The document provides an overview of non-steroidal anti-inflammatory drugs (NSAIDs), detailing their definitions, classifications, mechanisms of action, key examples, and uses. It highlights various chemical derivatives of NSAIDs, their synthesis, and the therapeutic applications for pain relief and inflammation management. Additionally, it discusses the differences between non-selective and selective COX-2 inhibitors, alongside recommended reading materials for further information.

1. Non-steroidalNon-steroidal
Anti-inflammatoryAnti inflammatory
Drugs ( NSAID)g ( )
Dr. Gopal Krishna Padhy
16-04-2020

2. Definition:
o NSAID are agents which selectively relives pain and
inflammation.
oThey also possess antipyretics properties.
o These are mild analgesic, relieve minor pain such as
head ache by acting through peripheral pain mechanism.
16-04-2020

3. Classification
Salicylic acid derivatives
3
Aspirin Salicylic acidp
IUPAC:Acetylsalicylic
acid
SodiumSodium
Salicylate 16-04-2020

4. N-Arylanthranilic acid derivativesy
IUPAC: N-(2,3-xylyl)anthranylic
Mefenamic acid
3 3 acid
IUPAC N (2 6 di hl l l)IUPAC: N-(2,6-dichloro-m-tolyl)
anthranylic acid
Meclofenamic acidMeclofenamic acid
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5. Heteroarylacetic acid derivativesy
33
23
Indomethacin Sulindac
IUPAC: 1-(4-chlorobenzoyl)-
5-methoxy-2-methylindol-3-
acetic acid
IUPAC: 5-fluoro-2-methyl-1-[4-
(methylsulfinyl)benzyliden]
inden 3 acetic acidacetic acid inden-3-acetic acid
16-04-2020

6. H3CO Continued.........
N CH2COOH
1
25
H3C
34
Tolmetin
IUPAC: 1-methyl-5-tolylpyrrole-
2-acetic acid
Zomepirac
IUPAC: 5-(4-Chlorobenzoyl)-1,4-
dimethyl-1H-pyrrole-2-acetic acid 16-04-2020

7. Arylacetic acid derivatives
3 3
y
3 2
3
Ibuprofen
DiclofenacIUPAC: 2-(4-iso-butylphenyl)
CH2COOH
1
7
8
propionic acid
IUPAC: 2-[(2,6-dichlorophenyl)-
amino]-phenylacetic acid
N
2
3
4
6
7 amino] phenylacetic acid
O
4
5
Ketorolac
IUPAC: 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid
Ketorolac
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8. Oxicam derivatives
3
PiroxicamPiroxicam
IUPAC: 1,1-dioxide-4-hydroxy-2-methyl-N-2-
d l 2H 1 2 b thi i 3 b idpyradyl-2H-1,2-benzothiazine-3-carboxamide
16-04-2020

9. Pyrazolone & Pyrazolidinedione derivatives:y y
IUPAC: 4-butyl-1,2-diphenyl-
3 5 pyrazolidinedione3,5-pyrazolidinedione
Phenylbutazone
IUPAC: 1,5-Dimethyl-2-
phenyl 3 pyrazolonephenyl-3-pyrazolone
Phenazone/ Antipyrine 16-04-2020

10. p-Aminophenol derivativesp p
IUPAC:p-acetaminophenol
A i h
IUPAC:p acetaminophenol
Acetaminophen
IUPAC N (4 E h h l)IUPAC: N-(4-Ethoxyphenyl)
acetamide
Phenacetin
16-04-2020

11. Mefenamic acid Synthesis
COOK
K CO5
COOK COOH
Cl + H2N
H C CH
K2CO3 HCl
1
2
3
4
561
2
H
N
H C CH
H
N
H C CHH3C CH3 HCl KClPotassium
2-Chloro
benzoate
2
2,3,-dimethylaniline Mefenamic acid
H3C CH3 H3C CH3
Uses-It is used for moderate pain.
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12. Ibuprofen Synthesis
Uses: It is used in treating
rheumatoid arthritis, gout,
radiculitis, neuralgia, myalgia,
spondylitis soft tissue inflammationspondylitis, soft-tissue inflammation,
and in the musculoskeletal system
pain.p
16-04-2020

13. CH O
Indomethacin synthesis
H3CO
NH
+ H3C C
O
CH2 CH2 C
O
OCH3
H3CO
NH N C
CH3
CH2 CH2 C
O
OC
H3
NH2
H
N CH3
HCl
H
N CH N OH
Fischer indole
Synthesis
H
H2OP-Methoxyphenylhydrazine
NH3
Methyl levulinate
N
H3CO
CH3
CH2
N
H3CO
CH3
CH2
NaOHH
N
H3CO
CH3
CH2 C
O
OC(CH3)3
C
O
OCH3COOH
(CH3)3OH
O
Cl COCl
HCl
Cl Cl
210 0
C
N CH3
C O
N
H CO
CH3
C O
210 C
H3CO CH2 C
O
OC(CH3)3
H3CO CH2 C
O
OH
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14. Piroxicam synthesis
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15. SAR of Indomethacin
Indole acetic acids are represented by the following general
structure
Carboxylic group
• Carboxylic group is essential for anti-inflammatory
activity. Replacement of carboxylic group with other acidicy p y g p
group decreases activity.
•Anti-inflammatory activity increases as the acidity ofy y y
carboxylic group increases and decreases as the acidity
decreases.
•Amide analogues are inactive. 16-04-2020

