NON-STEROIDAL ANTI-INFLAMMATORY DRUGs

1. NSAIDs
[Non Steroidal Anti inflammatory Drugs]
Dr. Kratika Daniel
Associate Professor
Mandsaur University

2. • Inflammation can be defined as defensive and
exaggerated local tissue reaction in response to
exogenous or endogenous injury.
• It is a complex phenomenon comprising of biochemical
as well as immunological factors.
• Inflammation (from Latin inflammatio = to set on fire)
• is part of the complex biological response of body
tissues to harmful stimuli, such as pathogens, damaged
cells, or irritants and is a protective response involving
immune cells, blood vessels, and molecular mediators.

3. How inflammation occur

4. • Inflammation recognised by
• CALOR (Heat)
• Rubor (Redness)
• Tumor (Swelling)
• Dolor (pain)
4 signs of inflammation
• Redness ‐due to local vessel dilatation
• Heat ‐ due to local vessel dilatation
• Swelling – due to influx of plasma proteins And
phagocyte cells into the Tissue spaces
•Pain – due to local release of enzymes and increased
tissue pressure

6. ANALGESICS = Pain Killer
Opioids:
Morphine & morphine
like drugs
Non-Opioids:
NSAIDs
• Without steroidal ring.
• Are also used as
analgesic and anti
pyretic drugs.
The word analgesics derives from Greek an-
(“without”) and algos (“pain”).

7. 1)
• Nonsteroidal Anti-Inflammatory Drugs
2)
• Corticosteroids
3)
• Opioids
4)
• Neurological Analgesia
5)
• Anesthetic Nerve Blockade

8. Fever = Pyresis
• Antipyretics (from anti- 'against' and pyretic
'feverish') are substances that reduce fever.
Fever  release of endogenous pyrogens
(e.g., interleukin-1) released from leucocytes
 acts directly on the thermoregulatory
centers in hypothalamus  increase body
Temperature.

9. Mechanism of Action of NSAIDs
2 Ways
I Biochemical Mechanism
II Cellular or immunologic
Mechanism
•Inhibition of hydrolytic
enzyme.
•Inhibition of Arachidonic
metabolism.
Inhibition of COX & LOX
pathway
•Inhibition of free radical
generations
•Inhibition of
Polymorphonuclear
leucocytes.
•Monocyte modification.
•Action through
lymphocytes.

10. Biochemical Mechanism
• Inhibition of hydrolytic enzyme: this concept is
related with lysosymes, which contains hydrolytic
enzyme and participate in process of inflammation.
NSAIDs inhibited the lysosymes to release of
hydrolytic enzymes.
• Inhibition of Arachidonic metabolism : PGs play an
imp role in erythema, oedema, pain and fever.
• Most of NSAIDs inhibit the formation of PGs and
Leuctotrienes which are metabolic product of
arachodonic acid and are responsible for
inflammation. NSAIDs inhibit COX and LOX enzyme
• COX also known as PGs Synthetase

13. • Inhibition of free radical generations: - No. of free
radicals species generated during biosynthesis of PGs
which was inhibited by NSAIDs.
•Inhibition of Polymorphonuclear leucocytes: - PMN
is first cell to arrive at site of inflammation and
NSAIDs restrict their arrival at site of inflammation.
•Monocyte modification: - monocyte are central cell
in inflammatory process. NSAIDs modify the function
of movement and function of monocyte.
• Action through lymphocytes: - the second line drug
such as penicllamine, gold salts and dapsone used in
treatment of inflammation. Lymphocyte may
influence chronic inflammation
II Cellular or immunologic Mechanism

14. Classification of NSAIDs
Acidic Drug
Classical & Non classical
[gold compound]
Basic Drug
Timegadine  inhibit
neutrophil de granulation
Non Acidic Drug
e.g. Indoxle
nictindole
Timegadine: more than a non-steroidal for the
treatment of rheumatoid arthritis.

