Analgesics, Anti-pyretics and NSAIDs

Fever usually results from microbes such as bacteria or viruses triggering the body’s defence
mechanisms. This activates certain types of cells, some of which release the substance
interleukin. Prostaglandin is another chemical released by the body that plays a part in this
process. Prostaglandin is induced by bacterial pyrogens and is produced in the CNS.
Interleukin affects the hypothalamus, which is the part of the brain that regulates body
temperature, signalling it to raise the temperature by a few degrees. Prostaglandins causes
inflammation.
Antipyretic analgesics or febrifuges are remedial agents that lower the temperature of the
body in pyrexia i.e., in situations when the body temperatures has been raised above normal.
In therapeutic doses they do not have any effect on normal body temperature. They exert
their action on the heat-regulating centre in the hypothalamus. Analgesics may be defined
as–‘agents that relieve pain by elevating the pain threshold without disturbing
consciousness or altering other sensory-modalities’. Besides, ‘pain’ may also be defined in
psychological perspective as—‘a particular type of sensory experience distinguished by
nerve tissue from sensations, such as : touch, heat, pressure and cold’
Nonsteroidal anti-infl ammatory drugs (NSAIDs) are used primarily to treat infl
ammation, mild-to-moderate pain, and fever. Specific uses include the treatment of
headache, arthritis, sports injuries, and menstrual cramps. Aspirin is used to inhibit the
clotting of blood and prevent strokes and heart attacks in individuals at high risk. NSAIDs
are also included in many cold and allergic preparations.
Classification

 p-Amino phenol derivatives: Paracetamol, Phenacetin

 Salicylic acid derivatives: Aspirin, Diflunisal, Salol, Methyl salicylate, Sodium
salicylate, Salsalate, Sulphasalazine.
 Quinoline derivatives: Cinchophen, Neocinchophine, Thalline.
 Pyrazolidinedione derivatives: Phenylbutazone, Oxyphenbutazone, Sulphinpyrazone.
 Pyrazolone derivatives: Dipyrone, Phenazone, Aminophenazone.
 Anthranilic acid derivatives: Mefenamic acid, Flufenemic acid, Meclofenamic Acid.
 Aryl acetic acid derivatives: Diclofenac, Ibufenac, Fenclofenac.
 Aryl propionic acid derivatives: Ibuprofen, Flurbiprofen, Naproxen, Ketoprofen.
 Heteroaryl acetic acid derivatives: Indomethacin, Sulindac, Tolmetin, Ketorolac.
 Oxicams: Piroxicam, Meloxicam, Tenoxicam.
 Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib.
 Gold compounds: Auronofin, Aurothioglucose, Aurothioglucamide, Aurothiomalate
sodium.
 Miscellaneous: Nabumetone, Nimesulide, Analgin.
 Drugs used in gout: Allopurinoll, Probenecid, sulphinpyrazon

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 p- Aminophenol Derivatives

These derivatives possess analgesic and antipyretic actions but lack anti-inflammatory effects.
Acetanilide was introduced into the therapy 1886 as an antipyretic–analgesic agent, but was
subsequently found to be too toxic, having been associated with methemoglobinemia and
jaundice. Phenacetin was introduced in the following year and was widely used, but was
withdrawn recently because of its nephrotoxicity. Acetaminophen (paracetamol) was
introduced in 1893 and it remains the only useful agent of this group used as an antipyretic–
analgesic agent.
Paracetamol
Paracetamols exist as white crystalline powder, sparingly soluble in water, soluble in alcohol,
and very slightly soluble in methylene chloride
Mechanism of Action
It causes antipyresis by exerting its action on the hypothalamic heat-regulating centre, and
analgesia by enhancing the pain threshold profile appreciably. It is found to lack the anti-
inflammatory activity of salicylates. Paracetamol primarily inhibits COX-2 in the brain. This
inhibition reduces the production of prostaglandins, which are signaling molecules involved
in inflammation, pain, and fever. By lowering prostaglandin levels in the brain, paracetamol
helps alleviate pain and reduce fever.
Therapeutic Application
1- As anti-pyretic: to reduce body temperature during fever.
2- As Analgesic: to relieve headache, toothache, myalgia etc.
3- It is the preferred anti-pyretic and analgesic in patients with peptic ulcer, haemophilia,
bronchial asthma and children.
Synthesis

It may be prepared by the reduction of p-nitrophenol and the resulting p-aminophenol is

acetylated by a mixture of acetic anhydride and glacial acetic acid. The crude product can be
purified by recrystallization from a water : ethanol mixture (1 : 1) or from other appropriate
solvents.

