tested

for their other pharmacological properties. The known examples along

with their activity are listed in table 1.11.

Table 1.11 Miscellaneous activities of NSAID derivatives

S.No. Drug Improved activity Structure Ref. No.

1 Ibuprofen Neuro degenerative

disorder

67

2 Ibuprofen,

paracetamol

Lipophilic, non

ulcerogenic

68

3 Naproxen Lipophilic, non

ulcerogenic

69

4 Nimesulide Antianaphylactic

and anti histamine

activity

70

5 Nimesulide Antihistamine and

anti- inflammatory

activity

O

NHSO2Me

N

N N

NH

70

Chapter-1

20

6 Nimesulide PDE4B Inhibitors

71

1.4 CONCLUSION

In this review we have given an overview of the different NSAIDs along

with their derivatives and discussed their putative role as drug candidate

against an impressive number of targets with the special attention to the

recent developments. In the everlasting effort to find small molecules

which alter protein function and ultimately might lead to new drugs,

NSAIDs has emerged as very attractive lead molecules. The chemical

world has witnessed amazing progress however, new mesmerizing

achievements is still needed. Therefore, it appeared interesting to

synthesize and evaluate biological activities of new compounds obtained

by chemical modifications of NSAIDs.

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