UNIT 1

ANTI- HISTAMINIC AGENTS

10 MARKS

1.define and classify antihistaminic agents with examples.

Outline the method for synthesis of diphenylhydramine and
promethazine?
These are the agents which blocks the action of histamines. Mainly used
to treat the hay fever, itching, drug rashes etc.

Classification
1.H1 RECEPTOR ANTAGONIST

a. ethylene diamine derivatives

Ex:- mepharamine

b. amino alkyl ether analogues

Ex:- diphenhydramine
c. amino propyl compound
Ex:- pheneramine

d. tricyclic compounds

Ex:-promethazine

e. cyclizines
Ex:- chlorcyclazine

f. newer agents
2. H-2 RECEPTOR ANTAGONISTS
a. ranitidine

b. climitidine

c.famotidine

3. H-3 ANTAGONIST

EX:- theoperamide
 1. DIPHENYL HYDRAMINE

2.PROMETHAZINE HYDROCHLORIDE
2.Classify Antineoplastic agents with examples. Outline the
synthesis of Mercaptopurine and Methotrexate.
These are medications used to treat cancer.
→ Other names are antineoplastic drugs are anticancer, Chemotherapy,
chemo, cytotoxic or hazardous drugs.
Classification

1). Alkylating agents: Mechlorethamine, Cyclophosphamide, Melphalan

Chlorambucil, Busulfan, Thiotepa

2) Antimetabolites: Mercaptopurine, Thioguanine, Fluorouracil

Floxuridine, Cytarabine, Methotrexate, Azathioprine

3) Antibiotics:- Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin

4) Plant products: Etoposide, Vinblastin sulphate, Vincristin sulphate

5) Miscellaneous: Cisplatin, Mitotane.

1. Mercaptopurine synthesis
 2. Methotrexate synthesis

3. What are Antineoplastic agents? Classify Antineoplastic agents

with examples. Discuss the mechanism of alkylating agents.
Outline the synthesis of Mechlorethamine.
These are medications used to treat cancer.

→ Other names are antineoplastic drugs are anticancer, Chemotherapy,

chemo, cytotoxic or hazardous drugs.

Classification
1). Alkylating agents: Mechlorethamine, Cyclophosphamide, Melphalan
Chlorambucil, Busulfan, Thiotepa
2) Antimetabolites: Mercaptopurine, Thioguanine, Fluorouracil
Floxuridine, Cytarabine, Methotrexate, Azathioprine
3) Antibiotics:- Dactinomycin, Daunorubicin, Doxorubicin, Bleomycin

4) Plant products: Etoposide, Vinblastin sulphate, Vincristin sulphate

5) Miscellaneous: Cisplatin, Mitotane.
MAO OF ALKYLATING AGENTS
These agents involve reactions with guanine in DNA.

these drugs add methyl or other alkyl groups onto molecules where they
do not belong. This in tiers inhibits their correct utilization by base pairing
of DNA. and Causes a miscoding of DNA
First mechanism by which alkylating agents

causes DNA damage is the formation of cross bridge, bonds b/w atoms in
the DNA

In this process, two bases are linked together by an alkylating agent that
has two DNA binding sites. Cross-linking prevents DNA Synthesis or
transcription. from being seperated by
Causes the mispairing of the nucleotides leading to mutation

MECHLOROETHAMINE SYNTHESIS
4. Define and classify H1 receptor antagonists with example.
Outline the synthesis of Promethazine and Triprolidine HCL.

H1 RECEPTOR ANTAGONIST
a. ethylene diamine derivatives

Ex:- mepharamine

b. amino alkyl ether analogues

Ex:- diphenhydramine
c. amino propyl compound

Ex:- pheneramine

d. tricyclic compounds
Ex:-promethazine

e. cyclizines
Ex:- chlorcyclazine

f. newer agents
 3. H-3 ANTAGONIST

EX:- theoperamide

1.PROMETHAZINE HYDROCHLORIDE

2. Triprolidine HCL
5. Define and classify H1 receptor antagonists with example.
Outline the synthesis of Promethazine and Triprolidine HCL.

1.H1 RECEPTOR ANTAGONIST

a. ethylene diamine derivatives

Ex:- mepharamine

Uses:- it is used to treat allergy

Used to treat hypersensitivity reactions

b. amino alkyl ether analogues

Ex:- diphenhydramine
Uses:- antinausent

In motion sickness
Radiation sickness

c. amino propyl compound

Ex:- pheneramine

Uses:-used to treat allergic rhinitis

d. tricyclic compounds
Ex:-promethazine

Uses:- used to treat perenial and seasonal rhinitis

Vasomotor rhinitis

e. cyclizines

Ex:- chlorcyclazine
Uses:-used to treat allergic symptoms

f. newer agents

2. H-2 RECEPTOR ANTAGONISTS

a. ranitidine

b. climitidine

c.famotidine
3. H-3 ANTAGONIST
EX:- theoperamide

SAR OF ANTI HISTAMINES

1) Aryl Groups

The di aryl substitution is essential for Significant H1 affinity.