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Structure Activity Relationship
1- Aminophenol ring is essential for antipyretic activity.
2- Amino and hydroxyl groups both should be at para positions, if not activity will be
terminated.
3- If both hydroxyl and acetyl groups removed it becomes aniline which is toxic in nature.
4- If we substitute any of the functional groups at position 1 acetamide and at position 2
hydroxyl, therapeutic activity will be terminated.
Dose: Usual oral adult dose is 500 mg to 1 g for three or four times a day
Note: Hepatic necrosis and death have been observed following over dosage; hepatic damage is
likely in an adult who takes more than 10 g in a single dose or if a 2-year old child takes more than
3 g.

Salicylic Acid Derivatives

Salicin was the first compound belonging to this category that exhibited medicinal value. It was
employed as a substitute for quinine as a febrifuge. Acetylsalicylic acid or aspirin was first
synthesized by Gerhardt in 1852, it gained entry into the world of medicine through Dreser, who
coined a new name ‘aspirin’ derived from “a” of acetyl and adding to it “spirin”, an old name of
salicylic or spiric acid, obtained from spirea plants. Salicylic acid derivatives includes,

Mechanism of Action
Salicylic acid derivatives works by inhibition of cyclooxygenase (COX) enzymes( COX-
1 and COX-2) leading to reduced prostaglandin synthesis and consequent anti-
inflammatory, analgesic, and antipyretic effects.
Therapeutic Application
1. Salicylates posses antipyretic, analgesic, and anti-inflammatory properties.
2. Salicylates promote the excretion of uric acid and they are useful in the treatment of
gouty arthritis.
3. Salicylates (aspirin) have ability to inhibit platelet aggregation, which may contribute
to heart attack and strokes, and hence, aspirin reduces the risk of myocardial infarction.
4. In addition, a recent study suggested that aspirin and other NSAIDs might be protective

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 against colon cancer.
Synthesis:
Aspirin

Acetylation of salicylic acid with acetic anhydride yields aspirin. The crude product may
be recrystallized from benzene, mixture of acetic acid and water (1 : 1) or various other
non-aqueous solvent. Dose : Usual, adult, oral 300 to 650 mg every 3 or 4 hours ; or 650
mg to 1.3 g as the sustained- release tablet every 8 hours ; Rectal, 200 mg to 1.3 g 3 or 4
times a day.

Salol

It may be prepared by heating together salicylic acid and phenol at 120°C in the presence
of phosphorus oxychloride or carbonyl chloride (COCl2)

Salsalate

It is prepared by the condensation of two moles of salicylic acid in the presence of thionyl chloride.It
has antipyretic, analgesic and anti-inflammatory properties similar to those of Aspirin.

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Sodium Salicylate

It may be prepared by mixing together a paste of salicylic acid in distilled water with
sufficient pure sodium carbonate in small lots at intervals. The reaction mixture is filtered through
iron-free filter paper and evaporated to dryness under reduced pressure. Caution must be taken to
avoid contact with iron which will alter the original white colour of the product.
Structure Activity Relationship of Salicylic acid derivatives
1. Substitution on either the carboxyl or phenolic hydroxy groups may affect the
potency and toxicity.
2. Reducing the acidity of the COOH, e.g., the corresponding amide
(salicylamide), retains the analgesic action of salicylic acid but i 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 the 5-position of salicylic acid increases anti-
inflammatory activity (diflunisil).
6. Substitution on either the carboxyl or phenolic hydroxyl group may affect the
potency and toxicity. Benzoic acid itself has only week activity.

Quinoline Derivatives
The basic quinoline nucleus, present in the quinine molecule, contributes to antipyretic activity to
a certain extent. Two quinoline derivatives first synthesized though possessed significant
antipyretic action, yet could not gain cognizance as a drug because of their high toxic effects on
the red blood corpuscles and damaging after-effect on kidneys. These were, thalline and 6-methoxy
quinoline.

