Medicinal Chemistry: NSAIDs ; Analgesics & Antipyretics

1. NSAIDs ; Analgesics & Antipyretics
Introduction:
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.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a drug class that reduce pain, decrease
fever, prevent blood clots and,in higher doses, decrease inflammation. Side effects depend on the specific
drug, but largely include an increased risk of gastrointestinal ulcers and bleeds, heart attack and kidney
disease.
NSAIDs work by inhibiting the activity of cyclooxygenase enzymes (COX-1 and/or COX-2). In cells, these
enzymes are involved in the synthesis of key biological mediators, namely prostaglandins which are
involved in inflammation, and thromboxanes which are involved in blood clotting.
There are two types of NSAID available: non-selective and COX-2 selective. Most NSAIDs are non-
selective, and inhibit the activity of both COX-1 and COX-2.
The most prominent NSAIDs are aspirin, ibuprofen and naproxen, all available over the counter (OTC) in
most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because it has only
minor anti-inflammatory activity. It treats pain mainly by blocking COX-2 and inhibiting endocannabinoid
reuptake almost exclusively within the brain, but not much in the rest of the body.
Antipyretics are substances that reduce fever. Antipyretics cause the hypothalamus to override a
prostaglandin-induced increase in temperature. The body then works to lower the temperature, which results
in a reduction in fever.
Most antipyretic medications have other purposes. The most common antipyretics in the United States are
ibuprofen and aspirin, which are nonsteroidal anti-inflammatory drugs (NSAIDs) used primarily as
analgesics (pain relievers), but which also have antipyretic properties; and acetaminophen (paracetamol),
an analgesic with weak anti-inflammatory properties.
Analgesics are medicines that are used to relieve pain. They are also known as painkillers or pain
relievers. Technically, the term analgesic refers to a medication that provides relief from pain without
putting you to sleep or making you lose consciousness. Analgesic, any drug that relieves pain selectively
without blocking the conduction of nerve impulses, markedly altering sensory perception, or affecting
consciousness. This selectivity is an important distinction between an analgesic and an anesthetic.
Analgesics may be classified into two types: anti-inflammatory drugs, which alleviate pain by reducing
local inflammatory responses; and the opioids, which act on the brain.
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or swelling.
Anti-inflammatory drugs make up about half of analgesics, remedying pain by reducing inflammation as
opposed to opioids, which affect the central nervous system to block pain signaling to the brain. The most
important mechanism of antiinflammatory action of NSAIDs is considered to be inhibition of COX-2
mediated enhanced PG synthesis at the site of injury.

2. 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.
COX Is the enzyme cyclooxygenase, which is required for the formation of prostaglandins and is blocked
by painkillers such as aspirin and ibuprofen. Cyclooxygenase (COX) is found bound to the endoplasmatic
reticulum. It exists in 3 isoforms:
 COX-1 (constitutive) acts in physiological conditions.
 COX-2 (inducible) is induced in inflammatory cells by pathological stimulus.
 COX-3 (in brain).
COX-1 serves house-keeping functions.COX-2 is generated by cytokines and others during inflammation
(constitutive in brain and JG cells) – PG synthesis. Most NSAIDs inhibit COX-1 and COX-2 non-
selectively and inhibit PG synthesis.
Classification of NSAIDs:
A. Nonselective COX inhibitors (traditional NSAIDs):
 Salicylates: Aspirin.
 Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen.
 Fenamate: Mephenamic acid.
 Enolic acid derivatives: Piroxicam, Tenoxicam.
 Acetic acid derivatives: Ketorolac, Indomethacin, Nabumetone.
 Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
B. Preferential COX-2 inhibitors:
 Nimesulide, Diclofenac, Aceclofenac, Meloxicam, Etodolac.
C. Selective COX-2 inhibitors:
 Celecoxib, Etoricoxib, Parecoxib.

3. D. Analgesic-antipyretics with poor antiinflammatory action:
 Paraaminophenol derivative: Paracetamol (Acetaminophen).
 Pyrazolone derivatives: Metamizol (Dipyrone), Propiphenazone.
 Benzoxazocine derivative: Nefopam.
 Aspirin inhibits COX irreversibly – acetylation
 Other NSAIDs are competitive reversible inhibitors
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.
What is the basic difference between traditional NSAIDs and COX-2 inhibitors?

