Anti-Inflammatory Agents - Dr.

Venkatesh 02-02-2023

ANTI-INFLAMMATORY AGENTS
Agents which are used to cure inflammation are called as anti-
inflammatory agents

ANTI-INFLAMMATORY AGENTS

Mechanism of Action

These agents block the enzyme cyclooxygenase reversibly or competitively, there by

prevent the formation of (Prostaglandin) PG G2 from arachidonic acid and finally PG
E2, which produce inflammation
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

ANTI-INFLAMMATORY AGENTS
Classification

1. Salicylic acid derivatives: Aspirin, Diflunisal, Salsalate, Sulfasalazine.

2. p-Aminophenol derivatives: Paracetamol, Phenacetin.

3. Pyrazolidinedione derivatives: Phenylbutazone, Oxyphenbutazone,

Sulfinpyrazone

4. Anthranilic acid derivatives: Mefenemic acid, Flufenemic acid,

Meclofenamate.

ANTIINFLAMMATORY AGENTS
Classification
5. Arylalkanoic acid derivatives:
a. Indole acetic acid: Indomethacin
b. Indeneacetic acid: Sulindac
c. Pyrroleacetic acid: Tolmetin, Zomipirac
d. Phenyl acetic(propionic) acid: Ibuprofen, Fenoprofen, Flubiprofen, Diclofenac,
Naproxen, Ketoralac
6. Oxicams: Piroxicam, Meloxicam, Tenoxicam
7. Miscellaneous: Nambumetone, Nimesulide, Analgin.
8. Selective COX-II inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

ANTIINFLAMMATORY AGENTS - Salicylic acid derivatives

 Salicylates not only possess antipyretic, analgesic and anti-

inflammatory properties

 They promote excretion of uric acid and are used for the treatment
of gouty arthritis.

 They inhibit platelet aggregation (Aspirin) and is used to reduce the

risk of myocardial infarctions.

Salicylic acid derivatives - SAR

COOH

OH

1. Substitution on either the carboxyl or phenolic hydroxy groups may affect the
potency and toxicity.

2. Reducing the acidity of the –COOH, eg., the corresponding amide (salicylamide),
retain the analgesic action but is devoid of anti-inflammatory properties.

3. Placing the phenolic hydroxyl group meta or para to the carboxyl group abolishes
the activity.

4. Substitution of halogen atoms on the aromatic ring enhances potency and toxicity.

5. Substitution of aromatic rings at 5-position of salicylic acid increases anti-

inflammatory activity (Diflunisil)
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

p-Aminophenol derivatives
 These derivatives possess analgesic and antipyretic actions but lack anti-
inflammatory effects.
 Acetanilide was first introduced as an antipyretic-analgesic agent, but was
subsequently found to be too toxic associated with methemoglobinemia and
jaundice.
 Phenacetin was introduced later and was withdrawn because of its nephrotoxicity.
Acetaminophen (Paracetamol) was the only useful agent of this group.

p-Aminophenol Derivatives - SAR

1. Etherification of phenolic group with methyl or propyl group produces derivatives

with greater side effects than ethyl derivatives.
2. Substitution on the nitrogen atom, which reduces the basicity, also reduces activity
unless the substituent is easily metabolized like acetyl group.
3. Amides derived from aromatic acids, E.g. N-phenyl benzamide are less active or
inactive
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

Pyrazolidinedione derivatives
O

H
N
R 1 N
O

Name R R1
Phenylbutazone -H -C4H9
Oxyphenbutazone -OH -C4H9
Sulfinpyrazone -H -(CH2)2SOC6H5

Pyrazolidinedione derivatives - SAR

O

H 4
N
R 1 N
O

1. In pyrazolidinediones the pharmacological activities are closely related to their

acidity (the acidic –H at 4-position). The dicarbonyl functions at the 3- and 5-
position enhances the acidity of hydrogen at the 4-position.
2. Decreasing or eliminating acidity by removing the acidic –H at the 4-position
(e.g. 4,4-dialkyl derivatives) abolishes anti-inflammatory activity.
3. If acidity is enhanced too much, anti-inflammatory and sodium retaining
activities decrease, while other properties such as uricosuric effect increases.
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

Pyrazolidinedione derivatives - SAR

O

H 4 N
R 1 N
O

4. A single alkyl group at the 4-position enhances anti-inflammatory activity. Although n-butyl group
enhances activity to a maximum extent, propyl and allyl analogues also possess anti-inflammatory
activity.
5. Introduction of polar functions in the alkyl group like hydroxylation of n-butyl group at γ-position
decrease the anti-inflammatory activity but increase the uricosuric effects.
6. Substitution of 2-phenylthioethyl group at 4-position produce antigout drug (Sulfinpyrazone).
7. The presence of both phenyl rings is essential for anti-inflammatory effect.
8. Various substituents 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, is more
active and have quicker onset of action. Other derivatives such as methyl, chloro or nitro groups
also possess activity

Anthranilic acid derivatives

Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

Anthranilic acid derivatives - SAR

1. Substitution on the anthranilic acid ring generally reduces the activity.

2. Substitution on the N-aryl ring can lead to conflicting results. The order of potency
on monosubstitution with CF3 is 3’>2’>4’ (Flufenamic acid) and with chlorine the
order is 2’>3’>4’.
3. In disubstituted derivatives, where the nature of the two substituents is the same,
2’,3’-disubstitution appears to be most active (Mefenamic acid).
4. The NH moiety of anthranilic acid is essential for activity. Substitution of NH function
with O, S, CH2, SO2, N-CH3 etc., reduces the activity significantly.
5. Anthranilic acid derivatives are active whereas the m- and p- aminobenzoic acid
analogues are not active

Arylalkanoic acid derivatives

Indole acetic acid derivatives and Indene acetic acid derivatives:
Example: Indomethacin and Sulindac
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

Arylalkanoic acid derivatives

5

1. Replacement of the carboxyl group with other acid functionalities decreases activity and the amide
analogue is inactive
2. Acylation of the indole nitrogen with aliphatic carboxylic acid or arylalkyl carboxylic acid results in
decreased activity.
3. The N- benzoyl derivatives substituted with F, Cl, CF3 or S-CH3 groups at p-position are more active.
4. The 5-position of the indole when substituted with OCH3, F, N(CH3)2, CH3, COCH3 are more active.
5. The presence of indole ring nitrogen is not essential for activity because the corresponding 1-
benzylidene analog (Sulindac) was active.
6. Alkyl groups especially methyl group at 2-position is much active than aryl substituted analogs.
7. Substitution of a methyl group at the α-position of the acetic acid side chain leads to equipotent
analogs

Pyrrole acetic acid derivatives

SAR
Replacement of p-toluoyl group with a p-chlorobenzoyl moiety
produces little effect on activity whereas introduction of a methyl group
in the 4th position and 5-p-chlorobenzoyl ring analog (Zomepirac) is
nearly 4 times more potent than tolmetin
Anti-Inflammatory Agents - Dr. Venkatesh 02-02-2023

Aryl- and Heteroaryl acetic/propionic acid derivatives

Oxicams
OH O
C R
NH
N
S R'
O O
SAR
1. Optimum activity was observed when R’ is methyl substituent.
2. The carboxamide substituent R is generally an aryl or heteroaryl substituent. Alkyl
substituents are less active.
3. N-heterocyclic carboxamides (Piroxicam) are generally more acidic and more
active.
4. Interchanging of benzene ring with thiophen (Tenoxicam) gives biologically active
compounds.