This document summarizes different types of non-steroidal anti-inflammatory drugs (NSAIDs). It discusses the classification of NSAIDs including salicylates like aspirin, propionic acid derivatives like ibuprofen, anthranilates like mefenamic acid, and acetic acid derivatives like indomethacin. It covers the mechanism of action, structure-activity relationships, metabolism and pharmacological properties of various NSAIDs. The key mechanisms involve inhibiting the cyclooxygenase enzymes COX-1 and COX-2 to reduce inflammation.

1. Presented by :- Mukesh Kumari
Submitted to:- Prof. Narsimahan B.

2. Introduction
• Drugs that are not steroids , can cure and prevent
inflammation called Non-steroidal Anti-
inflammatory Drugs (NSAIDs).
• Examples :- Penicillin (sore throat) , Colchicine
(acute gout) , Allopurinol (chronic gout).
• Aspirin is recognised as progenitor of NSAIDs.
• Later Phenlybutazone , Indomethacin and
Ibuprofen were discovered.
• Ibuprofen was 1st NSAID approved for non-
prescription(OTC).

3. Cont…….
• Used for treatment of Rheumatoid Arthritis ,
osteoarthritis , Acute gouty arthritis and
Dysmenorrhea.

4. Evolution Of NSAIDs

5. Classification Of NSAIDs

6. Inflammation
• Inflammation means, “Response of the body to injurious stimuli”.
• Si
S b n sigsyisigklfgcnvgcfgccgfg
heat / fever (due to capillary dilation)
swelling ( due to passage of plasma from blood
stream to damaged site)
pain (due to destruction of tissue )
redness (due to destruction of tissue)
loss of function
• Redness is not a problem from functional point of view.
• Loss of functions because of permanent fibrosis can not be reversed

7. Fever and pain are beneficial to our body
Infection occurs
fever develops
raised temperature kills
microbes
infection clear
Tissue damage occur
pain nerve endings are
stimulated
person feels pain
Get idea about tissue
damage and tries to
remove the source of
injury

8. Raised Temperature:-
May make a person incapable for doing his job.
May inactivate several enzymes required to
maintain normal metabolism.
In extreme cases, interfere with the state of
consciousness.
Excessive Pain:-
May interfere with quality of life.
May frighten the patient.
In extreme case produce shock.

9. How does inflammation
occur ?????

10. Biosynthesis Of Prostaglandins
• Inflammation is caused by prostaglandins.
• Arachidonic acid is primary precursor of protanoids.
• Prostanoids are also called Ecosanoids.
• Arachidonic acid is a componant of the phospholipids
of cell membrane.
• Free Arachidonic acid is released by cell damage
mainly bye the action of phospholipase A2 enzyme.
• Arachidonic acid undergoes two pathways, by the
enzymes cyclogenase and lipoxygenase.

14. Prostaglandins - Nomenclature
• Nomenclature is derived from hypothetical
compound prostanoic acid.
• Prostaglandins are differ each other with regard
to functions on the five – membered ring.
• Thus prostaglandins A,B,C,D,E and F have
differently substituted cyclopentane ring.
• Subscript α and β pertains to configuration of the
hydroxyl group at position - 9.
CH3
OH
O
7-((2S)-2-octylcyclopentyl)heptanoic acid

15. Prostaglandins produce……….
• Pain:-
Peripherally Centrally
PGs sensitize nerve PGs lower the threshold for
endings to bradykinine central pain
and histamine
Pain

16. • Fever :-
tissue damage/ infection
neutrophil releases IL-1
stimulates COX-2 enzyme
increased PGE2 synthesis in hypothalamus
increase heat production or shuts down heat
lossing mechanism
Raised body temperature (fever)

17. • Inflammation :-

18. Non - steroidal anti- inflammatory drugs
(NSAIDS)………

19. Mechanism Of Action
• Act by inhibiting the action of enzymes.
• Cyclooygenase-1 and Cyclooygenase-2.
• Enzymes responsible for converting arachidonic acid to
prostaglandins.
• As a result prostaglandins cause inflammation.
• So by inhibiting the action of enzymes inflammation
can be prevented.