4.  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 anti-inflammatory 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..
Paracetamol
Paracetamol (acetaminophen) the deethylated active metabolite of phenacetin, was also introduced in the
last century but has come into common use only since 1950.
Paracetamol can not inhibit peripheral prostaglandin synthesis as aspirin does.So act as a weak
antiinflammatory agent.paracetamol does not appear to inhibit the function of COX enzyme outside the
CNS.It does appear to selectively inhibit COX activities in the brain,which may contribute to its ability to
treat fever and pain.This activity does not appear to be direct inhibition by blocking an active site, rather
by blocking COX. The central analgesic action of paracetamol is like aspirin, i.e. it raises pain threshold,
but has weak peripheral antiinflammatory component. Analgesic action of aspirin and paracetamol is
additive. Paracetamol is a good and promptly acting antipyretic.
Paracetamol has negligible antiinflammatory action. It is a poor inhibitor of PG synthesis in peripheral
tissues, but more active on COX in the brain. One explanation offered for the discrepancy between its
analgesic-antipyretic and antiinflammatory actions is its inability to inhibit COX in the presence of
peroxides which are generated at sites of inflammation, but are not present in the brain. The ability of
paracetamol to inhibit COX-3 (an isoenzyme so far located in dog brain) could also account for its
analgesic-antipyretic action.
Synthesis of Paracetamol:
Preparation of paracetamol involves treating an amine (p-aminophenol) with an acid anhydride (acetic
anhydride) to form an amide (p-acetamidophenol).
SAR of paracetamol:
1.Amino benzene group is responsible for
antipyretic activity.
2.Amino & OH group should be on para position ;
on other position it becomes inactive.

5. 3.If both OH & acetylated group are removed, the compound becomes aniline & is more toxic.
4.If OH group is removed the compound becomes acetanilide,which is more toxic & inactive.
5.Methylation can reduce the unwanted side effects of the drugs.
Example: mono & di ortho-methylation with respect to the phenolic hydroxy group of paracetamol produce
analogues with reduced hepatotoxicity.It is believed that reduction is due to the methyl groups preventing
metabolic hydroxylation of these ortho positions.
Paracetamol as Poison:
Because paracetamol is a potent drug that is available without prescription, it is often used in suicide
attempts, and in this respect it is potentially more dangerous than other over-the-counter drugs such as
aspirin. This is because paracetamol overdoses often cause liver failure, and there have been many cases
where attempted suicides have awakened from an overdose and changed their minds, yet still died a few
days later from liver damage.The reasons for this poisoning are to do with the process by which paracetamol
is eliminated from the body. It is first metabolised to a quinone imine.
This compound is extremely toxic, and like other such compounds is eliminated in the liver by reaction
with a tripeptide, glutathione. If insufficient glutathione is available, the toxic quinone will not be
eliminated and begins to react with cellular proteins and nucleic acids in the liver, eventually causing
irreparable damage.
However, two compounds, methionine and N-acetylcysteine can boost levels of the vital glutathione in the
liver, and so can be used as antidotes for paracetamol poisoning if the overdose is discovered in time. A
new formulation of paracetamol is now being marketed in the UK which incorporates methianine, such that
the drug carries its own antidote with it.

6. Uses:
 Paracetamol is one of the most commonly used ‘over-the-counter’ analgesic for headache, mild
migraine, musculoskeletal pain, dysmenorrhoea, etc. but is relatively ineffective when
inflammation is prominent as in rheumatoid arthritis.
 Paracetamol is recommended as first choice analgesic for osteoarthritis by many professional
bodies.
 It is one of the best drugs to be used as antipyretic, especially in children (no risk of Reye’s
syndrome).
 Dose to dose it is equally efficacious as aspirin for non-inflammatory conditions. It is much safer
than aspirin in terms of gastric irritation, ulceration and bleeding (can be given to ulcer patients),
does not prolong bleeding time.
 Hypersensitivity reactions are rare; no metabolic effects or acid-base disturbances; can be used in
all age groups (infants to elderly), pregnant/lactating women, in presence of other disease states
and in patients in whom aspirin is contraindicated.
 It does not have significant drug interactions. Thus, it may be preferred over aspirin for most minor
conditions.
Indomethacin
 Chemical name: indomethacin
 Chemical class: analgesic, anti
inflammatory, anti gout
 Indometacin is one of the commonly used
and the most effective NSAIDs to reduce
fever, pain, stiffness, and swelling.
Synthesis of Indomethacin:

7. SAR of indomethacin:
 The carboxyl group is essential for anti-
inflammatory activity.
 Presence of methoxy (position 5) group on
the ring (5 or 6), methyl (2),
dimethylamino group (5) in indole moiety
of indomethacin exhibit activity.
 Presence of chlorine or fluorine or CF3
groups at para position of phenyl group
also exhibits anti-inflammatory activity.
 Indole ring N is not essential as C version
indene analog (Sulindac) is also active.
 Addition of OH group at ortho and meta
position will reduce its activity
Indication:
 Moderate to severe rheumatoid arthritis including acute flares of chronic disease
 Moderate to severe ankylosing spondylitis
 Moderate to severe osteoarthritis
 Acute painful shoulder (bursitis and/or tendinitis)
 Acute gouty arthritis
Propionic Acid Derivatives
 Aryl-propionic 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
 Naproxen (Synflex) ) is one of the most widely used NSAID’s
Chemistry:
 Proprionic acid Derivatives (Profens) are often referred to as the “profens” based on the suffix of
the prototype member, ibuprofen.
 Like the salicylates these agents are all strong organic acids(pKa = 3.0-5.0)and thus form water
soluble salts with alkaline reagents.
 The arylpropionic acids are characterized by the general structure Ar—CH(CH3)—COOH which
conforms to the required general structure.
 All of these compounds are predominantly ionized at physiologic pH and more lipophilic than
acetyl salicylic acid or salicylic acid.
 The α-CH3 substituent present in the profens increases cyclooxygenase inhibitory activity and
reduces toxicity of the profens.
 The α-carbon in these compounds is chiral and the S-(+)-enantiomer of the profens is the more
potent cyclooxygenase inhibitor.