16. R1 Substituents
•R1 substituents useful for increasing anti-inflammatory
b k d
1
activity can be ranked as
R1-C6H5 >Alkyl > H
N B l d i i b i d h i i i h• N-Benzoyl derivatives substituted at the para position with
fluoro, chloro, trifluorumethyl groups are most active.
R2 Substituents
•R2 Substituents for improved activity are ranked as CH3 > H.
lk l ll h l 2 d•Alkyl groups specially methyl group at 2nd position are more
active than aryl group.
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17. X substituents
The 5th position of the indole ring is most flexible for
substitution.
• Substituents such as methoxy, fluoro, dimethylamine,
methyl, alkoxy are more active than the unsubstituted
indole ring.
• For improved activity X substituents are ranked as
5-OCH3 > F > (CH3)2N > CH3
•The presence of indole ring nitrogen is not essential for
activity. e.g. Sulindac.
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18. Mechanism of action of NSAID
Most NSAIDs act as nonselective inhibitors of the
cyclooxygenase (COX) enzymes, inhibiting both the
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
isoenzymes to produce analgesic effect.
This inhibition is competitively reversible .
COX catalyzes the formation of prostaglandins and
thromboxane from arachidonic acid (derived from the cellular
phospholipid bilayer by phospholipaseA).
Prostaglandins act (among other things) as messenger
molecules in the process of inflammation.
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19. Membrane Phospholipids
Chemical
Arachidonic acid
Phospholipase A /Mechani
cal stimuli
PGG2 PGH2
Cycloxigenase NSAID
inhibitPGG2, PGH2
Transfer of signal to pain receptorg p p
(CNS)
Pain
Pain Pathway 16-04-2020

20. Aspirin Sodium Salicylate
3
Uses: Aspirin is widely used for
h d d l i i
Uses: It is used in medicine
head and neuralgic pains,
rheumatic pain, painful
t f i i i It i
as an analgesic and
antipyretic.
symptoms of various origin. It is
used in conditions such as
f ti dfevers, prevention and
treatment of myocardial
i f ti th b i dinfraction, thrombosis and
embolism. 16-04-2020

21. Meclofenamic acid Indomethacin
3
d f d
23
U I d h dUses:It is used for moderate
pain.
Uses: Indomethacin is used
in rheumatoid arthritis,
hgout, osteoarthritis,
spondylitis, back pain,
l i l i d hneuralgia, myalgia and other
diseases accompanied by
i fl iinflammation.
16-04-2020

22. Sulindac Tolmetin
H3CO
1N CH2COOH
H C
1
2
34
5
H3C
4
Uses It is used for relievingUses It is used for relieving Uses: It is used for relieving
weak to moderate pain in
rheumatoid arthritis and
Uses: It is used for relieving
weak to moderate pain in
rheumatoid arthritis and rheumatoid arthritis and
osteoarthritis.
rheumatoid arthritis and
osteoarthritis.
16-04-2020

23. Zomepriac Diclfenac
Uses: Diclfenac is used inUses: Zomepirac was
rheumatoid, gout, arthritis,
osteoarthritis, spondylitis,
Uses: Zomepirac was
indicated for the
management of mild to , p y ,
back pain, neuralgia,
myalgia and diseases with
management of mild to
severe pain.
y g
inflammation.
16-04-2020

24. Ketorolac Piroxicam
Uses: piroxicam is used in
back pain, myalgia,Uses: ketorolac to manage
post operative pain spinal neuralgia, rheumatoid
arthritis, gout,
post-operative pain, spinal
and soft tissue pain,
rheumatoid arthritis osteoarthritis, ankylosing
spondylitis, and other
rheumatoid arthritis,
osteoarthritis, spondylitis,
menstrual pain and diseases accompanied by
inflammation.
menstrual pain and
headaches. 16-04-2020

25. Phenylbutazone Antipyrin
Uses: Phenylbutazone is used
for relieving low to moderate
Uses: In combination with
benzocaine, antipyrine isg
pain in headaches,
osteoarthritis and rheumatoid
py
indicated for the
symptomatic relief of acute
arthritis.
y p
otitis media.
16-04-2020

26. Acetaminophen Phenacetin
/Pracetamol
2 5 3
Uses: Acetaminophen is widely
2 5 3
Uses: Acetaminophen isp y
used as an analgesic and for
reducing fever. Paracetamol is
Uses: Acetaminophen is
widely used as an analgesic.
g
also effective in headaches,
chronic pain, arthralgia,p , g ,
myalgia, oncological and post-
operative pain etc.p p
16-04-2020

27. Selective COX-2 inhibitors
• N l ti COX i hibit i t d ith id ff t lik• Non selective COX inhibitors are associated with side effects like
peptic ulcer and acidity, which can be avoided by using selective COX-2
inhibitors.inhibitors.
•The prostaglandins that mediates inflammation, fever and pain are
produced via COX-2 enzyme and prostaglandins important in GIT,
uterus are produced via COX-1.
• Certain drugs selectively inhibits COX-2 enzyme, thus they are
d id f id ff t lik ti ldevoid of side effects like peptic ulcer.
O
O
Celecoxib
H3C-O2S
Rofecoxib
Celecoxib
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28. BOOKS FOR FURTHER READING
Wil d Gi ld T b k f i M di i l
BOOKS FOR FURTHER READING
Wilson and Gisvold,Text book of organic, Medicinal
and Pharmaceutical Chemistry.
Foyes Principles of medicinal chemistry byWilliams
O. Foye.y
AText book of medicinal chemistry (Synthetic and
Biochemical Approach) vol I& II by SN PandeyaBiochemical Approach) vol. I& II by SN Pandeya.
Synthesis of Essential Drugs by R.S.Vardanyan and
VJ H bV.J. Hruby
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