22. •Different mechanisms involve for inhibition of enzyme:-
Irreversible inhibitors:-
example:- Aspirin.
Reversible non – competitive inhibitors:-
example:- Paracetamol.
Reversible competitive inhibitors:-
examples:- Ibuprofen ,
Propionic acid derivatives and Oxicams.

23. General structure and properties of
NSAIDs
• Structurally consist of an acidic moiety (carboxylic acid,
enols) attached to a planar, aromatic functionality.
• Also contain a polar linking group , which attaches the
planar moiety to an additional lipophillic group.
NSAID General Structure
X
COOH

24. • Properties :-
 Relatively strong organic acids with pKa in range 3-5.
 Acidic group is essential for COX inhibitory activity.
 Differ in their lipophilicities based on lipophillic character
of their aryl group and additional lipophillic moieties and
substituents.
 Acidic group serves :
- a major binding group with plasma proteins.
- a major site of metabolism by conjugation.

25. Salicylates
• Derivatives of 2 – hydroxybenzoic acid (salicylic acid).
• Discovered in 1836 following the extraction of salicylic
acid from willow bark.
• Used madicinally as the sodium salt
replaced therapeutically in late 1800s
by acetylated derivatives , acetylsalic-
ylic acid (ASA) or Aspirin
OHO
OH
2-hydroxybenzoic acid
O
OHO
O
2-acetoxybenzoic acid

26. Drugs:-
F
F
OH
OH
O
OHO
OO
OH
salsalate
O
O
ON
H
O
O benorylate
O
OHO
O
acetylsalicylic acid
Diffunisal

27. Aspirin:-

28. Mechanism of action of Aspirin:-

29. Structure Activity Relationship (SAR)
1. Salicylic acid is simplest active anti-
inflammatory compound.
2. Carboxyl group is necessary for activity and
hydroxyl group must be adjacent to it.
3. Halogenated derivatives are active but toxic.
4. Aspirin derivatives with hydrophobic aryl group
at position-5 has greater activity than aspirin.
O O
O-
O
acetylsalicylate
R

30. Synthesis of Aspirin :-
sodium phenoxide
Na+
-
O
OH
O
OH
salicylic acid
O
OH
O
O
aspirin
Pressure
H+
OO
O
CO2

31. Synthesis of diffunisal:-
F
NH2
2,4-difluorobenzenamine
F
F
OCH3
F
F
O
H
F
OH
OH
O
C6H11ONO
OCH3
HI/CH3COOH
CO2,K2CO3
Diffunisal
-CH3I
F
F

32. Action:-
-Mainly “COX-1 selective inhibitor”.
- Bound with higher affinity by COX-1
Uses:-
- potent anti inflammatory activity.
- as mild analgesic and antipyretic activity.
Toxicities:-
-GI irritation, hypersensitivity reations.
- ototoxicity and inhibition of platelet aggregation.

33. Metabolism:-
OCOCH3
COOH
Aspirin
OH
COOH
Salicylic acid
COOGlu
CONHCH2COOH
OH
OH
Salicyluric acid
Acyl - Glucoronoide
Plasma cholinestrase
Plasma esterase
Glycine conjugation
Glucoronoid conjugation

34. Propionic acid derivatives
• Structurally derived from aryl acetic acids, referred as
“profens”.
• Characterised by general structure Ar-CH( CH3 )-
COOH.
COOH
X R
CHCOOH
CH3
NSAID general structure General structure of Propionic acid NSAIDs

35. Structure Activity Relationship:-
1. α-substituent increases cyclooxygenase inhibitory
activity and reduce the toxicity of the profens.
2. α- carbon in these compounds is chiral and S-(+)-
enantiomer of the profens is more potent
cyclooxygenase inhibitor.
3. Most profens undergo , except naproxen , are
marketed as racemates.
R
CH-COOH
CH3
General structure of Propionic acid NSAIDs

36. Drugs:-
CH3 O
CH3
CH3
OH
Ibuprofen
O
OH
CH3 O
Fenoprofen
OH
CH3
O
F
Flurbiprofen
O
OH
CH3
O
Ketoprofen
CH3 O
OH
OCH3
Naproxen

