1

1 INTRODUCTION
The approach for the practice of medicinal chemistry has been
developed

by

synthesizing

new

compounds

based

largely

on

modification of known activity. In the search for safer and more potent
therapeutic agents, popular approach is synthesis and evaluation of
biologically active compounds. Literature survey reveals that majority
of pharmacologically active agents are heterocyclic compounds.
Heterocyclic compounds constitute the largest and most varied
family of organic compounds, and it has been estimated that more
than half of the organic chemistry publications are devoted to this
field. About 70% of all the drug molecules used in therapy are
heterocyclics. This is probably a reflection of the fact that many
heterocylclics can be included in the privileged scaffolds category
because they comply with the definition proposed by Evans in that
ligands for diverse receptors. In the light of these observations our
attention was drawn towards synthesis and study of pharmacological
activities of heterocyclic compounds containing halogens.
1.1.

Introduction to halogenated heterocyclic Compounds:

Halogen containing drugs have entered into usage only since

1820.

The incorporation of halogen atoms into a lead results in

anologues that are more lipophilic and so less water soluble.

Consequently halogen atoms are used to improve the penetration of
lipid membranes. However, there is an undesirable tendency for
halogenated drugs to accumulate in lipid tissue.

2
The chemical reactivity of halogen atoms depends on both their
point of attachment to the lead and nature of the halogen. Aromatic
halogen groups are far less reactive than aliphatic halogen groups,
which can exhibit considerable chemical reactivity. The most popular
halogen substituents are the less reactive aromatic fluorine and
chlorine groups. However, the presence of electron withdrawing ring
substituents may increase their reactivity to unacceptable levels. The
change in potency caused by the introduction of a halogen or halogen
containing group will, as with substitution by other substituents,
depend on the position of the substitution. For example, the
antihypertensive clonidine with its o,o-chloro substitution is more
potent than its p,m-dichloro analogue1.

Clonidine ED20 0.01mg kg-1

ED20 3.00mg kg-1

1.1.2. The importance of the halogens in the exploration of

structure-activity relationships:
The replacement of a hydrogen atom in an active molecule by a
substituent (alkyl, hydroxyl, nitro, cyano, alkoxy, amino, halogen, etc.)
can deeply modify the potency, duration, perhaps even the nature of
the pharmacological effect2.

The perturbations brought by the

substituent can affect various parameters of a drug molecule, such as

its

partition

coefficient,

electronic

density,

steric

environment,

3
bioavailability, pharmacokinetics and finally its capacity to establish
direct interactions between the substituent and the receptor or the
enzyme.
M

Solubility, Electronic
modifies: density, Steric factors
Bioavailability,
Interactions

Steric effects:
The obstruction of a molecule by means of halogen substitution
can impose certain conformations or mask certain functions. In the
case of clonidine the bulky halogen atom prevent free rotation and
maintain the planes of the aromatic rings in a perpendicular position
to each other.
Electronic effects:
The electronic effects of the halogens are ascribed to their
inductive electron attractive properties. These later are maximal for
chlorine and bromine, less marked for iodine, and very weak for
fluorine. The mesomeric donor effect of the halogen atoms is usually
not involved in biological media. The influence of halogens on the
potency of monoamino oxidase inhibition and of dopamine uptake
blockade in-vitro are as below:
Monoamino Oxidase Inhibition IC50 (nM)
X=H:
1200
X = Br :
200
X = CF3 :
100
X = SO2 CF3 : 27
[3H] Dopamine uptake: IC50 (nM)
R1 = R2 = CH3O : 2876
R1 = H, R2 = Cl : 115
R1 = R2 = Cl
: 75

4
The choice of the optimal substituent allows noticeable gains in
potency, compared with the parent molecule.
Hydrophobic effects:
The predominantly lipophilic influence of halogen substitution is
seen in the classical cases of the halocarbon anaesthetics, the
halogenophenol antiseptic and the halogenated insecticides. For these
compounds there is direct correlation between biological activity and
certain physicochemical parameters such as partition coefficient,
surface tension or vapour pressure. The accumulation of halogen
atoms favours the passage of the biomembranes and access to the
CNS.
1.1.3. Reactivity of the halogens:
In terms of bond strength, all C-halogen bonds, except C-F are
weaker than C-H.