15. A. Acidic Drug.
1 Classical
I Non Selective
COX Inhibitor
II Analgesic -
Antipyretic
Preferential
COX – 2 Inhibitor
Selective
COX – 2 Inhibitor
1. Salicylates – aspirin, salol, sodium salicylate.
2. Indole or aryl alkonoic or aryl acetic acid –
indometahcin, sulindac.
3. Propionic acid derivative – Iburofen, Naproxen.
4. Aryl acetic acid derivative – diclofenac, acelofenac
5. N – aryl Anthralinic acid Derivative or fenamates –
mefenamic acid, meclofenamic acid.
6. Oxicam (enolic acid) – piroxicam, tenoxicam
*PAAO Sa PAR (2) BEN Aya

16. II. Analgesic antipyretic drugs
7. Pyrazolone & pyrazolidine derivative-
phenybutazone, oxyphenbutazone,
antipyrine.
8. Pyrrolo – pyrrole derivative – ketorlac.
1. Para amino phenol derivative = paracetamol,
acetanilide.
2. Benzooxazine derivative - nefopam
III Preferential COX – 2 Inhibitor - Nimesulide
IV Selective COX – 2 Inhibitor – [COXIBs] –
celecoxib, valdecoxib etc

17. Salicylates
Compound Name R1 R2
Aspirin H - COCH3
Salol H
Sodium salicylate Na H
salsalate H
flufenisal
COOR1
OR2
1
2
3
4
5
6
COOH
OH
• The salicylates are derivatives of
2-hdroxybenzoic acid(salicylic
acid).
• They were discovered in 1838
following the extraction of salicylic
acid from willow bark.
• The salicylates have potent anti-
inflammatory activity with mild
analgesic and antipyretic
activities.
• These compounds are mainly
COX-1 selective—they are bound
with higher affinity to COX-1.
• The therapeutic and some of the
toxic actions (i.e. gut) of aspirin
can be related to its ability to
inhibit COX-1 in various tissues.

18. SAR of Salicylates
• The carboxyl group is necessary for activity and carboxyl
group must be adjacent to benzene ring.
• Side effects of salicylates is associated with carboxylic
acid.
• Carboxylic group is replaced with CONH2 (amide) –
maintain the same analgesic action but eliminates anti-
inflammatory properties and reduces side effect e.g.
salicylamide
Active Compound
COOH
OH
1
2
3
4
5
6
Salicylic Acid

19. • The derivative of salicylic acid are of 2 types: -
• Type I : - they are formed by modifying the carboxyl group.
(e.g. salts, esters)
• Type II: - they are derived by substitution on hydroxyl group.
• Substitution on either type I or II a hydroxyl group may effect
potency and toxicity. Benzoic acid has less activity
• Placing phenolic hydroxyl group at meta or para position to
carboxyl gp abolishes activity.
• Substitution of halogen atom on aromatic ring enhances
potency and toxicity e.g. 5 – chloro salicylic acid.
COOR COOH
OR
COOH
O C R
O
Type I
Type II a Type II b
COOH
OH
1
2
3
4
5
6
H2N
4-amino-salicylic acid
Inactive compound
Introduction of amino gp at position 4 reduces
activity.

20. • Introduction of methyl group at position 3 in aspirin
produces 3 methyl aspirin  have slower metabolic
excretion.
• Substitution of aromatic ring at
position 5  increases anti-inflammatory
properties. E.g. diflunisal.
• Asprin acetyl salicylic acid  potent agent but has
more adverse effect due to O – acetyl group
E.g. blood loss due to GIT haemorrhage.
• Diflunisal has fewer side effect than aspirin.
• The gastric irritancy of salicylates is associated with
carboxylic acid group  can be reduced by
modification of acidic characteristic e.g. by
esterification of carboxyl gp.
COOH
O C CH3
O

21. • Development of fendosal  have more analgesic
activity.
• Flufenisal  with introduction of hydrophobic gp
[F] at position 5  the compound become more
potent, longer acting with less gastric irritation.
Synthesis of Aspirin

