NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme and preventing the synthesis of prostaglandins. This summary inhibition of prostaglandin synthesis is responsible for their analgesic, antipyretic and anti-inflammatory effects. However, it can also lead to unwanted side effects like gastric irritation. NSAIDs can be classified based on their structure and selectivity for the COX-1 or COX-2 isoenzyme. The document discusses the mechanism of action, classification, synthesis and structure-activity relationships of various NSAIDs.

1. NSAIDS (NON STEROIDAL ANTI-
INFLAMMATORY DRUGS)
BY
SHOUVIK KUMAR NANDY

2. INFLAMMATION
• Inflammation (Latin, inflamatio, to set on fire) is
the complex biological response of vascular tissues
to harmful stimuli, such as pathogens, damaged
cells, or irritants.
• It is a protective attempt by the organism to
remove the injurious stimuli as well as initiate the
healing process for the tissue.

3. • Burns
• Chemical irritants
• Frostbite
• Toxins
• Infection by pathogens
• Physical injury
• Immune reactions due to hypersensitivity
• Radiation
• Foreign bodies
CAUSES OF INFLAMMATION

4. The classic signs and symptoms of acute
inflammation
• Redness
• Swelling
• Heat
• Pain
• Loss of function

5. Process of Inflammation
• Inflammation can be classified as either acute or chronic.
• The initial phase of cell injury is known as the acute
phase and is mediated by several autacoids like :
– Histamine
– 5-HT
– Bradykinin
– Prostaglandins
• When a tissue is injured, from any cause, prostaglandin
synthesis in that tissue increases.

6. Synthesis of Prostaglandins
Cyclo-oxygenase (COX) pathway
Membrane Phospholipids
Phospholipase A2
Arachidonic Acid
Prostaglandins
Thromboxanes
Prostacyclin
COX

7. • Among the most widely used all therapeutic agents
world wide
• They are frequently prescribed for ‘rheumatic’
musculo-skeletal complaints and are often taken
without prescription for minor aches and pains
• More than 50 different NSAIDs on the market and
none of these is ideal in controlling or modifying the
signs and symptoms of inflammation
NSAIDs

8. • Analgesic
• Antipyretic
• Anti-inflammatory actions
• Compared to Morphine:
– Weaker analgesics
– Do not depress CNS
– Do not produce physical dependence
– No abuse liability
NSAIDs Continued..

9. • They are also called:
– Non norcotic
– Non opioid
– Aspirin like analgesics
• They act primarily on peripheral pain
mechanisms but also in CNS to raise pain
threshold
• These drugs are chemically diverse, but most
are organic acids.
NSAIDs Continued..

10. • All are analgesic, antipyretic, anti-inflammatory
(expect paracetamol).
• Do not produce CNS depression.
• Dose dependent uricosuric action.
• Act by inhibition of PGs except Nimesulide,
Nefopam.
Common characteristics of all NSAIDs
Continued..

11. Sl. No. Class Example Structure
1. Salicylate derivative Aspirin
2. 3,5-Pyrazolinediones
derivatives
Phenylbutazone
3. Propionic acid derivative Naproxen
4. Anthranilic derivative Mephenamic acid
5. Aryl-acetic acid derivative Diclofenac
6. Oxicum derivative Piroxicam
7. Pyrrolo-Pyrrole derivative Ketorolac
8. Indole derivative Indomethacin
Structure-based Classification
Non selective COX inhibitors:

12. Preferential COX-2 inhibitors:
Nimesulide
Selective COX-2 inhibitors
Celecoxib
Structure-based Classification
Continued..

13. Analgesic –Antipyretics with poor Anti inflammatory action
Para amino phenol derivatives Paracetamol (Acetaminophen)
Pyrazolone derivatives Metamizole
Benzoxazocine derivative Nefopam
Structure-based Classification
Continued..