Bond

Bond Strength (Kcal mol-1)

C-H

93

C-F

114

C-Cl

72

C-Br

59

C-I

45

5
1.1.4. Usefulness of the halogens and of cognate functions3:
Depending upon their physical properties and their reactivity,
the derivatives of fluorine, chlorine, bromine and iodine present
various degrees of usefulness.
1) The most utilized halogens in medicinal chemistry are chlorine
and fluorine attached to a nonactivated carbon atom. Fluorine
presents the advantage of its small bulkiness (Vander Waals
radius comparable to that of hydrogen). It will be used
essentially to block metabolically sensitive positions of a
molecule. The CF3 group is comparable in size to chlorine and
can advantageously replace it when it is placed in an activated
position (e.g. R-CO-Cl

R-CO-CF3). A chlorine substituent

simultaneously produces an increase in lipophilicity, an electron

attracting effect and a metabolic obstruction.
2) In certain active molecules the role of the fluorine or chlorine
atoms is not apparent at first glance. Thus for example two
compounds, chemically as m- trifluoromethylphenylethylamine
and

5-hydroxy

tryptamine,

show

many

pharmacological

analogies. In this case the explanation lies in the similitude of

the electrostatic potential maps.
3) Bromine is the less used halogen, and is usually incorporated
as a bromoaryl. The disadvantage of using bromine is that it
generates alkylating reactive intermediates more easily than
chlorine or fluorine and therefore it can confer, during long term
treatment, toxic potentialities to the molecule that bears it. This

6
was

the

case

for

the

anti-inflammatory-analgesic

drug

bromfenac sodium withdrawn from the US market due to

reports of hepatotoxicity.
1.1.5. Biologically active halogenated compounds:
Introduction of the halogen atom into an organic molecule cause
dramatic changes in its biological profiles, mainly due to high
electronegativity of halogen. The changes in potency caused by the
introduction of a halogen by other substituents depend on the
position of the substitution. Halogen containing drugs with high
therapeutic value are presented in the following tables:

7
Table 1.1: Therapeutic agents with Fluorine
S.No.
01

Name

Structure

Activity
Antibiotic

Flucloxacillin
5-

02

Fluorocytosine

03

Mefloquine

04

Bicalutamide

Antibiotic

Antibiotic

O2N

NH

CH3

Flumazenil

SO2

Antineoplastic
agent

OH

CF3

05

CH2

CNS depresent

O
N
C

C2H5

N
N
F
CH3

06

Midazolan

CH3

CNS depressant

Cl

07

Haloperidol

Anti psychotic

O
OH
F

CH2CH2CH2

Cl

08

Penfluridol

CF3
N

Antipsychotic

Cl
OH

09

Fluoxetine

CNS stimulant
CF3
O

NHCH3

8
10

Atorvastatin

HO

OH

OH O
N
H
N
O

11

Sulindac

Analgesic agent

CH2COOH

Cardiovascular
agent (for
inhibition of
HMG-CoA
reductase)