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Mechanism of Action
The antipyretic and analgesic effects of quinoline derivatives such as cinchophen are primarily
due to their ability to inhibit COX enzymes and reduce prostaglandin synthesis, modulate
inflammatory cytokines, affect the central nervous system, and inhibit neutrophil activity.
Therapeutic Application:
1- As anti-pyretic: to reduce body temperature during fever.
2- As Analgesic
3- In management of chronic gout and rheumatic conditions.
Synthesis:
Cinchophen: Method-I : From o-Amino benzaldehyde cyanohydrin

Condensation of o-aminobenzaldehyde cyanohydrin and methylphenyl ketone yields

cinchophen.
Method-II : From Isatin:

Cinchophen may be prepared by the interaction of isatin and acetophenone in the presence of
excess of aqueous ammonia.
Dose: 300 to 600 mg.
Note: Because of its high toxicity, e.g., liver damage resulting in acute jaundice,
cinchophen has been completely withdrawn and replaced by safer drugs.

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Neocinchinophen

It occurs through the reaction of p-toluidine, ethyl pyruvate and benzaldehyde in the presence of a
small amount of nitrobenzene, when the products get condensed to form an intermediate
compound. This when subjected to dehydrogenation yields neocinchophen.
Dose: 500 mg.

Pyrazolones and Pyrazolodiones

These are the first synthetic organic compounds which were successfully used as drugs. These
are heterocyclic compounds and the pharmacodynamic spectrum of these compounds has a close
resemblance to that of aspirin.

Name R
R1
Phenyl butazone –H –C4H9
Oxyphenbutazone –OH –C4H9

Sulphinpyrazone –H –
(CH2)2SOC6H5

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Mechanism of Action

Pyrazolones (Dipyrone,phenazone, Aminophenazone)

 Cyclooxygenase (COX) Inhibition: Pyrazolones inhibit COX enzymes (COX-1 and

COX-2), reducing the synthesis of prostaglandins, which are mediators of pain and
inflammation.
 Prostaglandin E2 (PGE2) Suppression: Decreases fever by reducing PGE2 levels,
which regulate body temperature.
 Nitric Oxide (NO) Modulation: Some pyrazolones increase NO production,
contributing to vasodilation and anti-inflammatory effects.
 Central Analgesic Effects: May involve modulation of central pain pathways,
potentially affecting the endogenous opioid system.

Pyrazolidinediones (Phenylbutazone, oxyphenylbutazon, Sulphinpyrazone)

 Cyclooxygenase (COX) Inhibition:

 Leukocyte Modulation: Reduce leukocyte migration and accumulation at inflammation
sites, diminishing the inflammatory response.
 Phospholipase A2 Inhibition: Reduces the release of arachidonic acid, a precursor to
prostaglandins, further decreasing prostaglandin synthesis.
 Oxidative Stress Reduction: Some pyrazolidinediones have antioxidant properties, which
help reduce oxidative stress associated with inflammation.

Therapeutic Application

 Pyrazolones: Primarily used for pain relief, fever reduction, and in conditions with
significant inflammation. Dipyrone, in particular, is noted for its additional spasmolytic
effects.
 Pyrazolidinediones: Primarily used in the management of inflammatory conditions like
rheumatoid arthritis and gout, with additional applications in pain relief and fever
reduction.

Synthesis

Phenazone
It may be prepared by the condensation of one mole each of phenyl-hydrazine and the lactim- form
of ethylacetoacetate when 1-phenyl-3-methyl-pyrazolone is obtained by the elimination of a mole
each of water and ethanol. The resulting product is subjected to methylation either with methyl
iodide or dimethyl sulphate to yield phenazone

As antipyretic, it possesses local anaesthetic and styptic actions and solutions containing 5% are
used locally as ear drops.

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Aminophenazone
Aminopyrine (amidopyrine) may be prepared commercially first by treating antipyrine
with nitrous acid to yield nitrosoantipyrine. The resulting product can now be routed
through two different course of reactions, namely : (a) treatment with two moles of
chloroacetic acid followed by decarboxylation producing thereby aminopyrine ; and (b)
treatment with dimethyl ether in the presence of catalyst and at high pressure eliminates a
mole of water to give aminopyrine. However, aminopyrine can be prepared conveniently
in the laboratory by first treating antipyrine with bromine partially to obtain 4-bromo-
antipyrine which on subsequent treatment with dimethylamine yields the official
compound.
It has antipyretic actions similar to those of phenazone but owing to the risk of
agranulocytosis its use is discouraged and mostly abandoned. However, the gentisate has
sometimes been used. Aminopyrine is often employed in drug metabolism studies.
Dose : 300 to 500 mg ; max in 24 hours 3 g.

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Synthesis

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Dipyrone
It possesses similar properties to that of amidopyrine. Its use is really justified only in
serious orlife-threatenting situations where no alternative antipyretic is available or suitable.
Its use is restricted in some countries.
Dose : Usual, 0.5 to 1 g, 3 times per day

Phenylbutazone

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Phenylbutazone may be prepared by condensation either from diethyl-n-butyl malonate or n-
butyl malonyl chloride with hydrazobenzene in either solution at 0°C with the aid of pyridine.
Subse- quently, the pyridine is extracted with aqueous hydrochloric acid, the phenylbutazone is
extracted with aqueous sodium bicarbonate and finally precipitated by addition of hydrochloric
acid.

Structure-Activity Relationship of Pyrazolidinediones

1. Substitution of 2-phenyl thio ethyl group at the 4th position
produces antigout activity (sulphinpyrazone).
2. Presence of both the phenyl groups is essential for neither
anti-inflammatory nor analgesic activity.
3. Presence of a keto group in the γ-position of the butyl side
chain produces the active compound.
4. m-Substitution of aryl rings of the phenylbutazone gives uniformly inactive compounds.
p-Substitution, such as methyl, chloro, nitro, or OH of one or both rings retains activity
5. Replacement of one of the nitrogen atom in the pyrazolidinediones with an oxygen atom
yields isoxazole analogues, which are as active as pyrazolidinediones derivatives
6. Presence of both the phenyl groups is essential for neither anti-infl ammatory nor
analgesic activity.
7. If acidity is enhanced too much, anti-infl ammatory and sodium-retaining activities
decrease while other properties, such as the uricosuric effect increases

N-Arylanthranilic Acid
N-arylanthranilic acids, commonly known as fenamates, are a class of nonsteroidal anti-
inflammatory drugs (NSAIDs) with anti-inflammatory, analgesic, and antipyretic properties.
These compounds are derivatives of anthranilic acid and include drugs such as mefenamic acid,
flufenamic acid, and tolfenamic acid, meclofenamic acid.

Mechanism of Action

N-arylanthranilic acids (fenamates) exhibit their therapeutic effects through multiple

mechanisms:
1. COX Inhibition: Non-selective inhibition of COX-1 and COX-2 enzymes reduces
prostaglandin synthesis, leading to decreased inflammation, pain, and fever.
2. Ion Channel Modulation: Modulation of chloride (blocking Cl channels) and other ion

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 channels contributes to analgesic effects.
3. Leukotriene Inhibition: Inhibition of the lipoxygenase pathway reduces leukotriene
synthesis, further decreasing inflammation.
4. Membrane Stabilization: Stabilizing cell membranes reduces the release of inflammatory
mediators.
5. NF-κB Inhibition: Reducing NF-κB activity decreases the expression of inflammatory
genes.

Therapeutic Application
They are used to treat various conditions due to their anti-inflammatory, analgesic, and antipyretic
properties

 Mefenamic acid: Dysmenorrhea, mild to moderate pain, Rheumatoid arthritis,

osteoarthritis menorrhagia, and migraine.
 Flufenamic acid: Rheumatoid arthritis, osteoarthritis, and mild to moderate pain.
 Meclofenamic Acid: Rheumatoid arthritis, osteoarthritis

Synthesis
Mefenamic Acid

An analogues approach by reaction of o-chloro benzoic acid with 2,3-dimethyl aniline.

Dose : Usual, adults, children over 14 years of age, oral, 500 mg, followed by 250 mg 4 times
daily. Caution : Must not be used for more than 7 days

Flufenamic Acid

Dose : 400 to 600 mg per day in divided doses.