It is present both in fist generation & antihistamines Second generation
antihistamines.
The optimal antihistaminic activity depends on planarity of two aryl
substitutions.
Active aryl substitutions are as follows:
Ar- phenyl and hetero aryl group Like 2-pyridyl
Ar Aryl or Aryl methyl group.

2) Nature of X:-
Antihistamines with x = carbon (phenaramine series) represents The
stereo selective receptor binding to the receptors due to its chirality.

The active substitutions of X are as follows:

Where, X = Oxygen Camino alkyl ether analogue)

X = Nitrogen (Ethylene - diamine derivative)

X = Carbon (Mono amino propyl analogue)

3.The alkyl chain:-

Most of the antihistamines have ethylene chain and branching of this

chain results in compound in a less active compound
4.Terminal Nitrogen atom:-
The terminal N-atom should be at 3° amine for maximum activity. The
terminal nitrogen may be a parrt of heterocyclic ring.

Ex: Antazoline and Chlorcyclizine, retains high antihistaminic activity.

CHLORCYCLAZINE
5MARKS

1. What are H2 receptor antagonists? Give the synthesis of

Cimetidine.
H2 antagonists, sometimes referred to as H2RAs and also called H2
blockers, are a class of medications that block the action of histamine at
the histamine H2 receptors of the parietal cells in the stomach. This
decreases the production of stomach acid. H2 antagonists can be used in
the treatment of dyspepsia, peptic ulcers and gastroesophageal reflux
disease.
2. Explain in detail about histamine receptors and their biological
importance.
Histamine receptors are proteins that bind with histamine, a
neurotransmitter involved in various physiological processes. There are
four main types: H1, H2, H3, and H4. H1 receptors are linked to allergic
responses, H2 to gastric acid regulation, H3 to neurotransmitter release
modulation, and H4 to immune system function.

There are four known histamine receptors:

H1 receptor H1 Receptors: These receptors are primarily located on

smooth muscle cells, endothelial cells, and neurons. Activation of H1
receptors mediates various responses, including smooth muscle
contraction (leading to bronchoconstriction, intestinal cramping),
increased vascular permeability (resulting in edema), and stimulation of
sensory nerve endings (causing itching and pain). H1 antagonists,
commonly known as antihistamines, are used to alleviate symptoms of
allergies and allergic reactions.

H2 receptor H2 Receptors: Found mainly in the stomach lining (parietal

cells), H2 receptors regulate gastric acid secretion by stimulating the
production of hydrochloric acid. H2 antagonists (H2 blockers) are used to
reduce stomach acid production and treat conditions like
gastroesophageal reflux disease (GERD) and peptic ulcers
H3 receptor H3 Receptors: These receptors are predominantly located in
the central nervous system (CNS), particularly in regions associated with
neurotransmitter release and modulation. H3 receptors act as presynaptic
autoreceptors and heteroreceptors, regulating the release of
neurotransmitters such as dopamine, serotonin, norepinephrine, and
acetylcholine. Modulation of H3 receptors is being explored as a potential
target for various neurological and psychiatric disorders.

BIOLOGICAL IMPORTANCE: play a crucial and significant role in the

development of various allergic diseases.

3. Define and classify Antihistaminic agents with examples.

Outline the method for synthesis of Promethazine.

These are the agents which blocks the action of histamines. Mainly used
to treat the hay fever, itching, drug rashes etc.
Classification
1.H1 RECEPTOR ANTAGONIST

a. ethylene diamine derivatives

Ex:- mepharamine

b. amino alkyl ether analogues

Ex:- diphenhydramine
c. amino propyl compound
Ex:- pheneramine

d. tricyclic compounds

Ex:-promethazine

e. cyclizines
Ex:- chlorcyclazine

f. newer agents

2. H-2 RECEPTOR ANTAGONISTS

a. ranitidine
b. climitidine

c.famotidine

3. H-3 ANTAGONIST

EX:- theoperamide
2.PROMETHAZINE HYDROCHLORIDE

4. Classify alkylating agents with examples. Outline the synthesis

of Mechlorethamine.
1).ALKYLATING AGENTS:-

Mechlorethamine
Cyclophosphamide,
Melphalan
Chlorambucil,

Busulfan,
Thiotepa

MECHLORAMINE SYNTHESIS
5.Write note on antimetabolites. Explain the synthesis of
Mercaptopurine.
Antimetabolites interfere with DNA production and therefore cell division
and tumour growth because cancer cells spend more time dividing than
other cells inhibiting cell division harms tumour cells more than other cells