37. Ibuprofen:-
(CH3)2CHCH2 + CH3COCl
(CH3)2CHCH2 C-CH3
O
AlCl3
Ibuprofen
synthesis

38. Mechanism Of Action with Ibuprofen and Aspirin:-

39. SAR of Ibuprofen:-
1. Size of substituent R1 :-
R1 = Isobutyl substituent
(maximum activity).
= small substituent (-CH3 , -C2 H5 )
(reduced activity).
=longer substituents (-( CH2 )3 CH3 , -(CH2 )5 CH3 )
(sharply reduced activity).
2. R2 =CH3 (maximum activity), smaller or longer
substituents (H or C2 H5 , C3 H7 ) show diminish
activity.
Ibuprofen
R1
R2
R3

40. 3. Replacement of carboxyl group by an ester (COOC2
H5 ) ,alcohol (CH2 OH),amide (R3 =CONH2 )
Produce less active compounds.
4. anti-inflammatory activity resides in the S(+) isomer.

41. Action :-
- Slightly COX-1 selective except Naproxen which
is COX-2 inhibitor.
-as an anti-inflammatory compound.
-as an analgesic and antipyretic drug.
Uses :-
- Rheumatoid arthritis.
-Osteoarthritis.
.

42. Anthranilates ( Fenamates)
• Considered to be N-aryl substituent derivatives of
anthranilic acid .
• Retains the acidic properties that are characteristic
of this class.
• Mefenamic acid and Meclofenamic acid are
derivatives of anthranilic acid , Diclofenac is derived
from 2-aryl acetic acid.
X
COOH COOH
NH2
Anthranilic acid R
COOH
NH
General Anthranilate structure
NSAID general structure

43. SAR:-
R1 R2 R3
• Mefenamic acid = CH3 CH3 H
• Flufenamic acid = H CF3 H
• Meclofenamic acid = Cl Cl CH3
COOH
NH
R1
R2
R3

44. SAR:-
1. Most active anthranilic acid derivatives have
substituents at position 2,3 and 6 of the ring
attached to the anthranilic acid nitrogen from 2,3 -
disubstitution pattern usually improves activity over
the 2- substituted compounds.
2. Replacing the –NH- group in fenamic acids produce
less active compounds.
3. Carboxylic function is required at the position -2 for
biological activity.

45. Synthesis :-
• Mefenamic acid:-
• Flufenamic acid:-
COOH
Cl
+
NH2
CH3
CH3
NHCH3
CH3
COOH
O-Chlorobenzoic acid 2,3 dimethyl aniline
mefenamic acid
Cu
COOH
Cl
+
NH2
CF3
NH
CF3
COOH
O-Chlorobenzoic acid 3- trifluoro- methyl aniline
Flufenamic acid
Cu

46. Metabolism :-
• Anthranilates show more balanced excretion
than other NSAIDs with a greater fraction
being eliminated in feces.
NH
COOH
Cl Cl
Diclofenac
NH
COO - Glu
Cl Cl
Diclofenac-O-Glucuronide

47. Acetic acid derivatives
• Derivatives of acetic acid and substituent at the 2-
position is a heterocycle or related carbon cycle.
• Classified as:-
- Indene /indole acetic acid
- Pyrroles
- Oxazoles
X
COOH
Heterocycle
OH
O
R
NSAID general structure General structure for Heterocyclic Acetic
Acids

48. Indole / Indene Acetic acid
derivatives:-
F OH
CH3
O
OH
CH3
O
CH3-S=O
N
N
OCH3
C2H5
Cl
O
CH3
OH
O
Sulindac Indomethacin
Etodolac

49. • Indomethacin:-
O
H
CH3
O
N
OCH3
Cl
Indomethacin
NH2
OCH3
Cl
O
1-(4-methoxyphenyl)-1-(4-chlorophenyl)-hydrazine
+
CCH2CH2COOH
O
CH3
Leulinic acid

50. SAR:-
1. Substituents R1 useful for increasing
activity are ranked as;
R C6 H5 CH2 > alkyl >H.
2. R2 substituents for improved activity are ranked;
CH3 >H.
3. X substituents are ranked as ;
5- OCH3 > (CH3 )2 N> CH3 > H.
4. Carboxyl group is necessary for activity.
5. At position -2 , a methyl group is better than an aryl group.
2
3
OH
O
N
4
5
6
7
R1
R2
X