14. Mechanism of action
• When a tissue is injured, from any cause, prostaglandin
synthesis in that tissue increases.
• PGs have TWO major actions:
• They are mediators of inflammation
• They also sensitize pain receptors at the nerve
endings, lowering their threshold of response to
stimuli and allowing the other mediators of
inflammation

15. • Naturally, a drug that prevents the synthesis of PGs is
likely to be effective in relieving pain due to inflammation
of any kind
• In 1971 Vane and coworkers made the landmark
observation that aspirin and some NSAIDs blocked PG
generation.
• This is they do by inhibiting cyclo –oxygenase (COX)
enzyme in the pathway for PGs synthesis
Mechanism of action Continued..

16. Membrane Phospholipids
Phospholipase A2
Arachidonic Acid
Prostaglandins
Thromboxanes
Prostacyclin
COX
Synthesis of Prostaglandins
Cyclo-oxygenase (COX) pathway
NSAIDs

17. COX
• Exists in two isoforms:
1. COX-1 (constitutive)
2. COX-2 (inducible)
– Oxidative stress
– Injury
– Ischemia
– Neurodegenerative diseases

18. Advantageous actions due to PG
synthesis inhibition
• Analgesia
• Antipyresis
• Antiinflammatory
• Antithrombotic
• Closure of ductus arteriosus

19. Some toxicities due to PG synthesis
inhibition
• Gastric mucosal damage
• Bleeding
• Limitation of renal blood flow/Na+ & water
retention
• Delay/prolongation of labour
• Asthma and anaphylactoid reactions in
susceptible individuals

20. 1. Reducing the acidity of this group maintains the analgesic actions of salicylic
acid derivatives but eliminates the anti-inflammatory properties.
2. Substitution on either the carboxyl or phenolic hydroxyl groups meta or para to
the carboxyl group abolishes this activity.
3. Substitution of aromatic ring enhances potency and toxicity.
4. Substitution of aromatic ring at the 5-position of salicylic acid increases anti-
inflammatory activity.
5. Substitution of halogen on aromatic ring increases the potency and decreases the
toxicity.
General Structure
SAR of Salicylate derivatives
DRUG R1 R2
Salicylic acid H H
Methyl salicylate CH3 H
sodium salicylate Na H
Phenyl salicylate C6H5 H
COOR1
OR2

21. Synthesis of Aspirin

22. Synthesis of Salol

23. Synthesis of Salol (Continued)

24. Synthesis of Salsalate

25. Synthesis of Salicylamide

26. Synthesis of Sodium salicylate

27. Synthesis of Benorilate

28. 1. 2,4-difluoro aniline,
2. Amyul nitrite,
3. Methyl Phenoate.
Synthesis of Diflunisal

29. Synthesis of Sulphasalazine

30. 1. The acidic H at 4-position is related to their activity.
2. The dicarbonyl functions at the 3 and 5 positions enhance the acidity of
hydrogen atom at the 4-position.
3. Decreasing or eliminating acidity by removing the acidic proton at the 4
position (e.g. 4,4-dialkyl derivatives) abolishes the activity.
4. If acidity is too much, anti-inflammatory and sodium-retaining activities
decrease, while other properties such as uricosuric effect increase.
5. A single alkyl group (n-butyl group) at the 4-position enhances anti-
inflammatory activity.
SAR of 3,5-PYRAZOLINEDIONES
Derivatives
N
N
H
O
O
R4
R
DRUG R R4
Phenyl butazone H -C4H9
Oxyphenbutazon
e
OH -C4H9
Sulphinpyrazone H -(CH2)2SOC6H5General Structure

31. 6. Introduction of polar functions in these alkyl groups gives mixed results.
7. The gama-hydroxy-n-butyl derivative possesses pronounced uricosuric activity
but gives fewer anti-inflammatory activity.
8. Substitution of phenylthiol group at the 4-position produces anti-gout drug.
(Example: Sulfinpyrazone)
9. The presence of both phenyl groups is essential for both anti-inflammatory
analgesic activity.
10. Various substituent's in the para position of one or both aromatic ring do not
drastically affect activity. A p-hydroxy group present in oxyphenbutazone, the
major metabolite of phenylbutazone, contributes therapeutically useful anti-
inflammatory activity. Other derivatives such as methyl, chloro, or nitro groups
also possess activity.
SAR of 3,5-PYRAZOLINEDIONES
Derivatives (Continued)