CH3
CH
O
S

H3C

12

Progabide

Antiepileptic

OH
F

NCH2CH2CH2CONH2

Cl

13

Diflunisal

Analgesic
Antiinflammatory
agent

COOH
OH

14

Enoxacin

HN

CH2CH3
N

In the treatment
of Urinary tract
inflections

COOH
O

15

Flutrimazole

N
F

Antifungal

N
F

16

Fluconazole

Antifungal

N
N
N
CH2

N
N

CH2COH

N
F

17

Fluorouracil

Antineoplastic
agent

O
F
NH
N
H

9
Table 1.2: Therapeutic agents with Chlorine
S.No.

Name

Structure

Chloroquine

CH3
CH

CH2

01
Cl

02

Activity
CH2CH3

CH2

Antimalarial

CH2

CH2CH3

Amodiaquine

Antimalarial

C2H5

OH

C2H5

CH2

H
N

Cl

03

Pyrimethamine

Antimalarial

H3C
CH2
N
NH2

Cl
N
H2N

04

Proguanil

HN
Cl

Antimalarial

H
N

NH
NH

05

Dicloxacillin

Cl

H
N

N
H

Cl
O

06

Cefachlor

H
C

NH2

Antibacterial

Antibacterial

NH

CH3

COOH

CH3 O

CH3

CH3

CH3

Cl

COOH

07

Mitotane

Antineoplastic

Cl
CH

Cl

agent

CHCl2

08

Clonidine

Cl

H
N
NH
N
H

Cl

Antihypertensive

10
09

Ticlopidine

Cl

Cardiovascular

CH2 N

agents

(Anti

Angina)
10

Diuril

Cl

Diuretic

NH2SO2

NH

S
O

11

Mefruside

Cl

N
NH2SO2

12

Dichloroisoproterenol

Diuretic

CH3
CH2

SO2

H3C

OH
NHCH(CH3)2

Cl

Guanabenz

Cl

Antihypertensive

NH
CH

NNHCNH2

Cl

14

Adrenergic
agent

Cl

13

Diazepam

CH3

agent
CNS depressant

Cl

15

Oxazepam

CNS depresents

H
N

CHOH
N

Cl

16

R=NH2 ,
Aproclonidine,

Cl
N

R
Cl

R=H, Clonidine,
R=OH,
4-hydroxyclonidine

H
N
N
H

Antihypertensive
agent

11
17

Chloropheniramine

Antihistaminic

Cl

maleate

agent

CHCOOH
CH

CH2CH2N(CH3)2
CHCOOH

18

Niclosamide

OH

Anthelmintic

Cl
CONH

NO2

Cl

19

Zomepirac

Cl

Analgesic

CH3

CH2COONa

N
CH3

20

Chlorcyclizine

Antihistamine
CH

CH3

Cl

21

Lamotrigine

Antiepileptic
N

Cl
Cl

H2N

22

Chloroquine

Cl

N
NH2

Antimalarial

CH2CH3
NHCHCH2CH2CH2N
CH3

23

Miconazole

Antifungal

N
N
O
CH2

CH

Cl

Cl

CH2
Cl

Cl

CH2CH3

12
Table 1.3: Therapeutic agents with Bromine
S.No.
01

Name

Structure

Sulphobromoph

Br

Diognastic

O
SO3Na

Br

thalein

Activity

agaent

OH

Br
Br
SO3Na
OH

02

Remoxipride

C2H5

D2

blocker

H2C
O

recedptor

NH

MeO

(CNS

depressant)

OMe
Br

03

Bretylium
Torsylate

04

Adrenergic agent

CH3
C N CH2CH3 . SO3H2
CH3

CH3

(Antiarrhythmic)