MERCAPTOPURINE SYNTHESIS
6. Write a note on antimetabolites. Explain their mechanism of
action.
Antimetabolites interfere with DNA production and therefore cell division
and tumour growth because cancer cells spend more time dividing than
other cells inhibiting cell division harms tumour cells more than other cells
MECHANISM OF ACTION

These agents binds covalently with the structure of DNA which inhibit the
replication of DNA resulting in the decrease of the cell division
It blocks the replicaion of DNA

These are the derivatives of niotrogen mustard

These agents binds covalently at 7th position of guanine in DNA chain

7. WRITE A NOTE ON GASTRIC PROTON PUMP INHIBITORS

The proton pump is a alpha, beta-heterodimeric enzyme

The gastric acid secretion is regulated by the functioning of H+ K+ ATPase

pump present in the parietal cell membrane

* Proton Pump
It is an integral membrane protein in the parietal cells of the stomach

Pumps proton into the stomach.

By using ATP, an acidic hydrogen ion replaces a non- acidic potassium ion

Proton pump Inhibitor

They are prodrugs that activate in acid environment.

After absorption, The active metabolite diffuses into The parietal cells &
accumulates in the acidic Serectory canaculi
 MOA

The consumption of food stimulates and secretion and acid secretion

activates PPIs.

Then activated PPI is converted to a Sulfenamide in the acidic secretary

canceuli of the parietal cell.

→ Sulfenamide interact covalently with sulfhydryl groups in the proton

pump and make complex, thereby irreversibly inhibiting its activity.

Ex:- omeprazole
Lansoprazole

Rabeprazole
Pantoprazole

8 Discuss the SAR of Phenothiazine derivatives as antihistamines.

Activity of phenothazines is determined by the following:

1. Modification of alkyl side chain

• Potency is maximum when there is three carbon between two ‘N’ atom (ring and
side chain N ).
• Introduction of methyl group at C-1 decreases antipsychotic activity and produces
imipramine-like activity.
• If C-1 is incorporated into cyclopropane ring imipramine-like activity is obtained.
• When oxygen is introduced into C-1 results in potent antidepressant effect. Example:
Chloracizine.
• Addition of –CH3 at C-2 or C-3 has very little effect on activity.
• Bridging of position 3 of side chain to position 1 of phenothiazine nucleus decreases
neuroleptic activity.

2. Amino group modification

• 3° nitrogen shows maximum potency and 2° or 1° nitrogen shows reduced or

abolished activity.

N-alkylation with more than one carbon decreases activity.

• Activity is decreased when dimethylamino group is replaced by pyrolidinyl,

morpholinyl, or thiomorpholinyl groups. However, piperidine or piperazine is more
potent than dimethylamino group.
• Bridged piperidine derivates retain high degree of activity although bulky.
• Introduction of OH, CH3 , CH3CH2OH at C-4 of piperazine results in increased
activity.
• Piperazine and phenothiazines may be esterified with long-chain fatty acids to
produce slowly absorbed long-acting lipophilic prodrugs. Due to the slow release
from oily deposition, significant activity is retained
• When N-4 piperazine substituents are as large as phenyl, ethyl, or p-amino phenyl
ethyl (e.g. Azaspirane, Chlorspirane) are active.

3. Phenothiazine ring

• Substitution at C-2 position is optimal for neuroleptic activity. In general, potency at

different positions increases in the following order 1 < 4 < 3 < 2. Potency of the
various groups increase in the following order OH < H< CN < CH3 < Cl < CF3.
• Disubstitution (or) trisubstitution of the C-2 substituted drugs results in harmful
potency.
• CF3 is more potent than Cl, but EPS appears, hence, chlorpromazine is much used,
rather than triflupromazine.
• The electro-negative chlorine atom at C-2 is responsible for imparting asymmetry to
this molecule and the attraction of the amine side chain towards the ring containing
the chlorine atom indicate an important structural feature of such molecules.
• Oxidation of the sulphur at 5th position of antipsychotic phenothiazine decreases
activity.
•

9. Write a note on antineoplastic antibiotics.

It is also known as anticancer or antitumour antibiotic and it acts quite

similar as quinolines.
The main difference b/w antibiotics & antineoplastic antibodies is the
former one act on bacterial cells, while the latter act on tumourous or
cancerous cells in human body.
Antineoplastic antibiotics affects DNA Synthesis and replication by
inserting into DNA strands or by producing Superoxide that cause breakage
in DNA strands & prevent the tumourous or Cancerous Cells to divide
further.