23. Heteroaryl acetic acids
• All the agents posses a centre of acidity, which can be represented by –
COOH, an enol, hydroxamic acid, sulphonamide or tetrazole. The
following substituent's generally gives activity:
a. Indole substituent: - 5 methoxy, F, CH3.
b. Benzoyl Substituent: - p-Cl, F or CH3.
c. Acetic acid substituent: α – CH3, CO2CH3
• The carboxyl gp is necessary for anti – inflammatory activity. The more
acidic the gp the greater the activity.
• The centre of acidity is generally located one carbon atom adjacent to a
flat surface represented by an aromatic / heteroaromatic ring.
• The distance between these centres is critical because increasing this
distance to 2 or 3 carbons generally decreases the activity.
• Susbt. of –CH3 group on the carbon atom separating the aromatic ring
tends to increase the anti-inflammatory activity
• The indene isostere has similar activity to indomethacin.
• The study of SAR result in development of sulindac, tolmetin,
zomiperac

24. Indomethacin
a) Replacement of the –COOH group at 3rd position with
other acidic functionalities decreases the activity. Amide
analogs are inactive.
b) Subst. at R1, useful for increasing anti-inflammatory activity are ranked as
C6H4CH2 > CH3 > H
c) Acylation of the Indole Nitrogen with aryl / alkyl carboxylic acids results in the
decreasing of activity.
d) The N-benzoyl derivatives subst. in the Para position with F, Cl, CF3 & S-CH3
groups are the most active.
e) At the 5th position, X-subst. activity are ranked as OCH3 > F > N(CH3)2 > CH3 >
COCH3 > H than the unsubstituted analogs.
f) Presence of Indole ring nitrogen is not essential for activity because the
corresponding 1-benzylidenylindene analogs (i.e. Sulindac) is also active.
g) CH3 group at 2nd position are more active than aryl subst. analogs.
h) Subst. of CH3 group at the α-position of the acetic acid side chain leads to equally
active analogs.
i) Anti-inflammatory activity is displayed only by the dextrorotatory enantiomer

25. Sulindac
• The isosteric replacement of indole ring with indene ring
 therapeutically effective as anti – inflammatory with
less CNS & GI side effects but have poor solubility and
crystalluria.
• 5 – methoxy gp replaced with fluorine (Carbon 5) 
activity enhanced.
• Z isomer of sulindac is more active than E.

26. Tolmetin Sodium Zomiperac
• Tolmetin contain a non coplanar p-chlorobenzoyl group
and acetic acid are necessary for activity.
• They possess pyrrole ring instead of indole ring  better
activity.
• Introduction of methyl group at position 4  enhanced
activity. Replacement of this methyl gp with chloro
compound is 4 times more potent i.e. zomiperac.

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

28. Aryl Acetic acid
• The two o – chloro group is
to force the anilino phenyl
ring out of plane of phenyl
acetic acid are essential for
activity  helps in binding
with enzyme.
• Diclofenac is used for
rheumatoid arthritis,
osteoarthritis and post-
operative pain.

29. Synthesis of Diclofenac
Wolf-kishner reduction is a chemical rxn 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.

30. Propionic Acid derivative [profen]
• are often referred to as the “profens” based on the
suffix of the prototype member, ibuprofen.
• The aryl propionic acids are characterized by the
general structure Ar—CH(CH3)—COOH which
conforms to the required general structure.
• Substitution of alpha methyl gp on alkanoic acid 
enhances activity.
• + enatiomer has greater activity.
SAR

31. • Isobutyl substituent has more activity with reduced toxicity.
• Replacement of carboxylic functional gp with ester, amide
or azole generally produces less active compound.
• Placing the phenoxy group at ortho or para position of aryl
propionic acid  less active compound e.g. fenoprofen.
• Replacement of oxygen with carbonyl in fenoprofen 
yields ketoprofen which has more activity than ibuprofen.
• Substitued the aryl gp with 2-naphthyl acetic acid leads to
maximum activity. Small lipophillic gp like Cl, CH3, etc yields
active analogue.
• Larger gp on place of methoxy yields less active
compounds.