32. Synthesis of Phenyl butazone

33. 1. The presence of a methyl group in the alkaline portion of the propionic acid
derivative gives rise to the compound ibuprofen which is much more active or
potent and much less toxicity (hepatototoxic) compared to the compound
without the alpha-methyl group (ibufenac).
Ibufenac
2. The (+) isomer of ibuprofen is much more active compared to (-) isomer.
3. The presence of the phenoxy group at 3rd position give rise to the compound
fenoprofen.
SAR of Propionic acid Derivatives

34. SAR of Propionic acid Derivatives
(Continued)
4. The replacement of the oxygen ring with the keto group gives rise to the
compound ketoprofen which is comparatively most active.
5. The presence of the methoxy group at 6 position of the naphthalene ring
give rise to the compound naproxen which has much greater anti-
inflammatory activity compared to ibuprofen.
Naproxen
6. The (+) isomer of naproxen is much more active compared to (-) isomer.

35. Synthesis of Ibuprofen

36. Synthesis of Ibufenac
Willgerodt oxidation is is an organic reaction converting an aryl alkyl ketone to the
corresponding amide and carboxylic acid as side reaction product by reaction with Sulphur,
Con. NH4OH and pyridine.

37. Synthesis of Naproxen
Willgerodt oxidation is is an organic reaction converting an aryl alkyl ketone to the
corresponding amide and carboxylic acid as side reaction product by reaction with Sulphur,
Con. NH4OH and pyridine.

38. Synthesis of Flurbiprofen

39. Synthesis of Caprofen

40. 1. Substitution on the anthranilic acid ring generally reduces the activity.
2. The NH moiety of anthranilic acid appears to be essential for activity
since replacement of NH function with O, S, CH2 functionalities
significantly reduced the activity.
3. In the UV erythema assay for anti-inflammatory activity, the order of
activity is generally 3’>2’>4’ for mono substitution with the CF3
derivative (Flufenamic acid) particularly potent.
General Structure
SAR of Anthranilic acid Derivatives
COOH
NH
R1
R2
R3
DRUG R1 R2 R3
Mefinamic acid CH3 CH3 H
Flufinamic acid H CF3 H
Meclofinamic
acid
Cl CH3 Cl

41. 4. In rat paw edema assay, with 2’-Cl derivative is more potent than 3’-Cl
analogue.
5. In di-sustituted derivatives, where the nature of the two substituents is the
same, 2’3’ distribution appears to be more effective.
6. The substituents on the N-aryl ring which force the ring to be non coplanar
with anthranilic acid ring should enhance the binding at the site thereby
increase the activity.
7. Meclofenamic acid has greater anti-inflammatory activity over flufenamic acid
and 25 times more than mefenamic acid.
8. Finally, the position of the acidic function is critical for activity. Anthranilic
acid (O) derivatives are active, whereas the m- and p- aminobenzooic acid
analogues are not. Replacement of carboxylic acid funcvtions with the
isosteric tetrazole has little effect on activity.
SAR of Anthranilic acid Derivatives (Continued)

42. Synthesis of Flufenamic acid
Synthesis of Mefanamic acid
Ullman condensation is type of Aromatic amination
reaction between aryl halogen acids and aryl amines.

43. 1. The p-toluoyl and acetic acid function must be coplanar in tolmetin.
2. Introduction of methyl group at 4-position of pyrrole ring produces Zomipirac.
is more potent than tolmetin.
3. Propionic acid analogue slightly less potent than tolmetin.
SAR of Arylacetic acid Derivatives

44. SAR of Aryl Alkanoic Acid Derivatives
a) All the agents posses a centre of acidity, which can be represented by –COOH,
an enol, hydroxamic acid, sulphonamide or tetrazole.
b) The centre of acidity is generally located one carbon atom adjacent to a flat
surface represented by an aromatic / heteroaromatic ring.
c) The distance between these centres is critical because increasing this distance to
2 or 3 carbons generally decreases the activity.
d) Susbt. of –CH3 group on the carbon atom separating the aromatic ring tends to
increase the anti-inflammatory activity.