10. Explain the chemistry of piperazine class of antihistamines

The piperazine class of antihistamines is characterized by the presence of
a piperazine ring in their chemical structure. This class includes drugs like
hydroxyzine, cetirizine, and meclizine. Let's delve into the chemistry of
these compounds:

1.Basic Structure: The basic structure of piperazine-class antihistamines

consists of a central piperazine ring with various substituents attached to
it. The piperazine ring is a six-membered heterocyclic ring containing two
nitrogen atoms at positions 1 and 4. These nitrogen atoms are key for the
pharmacological activity of these compounds.

2.Substituents:different substituents attached to the piperazine ring can

impart different properties to the molecule, affecting its potency,
selectivity, and pharmacokinetic profile. For example, hydroxyzine
contains a piperazine ring with a chlorophenyl group and a hydroxyethoxy
group attached, while cetirizine contains a piperazine ring with a
carboxylate group and a substituted phenyl group.

3.Histamine Receptor Binding: Piperazine-class antihistamines work

by competitively binding to histamine receptors, particularly the H1
receptors, in the body. By binding to these receptors, they prevent
histamine, a compound released during allergic reactions, from binding
and activating them. This blocks the allergic response mediated by
histamine, thereby reducing symptoms such as itching, sneezing, and
runny nose.

4.Side Effects: While piperazine-class antihistamines are generally well-

tolerated, they can cause side effects such as drowsiness, dry mouth, and
gastrointestinal disturbances. The degree of sedation and other side
effects can vary among different members of this class and among
individuals.

2 MARKS
1.Mechanism of action of alkylating agents
These agents involve reactions with guanine in DNA.
these drugs add methyl or other alkyl groups onto molecules
where they do not belong. This in tiers inhibits their correct
utilization by base pairing of DNA. and Causes a miscoding of
DNA

2. List the names and uses of anticancer antibiotics.

* Dactinomycin:-- used for the treatment of various tremors and

muscle related cancers

* Daunorubicin:-chemotheurapeutic agent
*Doxorubicin:-used in brest cancer, soft tissue sarcomas

3.what are gastric pump inhibitors and write any one structure.
These are the medications used to reduce the production of stomach
acid
Ex:- omeprazole

4. Write the structure and uses of two amino alkyl ether

derivatives as antihistaminic agents.
amino alkyl ether analogues

Ex:- diphenhydramine

USED to treat mild local allergic reactions due to insect bites

5.Write the structure and uses of any two H2 antagonists b.

1.climitidine

Used for the treatment and management of acid reflux disorder

2.famotidine
Used for short term treatment of duedenal and benign gastric ulcers

6. Explain the mechanism of action of gastric proton pump

inhibitors .
The consumption of food stimulates and secretion and acid secretion
activates PPIs.
Then activated PPI is converted to a Sulfenamide in the acidic secretary
canceuli of the parietal cell.
→ Sulfenamide interact covalently with sulfhydryl groups in the proton
pump and make complex, thereby irreversibly inhibiting its activity.

7.Write the structure and uses of Azathioprine and Cisplatin.

1. Azathioprine
Used to treat autoimmune disease
Organ transplantation

2. cis platin

Used in treatment of various types of cancer like bladder cancer

8. Write the structure and uses of Tripelenamine and

Chlorpheniramine.
Tripelenamine

Chlorpheniramine.
It is used to treat allergic reactions

9. Write the synthesis and uses of Mercaptopurine.

Used to treat various types of cancer

10. Write the structure and uses of Mechlorethamine and

cyclophosphamide
Mechlorethamine
Used to treat prostate cancer

Cyclophosphamide

Used to supress the immunesystem

Used to treat vatrioustypesof cancer

11.Define gastric proton pump inhibitors and write the structure

of rabeprazole.
These are the medications used to reduce the production of stomach
acid
12. Illustrate the importance of histaminic receptors
mediating the allergic responses
Regulating inflammatory response
Controlling gastric acid secreation

13. Mention any two alkylating anticancer agents.

Mechlorethamine
Cyclophosphamide
Chlorambucil
Busalphan

14. Give the synthesis of Mechlorethamine.

15. How cyclophosphamide is activated after its administration.
It undergoes series of metabolic reaction to produce its active metabolite ,
primarily phosphoramide mustard

16.Write the structure and uses of Promethazine.

Vasomotor rhinitis
Perenial ans seasonal rhinitis

17. Write the mechanism of action of 6- thioguanine.

It mainly involves its incorporation into DNA and interference with nucleic
acid synthesis leading to cytotoxicity