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Meclofenamic Acid
Synthesis

Structure Activity Relationship

1. Substitution on the anthranilic acid ring generally
reduces the activity.
2. The NH moiety of anthranilic acid is essential for
the activity as the replacement of NH function with O,
CH2 , S, SO2 , N-CH3 , or NCOCH3 functionalities
significantly reduced the activity.
3. The position of the carboxyl function is important for the activity of anthranilic acid
derivatives that are active, whereas the 3 and 4 amino benzoic acid analogues are not active.
4. Replacement of carboxylic acid function with the isosteric tetrazole
results in the retention of anti-inflammatory activity
5. In disubstituted derivatives, where the nature of the two substitutes is the
same 2´, 3´-disubstitution appears to be the most effective (mefenemic acid).
6. The NH moiety of anthranilic acid is essential for the activity as the replacement of NH
function with O, CH2 , S, SO2 , N-CH3 , or NCOCH3 functionalities significantly reduced
the activity.
7. The most active aryl anthranilic acid derivative have substituent at position 2', 3' and 6’ of
the Ring attached with Anthranilic acid nitrogen.

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 Aryl Acetic Acid Derivatives
Aryl acetic acid derivatives are class of non-steroidal anti-inflammatory drugs with anti-
inflammatory analytic and antibiotic properties these compounds includes
 Diclofenac
 Ibufenac
 Fenclofenac

Mechanism of Action
Aryl acetic acid derivatives work by inhibiting cyclooxygenase (COX) enzymes, specifically
COX-1 and COX-2. These enzymes are essential for converting arachidonic acid into
prostaglandins, which are compounds that mediate inflammation, pain, and fever. By blocking
COX enzymes, aryl acetic acid derivatives reduce prostaglandin synthesis, leading to decreased
inflammation, pain, and fever. This inhibition also impacts platelet aggregation and can reduce the
protective lining of the stomach, potentially causing gastrointestinal side effects. The overall effect
is an anti-inflammatory, analgesic, and antipyretic response.

Therapeutic Applications
Aryl acetic acid derivatives are primarily used for their anti-inflammatory, analgesic, and
antipyretic properties. Here are some of their main therapeutic applications:
 Rheumatoid Arthritis
 Osteoarthritis
 Ankylosing Spondylitis
 Acute Gouty Arthritis
 Postoperative Pain
 Dysmenorrhea
 Musculoskeletal Pain
 Bursitis and Tendinitis
 Migraine
Diclofenac
Dose : 20 to 50 mg 3 times day. It is also given as a suppository.
Structure-Activity Relationship of Diclofenac
1. There are two benzene rings are present in diclofenac sodium. Both are essential and
unsubstituted. If we remove any one of the group, the therapeutic activity will be
terminated.
2. There is an amino bridge present in between two rings in diclofenac sodium. This bridge
is essential and unsubstituted. If we change the position or presence of this bridge, the
therapeutic activity will be terminated.
3. There are two chlorides present in diclofenac sodium at position 2 and 6. Both are essential
and unsubstituted. If we remove any one with other halogen or change the position, the
therapeutic activity will be terminated.
4. There is acetic acid present at position 1 in diclofenac sodium. It is essential and

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 unsubstituted. If we change the position of this group or replace it with any other carboxylic
acid, the therapeutic activity will be terminated.

Synthesis

Aryl Propionic Acid Derivatives

Like the arylacetic acids the arylpropionic acid analogues also exhibit potent anti-inflammatory
properties besides usual antipyretic and analgesic characteristics. A few examples of this category
of compounds,
 Ibuprofen flurbiprofen

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  Naproxen indoprofen
 Ketoprofen fenoprofen calcium.
Mechanism of Action
Aryl propionic acid derivatives inhibit cyclooxygenase (COX) enzymes, particularly COX-1 and
COX-2, which are involved in converting arachidonic acid into prostaglandins. By blocking these
enzymes, the drugs reduce prostaglandin synthesis, leading to decreased inflammation, pain, and
fever. This inhibition also affects platelet aggregation and can reduce the stomach's protective
lining, potentially causing gastrointestinal side effects. Their overall effect is anti-inflammatory,
analgesic, and antipyretic.
Therapeutic Applications
Aryl propionic acid derivatives are primarily used for their anti-inflammatory, analgesic, and
antipyretic properties. Here are some of their main therapeutic applications:
 Rheumatoid Arthritis
 Osteoarthritis
 Ankylosing Spondylitis
 Acute Gouty Arthritis
 Postoperative Pain
 Dysmenorrhea
 Musculoskeletal Pain
 Bursitis and Tendinitis
 Migraine
Structure

Naproxen ketoprofen

flurbiprofen Ibuprofen

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Ibuprofen
Synthesis

p-Isobutyl acetophenone is prepared by the acetylation of isobutyl benzene which upon treatment
with hydrocyanic acid yields the corresponding cyanohydrin. This on heating with hydrogen iodide
in the presence of red phosphorous helps to reduce the benzylic hydroxyl moiety ; further
hydrolysis of the nitrile groups gives the official compound.
Dose: Usual, oral adult, analgesia (dysmenorrhea), 200 to 400mg 4 to 6 times per day ; in
rheumatoid arthritis, osteoarthritis, 300 to 400mg 3 or 4 times daily.