45. 4. The function of 2-ortho chloro group is to force anilino-phenyl ring out of
the plane of the phenyl acetic portion.
Diclofenac Sodium
SAR of Arylacetic acid Derivatives (Continued)

46. Synthesis of Tolmetin

47. Synthesis of Zomepirac

48. Synthesis of Diclofenac
Wolf-kishner reduction is a chemical reaction that fully reduces a ketone or aldehyde
to an alkane. It involved heating the hydrazine with Na-ethoxide in a sealed vessel
at about 180 °C. Diethylene glycol (DEG) is usually used as solvent.

49. 1. The replacement of the carboxyl group with any other acidic functionalities
lead decreases the activity.
2. Acylation of the indole nitrogen with aliphatic carboxylic acid or aryl alkyl
carboxylic acids result in the decrease of activity.
3. Amide analogues are inactive.
4. The N-benzoyl derivatives substituted in the p-position with F, Cl, CF3 groups
are the most active.
5. The 5-position of the indole when F, OCH3 groups was more active than the
unsubstituted indole analogue.
6. The presence of indole ring nitrogen is not essential for activity because the
corresponding 1-benzylidenylindene analogue (Sulindac) was active.
SAR of Indole Derivatives

50. 7. Alkyl groups, especially methyl group, at 2-position are much more active than
aryl-substituted analogues.
8. Substitution of a methyl group at the alpha-position of the acidic acid side chain
leads to equiactive analogues.
9. Anti-inflammation activity is displayed only by the (S) (+) enantiomer.
SAR of Indole Derivatives
(Continued)

51. Synthesis of Indomethacin

52. Synthesis of Sulindac
Reformatski is an organic
reaction, which condenses
aldehydes or ketones with
α-halo esters using a metallic
zinc to form β-hydroxy-esters.

53. 1. Optimum activity is observed when methyl substituent present at 2-position.
2. The carboxamide sustituent R is generally an aryl or hetero aryl substituent
because alkyl substituents are less active.
3. N-heterocyclic carboxamides (piroxicam) are generally more acidic than the
corresponding N-aryl carboxamides.
4. Tenoxicam
4. Interchanging of benzene ring with thiophene (tenoxicam) gives biologically
active compounds.
5. For optimum activity 4-hydroxy-1,2-benzothiazine carboxamide ring is
required.
SAR of Oxicam Derivatives

54. Synthesis of Piroxicam

55. Synthesis of Meloxicam

56. SAR of Pyrollo pyrollo Derivatives
1. Ketorolac which lacks this benzylic methyl group is not
susceptible to the type of oxidation
observed for tolmetin and as a result its half-life is longer (4-
6 hours).
2. This drug is unique in
that it is formulate for orally and IM administration.
3. Good oral activity with primarily
analgesic activity, but also has antiiflammatory activity
and antipyretic actions.
Tolmetin

57. 1. Esterification of the phenolic function with methyl or
propyl produces derivatives with greater toxic side
effects than ethyl groups.
2. The substituent on the nitrogen atom which reduces
basicity also reduces activity except for acetyl which is
metabolically labile.
3. Amides derived from aromatic acid. E.g., N-phenyl
benzamides-are less active or inactive.
SAR of Para aminophenol Derivatives
Paracetamol

58. Synthesis of Paracetamol

59. Synthesis of Phenacetin

60. Synthesis of Phenacetin (Continued)

61. Synthesis of Acetanilide

62. Mechanism of Action (MOA) of Paracetamol
Paracetamol inhibits prostaglandin synthesis in the CNS but not in there
periphery. Therefore, by its CNS effects:
1. It reduces pain sensation,
2. It produces anti-pyrexia by exerting its action on the hypothalamic heat
regulating centre and analgesia but has virtually,
3. It is having no affect on inflammation,
4. It produces no hemorrhage.