51. Metabolism:-
OH
CH3
O
N
OCH3
Cl
Indomethacin
CH3
O
N
OCH3
Cl
Indomethacin-O-
Glucuronide
O- Glu

52. Actions:-
- COX-1 selective inhibitor.
- Primarily show anti-inflammatory activity with
some analgesic and antipyretic activity.
Uses:-
- Rheumatoid arthritis.
- Osteoarthritis.
- Alkylosing spondylitis.
- GI ulceration and hemorrhage (limits use).
CNS Toxicities:-
- ranging from headache to delusions to psychosis and
suicidal tendencies occur along with bone marrow
depression.

53. Pyrrole Acetic acid derivatives:-
N-CH3
O
OH
O
CH3
Tolmetin
N
O
O
OH
OH
H3N
OH
O
Ketorlac

54. Synthesis:-
Tolmetin:-
NCH3
CH2CN
+ COClH3C
NCH3
CH2CN
CO
H3C
NCH3
CH2COOH
CO
H3C
Tolmetin
NaOH
AlCl3
4-mthoxy benzoyl chloride
1-methyl-2-cyano methyl pyrrole

55. Actions:-
- non - selective COX inhibitor.
- analgesic and antipyretic activity.
Uses:-
- rheumatoid arthritis
- osteoarthritis
- anasthetics

56. Pyrazoles
• Characterized by the 1-aryl-3,5-pyrazolidinedione
structure.
• Presence of proton renders these compound acidic.
• Oxyphenylbutazone is a hydroxylated derivative of
phenylbutazone.
N
N
H3C
O
O
Phenylbutazone Oxyphenylbutazone
N
N
H3C
O
O
OH

57. SAR:-
1. butyl group of carbon 4 may be
replaced by a propyl or allyl group.
2. presence of keto group in gama position
of butyl side chain produce the active compound.
3. m- substitution of the aryl rings of phenylbutazone
gives uniformly inactive compounds.
4. replacement of one nitrogen atom in the pyrazolidenes
with an oxygen atom yields an isoxazole analogue which
as active as pyrazolidene.
N
N
H3C
O
O
R
1
2
34
5

58. Synthesis:-
Phenylbutazone:-
N
N
H3C
O
O
Phenylbutazone
CH3(CH2)3CH2
CO2C2H5
CO2C2H5
+
NH
NH
Diethyl-n-butyl malonate Hydrazobenzene

59. Oxicams (Enolic acids)
• New class of 4- hydroxy-benzothiazene-3-
carbaoxamide-1,1- dioxide derivative.
• Long active and often very potent anti-
inflammatory action.

60. Selective COX-2 inhibitors
NN
CF3
CH3
H2NO2S
Celecoxib

61. Drugs:-
N
S
HN
OH
R
CH3
OO
O
Piroxicam
Isoxicam
Sudoxicm
N
O
N
S
N
R
=
=
=

62. Common unwanted effects of NSAIDs
1. Gastrointestinal side effects:-
dyspepsia, nausea and diarrhoea
also occur.
2. Renal disease:-
chronic consumption of phenacetin or
paracetamol could cause chronic nephritis and renal papillary
necrosis.
3. Skin reaction:-
mefenamic acid and sulindac can cause mild skin
rashes,urticaria.
4. bone marrow disturbance and live disorders.

63. References
• Singh Harikishan and Kapoor V. K. , “Medicinal and
Pharmaceutical Chemistry,” 1st edition , Published by- Vallabh
Prakashan , Delhi, Page no.-264- 289.
• Prof. Pandya S. N. , Medicinal Chemistry , 5th edition,
Published by:- SG Publisher, Varanashi, Page no.- 352 – 381.
• www4.shu.ac.ak >_assets > pdf > bmrc- r…. as dated on
20/8/2017.
• www.auburn.edu > ~deruija > nsaids _ 2002 as dated on
21/8/2017.
• http://www.fda.gov > dockets > briefing as dated on
23/8/2017.
• http://en.m.wikipedia.org > wiki >Nonst… as dated on 23/8 /
2017.
• www.medicinenet.com > article as dated on 28/8/2017.

64. Thank you