32. Synthesis of Ibuprofen

33. Anthranillic acid [fenamates]

34. SAR
• Substitution on the anthranilic acid ring generally reduced the activity.
• Substitution on the N-aryl ring can lead to conflicting results.
• In the assay for the anti-inflammatory activity the order of activity was
generally 3’>2’>4’ for mono substitution with CF3 group (flufenamic acid).
The 2’Cl derivative being more potent than 3’Cl analogue.
• In di-substituted derivatives, where the nature of two substituent is the
same, 2’,3’ di-substitution appear to be the most effective (mefenamic
acid).
• The NH moiety of anthranilic acid appears to be essential for activity since
replacement of NH functional group with O, CH2, S, SO2, NH3 or NCOCH3
functionalities significantly reduce the activity.
• The position of acidic function is critical for activity, anthranilic acid
derivatives are active. Replacement of carboxylic acid functions with the
isosteric tetrazole has little effect on the activity.
H
N
COOH R1
R2
R3
1
2
3
4
5
6

35. Synthesis
Ullman condensation is type of Aromatic amination
reaction between aryl halogen acids and aryl amines

36. Pyrazolidinedione Derivative
COMPOUND R1 R2
phenylbutazone C6H5 n C4H9
oxyphenbutazone C6H4 –
OH (p)
n C4H9
sulfinpyrazone C6H5 CH2CH2
S C6H5
Antipyrine
(phenazone)
N
N
R1
O
H
R2
O
•the butyl gp (R2) of carbon 4 can
be replace with propyl or allyl
group.
•Presence of keto group in gamma
position of butyl side chain
produces active compounds.
•Meta substitution of aryl rings of
phenyl butazone give inactive
compounds.
•Para substituion with methyl,
cholro, nitro or OH of one of both
ring retains activity.
•Replacemnt of one nitrogen
atoms in pyrazolidine with oxygen
atom yields isoxazole analogs
equally active.

37. • Anti – inflammatory activity is directly proportional to
partition coefficient. Log P = 0.7
• Decreasing pKa value  shorter half lives.
• An enolizable B – dicarbonyl system is essential for activity.
• Subst. of 2-phenyl thio ethyl group at the 4th posn produces
anti-gout activity e.g. Sulphin pyrazone.
• Presence of both phenyl group is essential for both anti-
inflammatory & analgesic activity.

38. Pyrrolo- pyrrole derivative
•Ketorolac is only intended for short-term (up to 5 days)
treatment of moderately severe pain.
•It should not be used to treat minor or long-term pain.

39. OXICAM Derivative
• The most active analogs have
substituent CH3 on nitrogen &
electron withdrawing
substituent on anilide gp.
• An introduction of heterocyclic
ring in amide oxide 
significantly activity increases.
• When aryl gp is substituted at
meta position compound will
be most potent than para or
ortho e.g. Cl gp observe max.
activity.
• Carboxamide gp is required for
stabilization of enolate anion.
N
S
O O
OH
H
N
R
O
CH3
1
2
3
4
5
6
7
8
COMPOUND R1
PIROXICAM
ISOOXICAM
SUDOXICAM
N
N
O
S
N

40. Para amino phenol derivative
• a) Esterification of the phenolic grp
with methyl or propyl grps
produces derivatives with greater
side effects than ethyl derivatives.
• b) Subst. on the N2 atom which
reduces the basicity, and also
reduce activity unless the subst. is
metabolically labile. e.g. acetyl
• c) Amides derived from –COOH are
less active or inactive. e.g. N-
phenyl benzamides.
NHCOCH3
R
COMPOUND R
Acetanilide H
paracetamol OH
phenacetin OC2H5

41. Prefential COX 2 Inhibitors
• Nimesulide is a relatively
COX-2 selective, NSAID
with pain medication and
fever reducing properties.
Its approved indications
are the treatment of acute
pain, the symptomatic
treatment of osteoarthritis
and primary
dysmenorrhoea
Nimesulide

42. Selective COX 2 Inhibitors
• Selective COX-2 inhibitors are a type of NSAID that directly
targets cyclooxygenase-2, COX-2, an enzyme responsible for
inflammation and pain.
• Targeting selectivity for COX-2 reduces the risk of peptic
ulceration.
• The common pharmacophore is celcoxib and rofecoxib
consists of 5 membered heterocyclic gp which is essential for
binding with enzyme.
• 6 membered heterocyclic compound shows equal activity e.g.
etoricoib

44. Assignment question
• Write mechanism involved in inflammation.
• Write structural classification of NSAIDs.
• Write MOA of NSAIDs.
• Give SAR of each categories of NSAIDs.
• Write synthesis of asprin, mefenamic acid and
ibuprofen.