63. Nefopam:
• Different from other NSAIDs since it has atropin like
actions
• Effective in traumatic and post operative pain, and in
musculoskeletal pain not responding to other NSAIDs
• Atropine like adverse effects
• Contraindicated in epilepsy
Benzoxazocine Derivatives

64. These are:
Nimesulide, Meloxicam, Nabumatone
Nimesulide:
• Relative weak PGs inhibitor with COX-2 selective action
• Other mechanisms implicated are reduced superoxide
generation by neutrophils, inhibition of PAF synthesis
and free radical scavenging action
• Gastric and other adverse effects are similar to other
NSAIDs
 Has been reported to cause nephrotoxicity and hepatotoxicity
 Not licensed in some developed countries
 And it has been withdrawn from others
 Use should be avoided especially in children and old persons
Pref COX-2 inhibitors

65. Synthesis of Nimesulide

66. Synthesis of Nimesulide (Another Method)

67. • Selectively block COX-2 activity more than COX-1
activity
• Less action on stomach, blood vessels and kidneys
This group includes:
Celecoxib, Rofecoxib and Valdecoxib
• Given orally, absorption is complete
• Established analgesic- antiinflammatory NSAIDs
• They have to be shown effective in treatment of
osteoarthritis and rheumatoid arthritis
• Their major advantage is that they cause fewer gastric
ulcers and do not inhibit platelet aggregation
• Stomach friendly
Selective COX-2 Inhibitors

68. Adverse effects:
• The most common adverse effects are nausea, vomiting,
dyspepsia, abdominal pain, diarrhoea and edema of the
lower extremities
• Share some of the renal adverse effects of non selective
COX inhibitors and renal toxicity
• Hence their use should be restricted to patients who do
not tolerate other NSAIDs
Selective COX-2 Inhibitors (Continued)

69.  Recently, the use of rofecoxib and valdecoxib has
been reported to be associated with increased incidence
of MI and stroke
 Hence, they have been withdrawn by the original
manufacturers
 Currently all the selective COX -2 inhibitors are under
suspicion regarding their long term toxicity
 They have been described as drugs with “marginal
efficacy, heighted risk and excessive cost compared with
traditional NSAIDs”
Selective COX-2 Inhibitors
(Continued)

70. SAR of COX-2 Inhibitors
- Diaryl heterocycle with Cis-Stilbene moiety and changes in the Para position of one of the
aryl rings play an important role in the COX-2 selectivity.
(e.g) Celecoxib – SO2NH2 grp
Parecoxib – SO2NHCOCH3 grp (Prodrug for Valdecoxib)
Rofecoxib and Etoricoxib – SO2CH3 grp
- The oxidation state on the sulphur is important for selectivity.
- Sulfones and Sulfonamides are selective for COX-2 but Sulfoxides and Sulfides are not.

71. Synthesis of Celecoxib

72. Gout & Anti-gout Drugs
• Gout is usually characterized by excruiating, sudden, unexpected, burning
pain, as well as swelling, redness, warmth, and stiffness in the affected
joint. This occurs most commonly in men’s toes but can appear in other
parts of the body and affect women as well. Drugs used to treat gout may
act in the following ways:
• Classification of anti-gout drugs:
1. By inhibiting uric acid synthesis: Allopurinol
2. By increasing uric acid excretion: Probenecid, Sulfinpyrazone
3. Miscellaneous: Colchicine (alkaloid obtained from Colchicum autumnale)

73. Mechanism of Action of Allopurinol
In human beings, uric acid is formed primarily by the metabolism of
adenine. Adenine is converted to hypoxanthine which in turn to xanthine
and uric acid by the enzyme xanthine oxidase. At low concentrations,
allopurinol is a competitive inhibitor of xanthine oxidase enzyme; at high
concentration, it is a non-competitive inhibitor.

74. Synthesis of Allopurinol

75. Synthesis of Probenecid

76. Gold Compounds
• In general, gold compounds either suppress or prevent, but do
not cure arthritis and synovitis.
• The use of organic gold derivatives for the treatment of
rheumatoid arthritis was first reported in 1927.
• However, the monovalent gold compounds bring symptomatic
relief to rheumatoid arthritis in patients.
• A few classical examples of this class of compounds are
discussed below.
• Examples: auranfin; aurothioglucose; aurothioglycanide;
sodium aurothiomalate.

77. Synthesis of Auranofin

78. Synthesis of Aurothioglucose
Synthesis of Sodium
aurothiomalate

79. THANK YOU