8. Ibuprofen
Ibuprofen is a medication in the nonsteroidal anti-inflammatory drug (NSAID) class that is used for treating
pain, fever, and inflammation.This includes painful menstrual periods, migraines, and rheumatoid
arthritis.It may also be used to close a patent ductus arteriosus in a premature baby.
Chemistry: Ibuprofen is practically insoluble in water, but very soluble in most organic solvents like
ethanol (66.18 g/100mL at 40 °C for 90% EtOH), methanol, acetone and dichloromethane.
Synthesis of Ibuprofen:
First, a Friedel-Crafts acylation functionalizes benzene with an isobutyryl moiety (1). This substituent is
reduced to an isobutyl group through a Clemmensen reduction, yielding isobutylbenzene (2).
Two of the most popular ways to obtain ibuprofen are the Boot process and the Hoechst process.
 The Boot process is an older commercial process developed by the Boot Pure Drug Company, and
the Hoechst process is a newer process developed by the Hoechst Company.
 Most of these routes to ibuprofen begin with isobutylbenzene and use Friedel-Craft’s acylation.
 The Boot process requires six steps, while the Hoechst process,with the assistance of catalysts, is
completed in only three steps.
 Process of two methods are given below:

9. SAR of Ibuprofen:
Indication of Ibuprofen:
 Ibuprofen is used to relieve pain from various conditions such as headache, dental pain, menstrual
cramps, muscle aches, or arthritis.
 It is also used to reduce fever and to relieve minor aches and pain due to the common cold or flu.
 Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). It works by blocking your body's
production of certain natural substances that cause inflammation. This effect helps to decrease
swelling, pain, or fever.
Naproxen
Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug
(NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, and
fever.

10. Chemistry: Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs.The free acid is
an odorless, white to off-white crystalline substance. It is lipid-soluble and practically insoluble in water. It
has a melting point of 152–155 °C
Synthesis of Naproxen:
Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows:
Indication of Naproxen:
 Naproxen is used to relieve pain from various conditions such as headache, muscle aches,
tendonitis, dental pain, and menstrual cramps.
 It also reduces pain, swelling, and joint stiffness caused by arthritis, bursitis, and gout attacks.
 This medication is known as a nonsteroidal anti-inflammatory drug (NSAID). It works by blocking
your body's production of certain natural substances that cause inflammation
Probenecid
Probenecid, also sold under the brand name Probalan, is a medication that increases uric acid excretion in
the urine. It is primarily used in treating gout and hyperuricemia.
Synthesis:

11. Phenylbutazone
Phenylbutazone is a nonsteroidal anti-inflammatory drug (NSAID) effective in treating fever, pain, and
inflammation in the body.
Phenylbutazone has analgesic & antipyretic effects with similar potency as aminophenazone and phenazon.
It has enhanced antiinflammatory effects and is used to treat rheumatoid arthritits.
Chemistry: Phenylbutazone is a crystalline substance. It is obtained by condensation of diethyl n-
butylmalonate with hydrazobenzene in the presence of base. In effect, this represents the formation of the
heterocyclic system by simple lactamization.
Synthesis: Phenylbutazone and its derivatives could be prepared from condensation of n-butylmalonic
acid ester like substituted malonic acid
SAR:
 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
Indiction:
Phenylbutazone was originally made available for use in humans for the treatment of rheumatoid arthritis
and gout & to treat ankylosing spondylitis.

12. N-Arylanthranilic acid derivatives
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
Synthesis:
Via reaction of 2-chlorobenzoic acid and 2,3dimethylaniline
Phenacetin
Phenacetin (or acetophenetidin) is a pain-relieving and fever-reducing drug, which was widely used
between its introduction in 1887 and the 1983 ban imposed by the U.S. Food and Drug Administration.

13. Phenacetin was widely used until the third quarter of the twentieth century, often in the form of an A.P.C.,
or "aspirin-phenacetin-caffeine" compound analgesic, as a remedy for fever and pain. In the United States,
the Food and Drug Administration ordered the withdrawal of drugs containing phenacetin in November
1983, due to its carcinogenic and kidney-damaging properties.
Synthesis: