Faran Ali

Medicinal Chemistry of Non-

Steroidal Anti-Inflammatory Drugs
1
(NSAIDs)
 Non-Steroidal Anti-Inflammatory Drugs
(NSAIDs)
•NSAIDs are a class of drugs that relieve pain, reduce inflammation (redness and
swelling) and bring down a high temperature (fever).

•NSAIDs are used to treat a wide range of conditions: Headaches, painful periods,
toothache, sprains and strains infections, such as the common cold or the flu
inflammation of the joints (arthritis) and other tissues

•NSAIDs work by blocking the production of prostaglandins, chemical messengers

that often are responsible for the pain and swelling of inflammatory conditions.

2
 Mechanism of Actions for NSAIDs

The prostaglandins are the mediatiors of inflammation. Inflammatory response

is the body's natural response that occurs immediately following tissue damage.

Most of the The NSAIDs are irreversible inhibitors of cyclooxygenase activity,

thus they prevent the formation of prostaglandins and consequently reducing the
signs and symptoms of inflammation.

Prostaglandins are a family of chemicals that are produced by the cells of the
body in response to illness or injury. They promote inflammation, pain, and fever;
support the blood clotting function of platelets; and protect the lining of the
stomach from the effects of acid.

4
 What is the basic difference between traditional NSAIDs and
COX-2 inhibitors?

Selective COX-2 inhibitors are NSAIDs that selectively block the COX-2
enzyme and not the COX-1 enzyme. Blocking this enzyme prevents the
production of prostaglandins by the COX-2 enzyme that often cause the pain and
swelling of inflammation and other painful conditions. Because they selectively
block the

With traditional antiinflammatory drugs such as aspirin, inflammation is reduced

by blocking Cox-2, but the protective mucus lining of the stomach is also reduced
because Cox-1 is blocked, which can cause stomach upset, ulceration, and
bleeding from the stomach and intestines..

5
 Examples of NSAIDs
Aspirin
Indometacin (Indocin)

2-acetoxybenzoic acid

Diclofenac (Voltaral) 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy

-2-methyl-1H-indol-3-yl}acetic acid

2-(2-(2,6-dichlorophenylamino)
phenyl)acetic acid
6
 Examples of NSAIDs
Ketoprofen
Ibuprofen (brufen) (dawfen)
2-(4-(2-methylpropyl)phenyl)
propanoic acid

(RS)-2-(3-benzoylphenyl)propanoic acid

Paracetamol Mefenamic acid

N-(4-hydroxyphenyl)acetamide 2-(2,3-dimethylphenyl)aminobenzoic acid

10
 Examples of NSAIDs
Nabumetone (Relafen) Naproxen (synflex) Phenylbutazone

4-butyl-1,2-diphenyl-pyrazolidine
4-(6-methoxy-2-naphthyl)-2-butanone (+)-(S)-2-(6-methoxynaphthalen-2-yl) -3,5-dione
propanoic acid
Celecoxib (Celebrex)
Piroxicam (Feldene)

4-[5-(4-Methylphenyl)-3-(trifluoromethyl) (8E)-8-[hydroxy-(pyridin-2-ylamino)methylidene]-
pyrazol-1-yl]benzenesulfonamide 9-methyl-10,10-dioxo-10λ6-thia-9-azabicyclo[4.4.0]8
deca-1,3,5-trien-7-one
 Arachidonic Acid

COX-1
COX Isoform Functions
COX-2
‘constitutive’
‘inducible’
Prostaglandins Prostaglandins
Thromboxane A2 Prostacyclin (PGI2)

• GI cytoprotection • Renal function(‘constitutive’)

• Inflammation
• Platelet aggregation • Vasodilation
• Pain
• Vasoconstriction • Inhibits platelet aggregation
• Fever
• Renal function • GI mucosal integrity & ulcer
Inflammatory healing
Physiologic
Physiologic

6
 NSAIDs – Salicylate Derivatives
Salicylates are derived from Salicylic acid which is a monohydroxybenzoic acid,
and are nonsteroidal anti-inflammatory drugs.
They inhibit the synthesis of prostaglandin and other mediators in the process
of inflammation and have anti-inflammatory, antipyretic and analgesic properties.

Salicylic acid (2-Hydroxybenzoic acid)

11
Synthesis of Salicylic Acid

12
 INTRODUCTION OF ASPIRIN

• Chemical name: acetyl salicylic acid

• Brand name: Disprin
• Uses: anti pyretic, analgesic, and anti-inflammatory
• Chemical class: salicylic acid derivative
• Therapeutic class: analgesic, antipyretic, and anti
inflammatory

13
 Synthesis of Acetylsalicylic Acid (Aspirin)
The synthesis of aspirin is classified as an esterification reaction

• Analgesic, antipyretic, anti-inflammatory, antiplatelet effect

14
 Structure Activity Relationship of
Salicylates
• For the optimal activity of aspirin acetyl group is necessary at position no. 2.
• Increase in carbon chain with acetyl group will decrease the activity.
• If carboxylic group is replaced by ester group its activity will decrease.
• Attachment of any substituent at position no 4 the pharmacological of
aspirin will lost.
• Halogen substituent to benzene ring result in increase activity but toxicity
increases.
• Removal of OH group from salicylic results in benzoic acid, that is less active

15
salicylic acid acetylsalicylic acid
 Introduction of paracetamol
• Chemical name:4 acetamide phenol, acetaminophen
• Brand name: Panadol, calpol
• Uses: anti pyretic, analgesic
• Chemical class: para amino pheol derivative
• Therapeutic class: analgesic, antipyretic.

16
 NSAIDs -The Para-amino Phenol
Derivatives

N-(4-Etoxyphenyl)acetamide N-(4-Hydroxyphenyl)acetamide

20
 Synthesis of Paracetamol
•The nitro group on 4-nitrophenol was reduced with sodium borohydride. The resultant
4-aminophenol is then acetylated with acetic anhydride.

HNO3

18
 SAR of Paracetamol

• Acetyl group must be present for the optimal activity of

paracetamol.

• No substitution should present at position no 2,4,5 and 6.

• The replacement of phenolic group of paracetamol with

ethoxy group, result in the formation of a metabolite that is
more toxic.
 Pyrazolone and Pyrazolidinedione
NSAIDs -
Derivatives
 1-phenyl-2,3-dimethyl-3-pyrazolin-5-one and 1,2-diphenylpyrazolidin-3,5-dione
derivatives

20
 Pyrazolidinedione Derivatives -
Phenylbutazone
Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) effective in
treating fever, pain, and inflammation in the body.
Phenylbutazone has analgesic ve antipyretic effects with similar potency as
aminophenazone and phenazon. It has enhanced antiinflammatory effects and
is used to treat rheumatoid arthritits
Synthesis: Phenylbutazone and its derivatives could be prepared from
condensation of n-butylmalonic acid ester like substituted malonic
acid
H
O
H9C4
COOC2H NH N
C2H5ONa O N
H9C4 +
5 CH
NH
COOC2H5
esters and 1,2-diphenylhydrazine Fenilbutazon
Phenylbutazone 24
 Pyrazolone Derivative - Dipyrone (Novalgene,
Metamizole sodium)

A drug that has analgesic, anti-inflammatory, and antipyretic

properties.
Associated with acute condition involving a severe and dangerous
leukopenia
 SAR for Pyrazolidinediones C4 H9

4
O
3

(phenylbutazone) O
5
1
N
2N

• The butyl group of carbon 4 may be replaced by propyl or allyl and

show similar activity.
•The meta substitution of the aryl ring are inactive but para
substitution such as CH3, Cl, NO2 or OH retains activity.
•Replacement of nitrogen in pyrazolidines with oxygen yield
isoxazole analog which is as active as pyrazolidine derivatives.
• Decreasing pKa values of phenyl butazone analogs have shorter half lives
decreasing anti inflammatory activity
• If pyrazolidine ring is replaced with cyclopentane or cyclopenten the resulting
compounds are inactive

23
NSAIDs - N-Arylanthranilic acid derivatives
(Fenamates)

 Fenamates are N containing analogues of salicylates 24

 Fenamates- Mefenamic acid
Mefenamic acid is an anti-inflammatory painkiller (NSAID).
It is used to treat painful conditions such as arthritis, pain associated with
heavy menstrual bleeding, and pain after surgical operations.
Mefenamic acid is a competitive inhibitor of COX-1 and COX-2, which are
responsible for the first step in prostaglandin biosynthesis

2-(2,3-dimethylphenyl)aminobenzoic acid

•Synthesis: via reaction of 2-chlorobenzoic acid and 2,3-

dimethylaniline

25
 NSAIDs - Heteroaryl Acetic Acids and Propionic Acid
Derivatives

• Important class of NSAID drugs, classified according to aryl and heteroaryl

acetic acid derivative
• Typically used for treatment of rheumatoid arthritis

 Indole and Indene Acetic Acids (Arylalkanoic acids)

 Propionic Acid Derivatives
 Heteroaryl Acetic Acids
 Enolic acids
 Alkanones: Nabumetone

26
 Indole and Indene Acetic Acids
(Arylalkanoic acids) - Indometacin

• Chemical name: indomethacin

• Chemical class: analgesic, anti inflammatory, anti gout
• Description:-
• Indometacin is one of the commonly used and the most effective
NSAIDs to reduce fever, pain, stiffness, and swelling.
• Addition of OH group at ortho and meta position will reduce its
activity
 Structure
Activity
Relationship of
Indomethacin

28
 NSAIDs -Propionic Acid Derivatives

Arylpropionic acid derivatives are effective and useful NSAID’s.

They may offer significant advantages over aspirin and indomethacin
since they are usually better tolerated. However, they still share all of the
detrimental features of all the NSAID’s.

Ibuprofen (Brufen) was the first member of the propionic acid class
of NSAID’s to come into general use.
The S-isomer is more active than the R-isomer 29
 Naproxen (Synflex) ) is one of the most widely used NSAID’s.
 SYNTHESIS OF IBUPROFEN
•Ethyl 4-isobutylphenyl acetate, sodium ethoxide and diethylcarbonate
condensation gives 4-isobutyl phenyl malonate. Methylation is done with
methyl iodide and after decarboxylation ibuprofen is obtained.

30
 Synthesis of Naproxen
•Naproxen has been industrially produced by Syntex as
follows

31
 Heteroaryl Acetic Acids Derivatives -
Diclofenac

2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid

Diclofenac belongs to a class of drugs called (NSAIDs) that are used for
the treatment of mild to moderate pain, fever, and inflammation.

40
 Structure and Binding of COX-1
and COX-2
X-ray crystal structure analysis of COX-1 and COX-2 enzyme show
differences in their structures (different amino acid sequence).
COX-2 has smaller group valine in the active site whereas COX-1 has
larger isoleucine. This results in an increased volume of side pocket in
COX-2 enzyme which enables selective inhibition.

valine isoleucine
Simple competitive inhibition of COX-1 by COX-2 inhibitors is thought to occur
because of lack of access to the side pocket

34