Structure-Activity Relationship of Ibuprofen

In ibuprofen, 2 groups are attached at position 1 and 4.

1. At position 1, there is alkyl group with any other group, therapeutic activity will be
terminated.
2. At position 4, there is carboxylic acid functional group which is propionic acid, in
combinational chemistry, propionic acid was substituted by acetic acid which leads to the
formation of Ibufenac which can be used therapeutically but have increased therapeutic
effects.

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 Heteroaryl Acetic Acid Derivatives
This constitutes an important class of non-steroidal anti-inflammatory drugs which have gained
recognition in the recent past. A few classical examples of this group are,
 Indomethacin
 Sulindac
 Tolmetin
 ketorolac

Mechanism of Action

Heteroaryl acetic acid derivatives inhibit cyclooxygenase enzymes, particularly COX-1 and COX-
2. These enzymes convert arachidonic acid into prostaglandins and thromboxanes, which are key
mediators of inflammation, pain, and fever. By blocking COX enzymes, these drugs reduce the
production of prostaglandins. Prostaglandins play a crucial role in inflammation, pain
sensitization, and fever. Lowering prostaglandin levels results in reduced inflammation, pain, and
fever.

Therapeutic Applications

Heteroaryl acetic acid derivatives are primarily used for their anti-inflammatory, analgesic, and
antipyretic properties. Here are some of their main therapeutic applications:
 Rheumatoid Arthritis
 Osteoarthritis
 Ankylosing Spondylitis
 Acute Gouty Arthritis
 Postoperative Pain
 Dysmenorrhea
 Musculoskeletal Pain
 Bursitis and Tendinitis
 Migraine

Indomethacin
p-Methoxy phenyl diazonium chloride is obtained by the diazotization of p-anisidine which on
reduction with sodium sulphite yields p-methoxy phenyl hydrazine. The resulting product
undergoes the Fischer-indole synthesis in the presence of methyl levulinate to form a hydrazone
which on intra-molecular rearrangement gives an enamine. This on cyclization loses a molecule
of ammonia and forms an intermediate compound. It is then hydrolysed to the corresponding acid
which is re-esterified via the anhydride to give the tert-butyl ester. Finally acy ylation with p-
chlorobenzoyl chloride followed by debutylation gives rise to the official compound.

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Dose: In gout, usual, adult, oral, 100 mg initially, followed by 50 mg 3 times daily until pain is
relieved ; As antirheumatic, oral, 50 mg 2 or 3 times daily ; As antipyretic, oral, 25 to 50 mg 3
times daily
Synthesis

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Structure-Activity Relationship of Heteroaryl acetic acid derivatives

1. Placement of other acidic functionalities instead of the carboxyl group decreases activity
and the amide derivatives are inactive.
2. Substituents of R1 useful for increasing anti-infl ammatory activity are ranked as C6 H4
CH2 > alkyl > H.
3. Acylation of the indole nitrogen with aryl/alkyl carboxylic acids results in the decrease of
activity.
4. Presence of substituents on the N-benzoyl derivatives in the p-position with F, Cl, CF3 , or
S-CH3 groups provide greatest activity.
5. X substituents activity are ranked as 5-OCH3 > N (CH3 )2 > CH3 > H.
6. The presence of indole ring nitrogen is not essential for activity because the corresponding
1-benzylidenylindene analogue (sulindac) is also active.
7. Alkyl groups especially methyl group at 2nd position is much active than aryl substituted
analogues.
8. Substitution of a methyl group at the α position of the acetic acid side chain leads to
equiactive analogues.
9. Anti-infl ammatory activity was displayed only by the dextrorotatory enantiomer with
similar absolute configuration; it has 25 times the activity of phenylbutazone.

References
 Lectures by Dr. Mohsin Abbas Khan
 Textbook of Medicinal Chemistry—V. Alagarsamy.
 Medicinal Chemistry— Ashutosh Kar.
 Medicinal Chemistry—D. Sri Ram

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