Br

Pyridostigmine

O
O

Treating

CH3
CH3

Bromide
N

in

Myastheniagravis

Br

CH3

05

06

Demecarium

O CH3
O

Bromide

+
N
Br
H3C CHCH3
3

Bromodiphenly

Br

To

CH3O
(CH2)10N

+
N

Br
CH3
CH
3
CH3

treat

wide

angle glaucoma
Antihistaminic

dramine

CHOCH2CH2N(CH3)2 . HCL

agent

Hydrochloride
07

Bromophnirami
ne Maleate

Antihistaminic

Br

CHCOOH
C CH2CH2N(CH3)2
H

.
CHCOOH

agent

13
08

Bromhexine

Antitussive

Br
CH3
C N
H2
Br

09

NH2

Bromperidol

In

O
F

CH2CH2CH2

OH

the

treatament

of

Br

Schizophrenia
10

Bromazepam

H
N

Anxiolytic

Br

N
N

11

Temelastine

H
N

NHCH2CH2CH2CH2

N
H3C

12

C
H2

Benzbromarone

Br

Antihistamine

H3C

Antiinflammatory

O
CH2CH3
Br
O

OH
Br

and

analgesic

antipyretic

14
Table 1.4: Therapeutic agents with Iodine
S.No.
01

Name

Structure

Idoxuridine

Activity
Antiviral

H
N

O
HO

OH
02

Haloprogin

For the treatment of

superficial
tinea
inflections
I

Cl
Cl

O
Cl

03

Clioquinol

Used
in
dermatitis,
psoriasis
impetigo

Cl

atopic
eczema,
and

N
OH

04

Idoquinol

Anti-infective

05

Loxaglate

COOI

OHCH2CH2NHOC

CH
Diagnostic
3CO N CH3
I
I

CONHCH3

NHOCCH2NHOC
I

agent

15
06

Lopanoic
acid

Diagnostic agent

C2H5
H2C C COOH
H
I

NH2
I

07

Locetamic
acid

O
H3C

CH3

Diagnostic agent

N C C COOH
H2 H
I

NH2
I

08

Propyliodone

Diagnostic agent

O
I

I
N
CH2CO2C3H7

09

Lav
othyroxine

NH2
HO
I

sodium

C C COO-.Na+
H2 H

Hypothyroidism

16
1.2. MICROWAVE CHEMISTRY:
Since 1950s microwave energy has found a variety of technical
applications in chemical and related industries particularly in food
processing, drying, polymer industries, analytical chemistry (micro
wave digestion, ashing, extraction), biochemistry (protein hydrolysis,
sterilization), pathology (histo processing, tissue fixation) and medical
treatments (diathermy). The first academic reports on the use of
microwave heating to mediate organic chemical reactions were
published by the group of Gedye and Giguere in 19864-6. The early
experients on Microwave Assisted Organic Synthesis [MAOS] were
typically carried out on sealed teflon or glass vessels in a domestic
household microwave oven without any temperature and pressure
measurents7-18. In 1990s the first attempts were made by Loupy et. al
at solvent free microwave chemistry (so called dry media reactions)
with eliminated danger of explosions19. Particularly at the beginning of
microwave assisted organic synthesis, the solvent free approach was
very popular since it allowed the safe use of domestic microwave ovens
and standard open vessel technology. A large number of interesting
transformations using dry media reactions has been published.
However technical difficulties relating non-uniform heating, mixing,
precise

determination

of

reaction

temperature

and

scale-up

approaches remained unsolved in dry media techniques. Besides the

dry media attempts, microwave-assisted synthesis in solution has
been carried under open vessel conditions. However, if solvents are
heated by microwave irradiation at atmospheric pressure in an open

17
vessel, the boiling point of solvent limits the reaction temperature. In
order to achieve high reaction rates, good microwave absorbing
solvents (DMF, Ethylene glycol) with high boiling points have been
frequently used in open vessel microwave synthesis. However the use
of such solvents presented serious challenges during product isolation
and re-cycling of the solvent. In the mid 1990 christopher R. Strauss
developed a technique i.e. MAOS in dedicated sealed vessels using
standard solvents. Recently published [since 2001] literature in the
area of controlled MAOS reveals that this approach will be the method
of choice due to beneficial combination of rapid heating by microwaves
with sealed vessel technology for performing organic synthesis on a
laboratory scale in future. Since the year 2000, among academic
laboratories number of publications realated to MAOS has increased
dramatically, reaching the overall number of about 3000 by the end of
2005. Besides the drastic-reduction in reaction times, microwave
heating is also known to suppress side reactions, increase yield, and
improve purity and reproducibility20-25.

Today dedicated microwave

reactors allow for careful control of time, temperature, pressure

profiles and also ensure reproducible protocol development, scale up
and transfer from laboratory to laboratory and from instrument to
instrument. Therefore, many academic and industrial groups are
already using MAOS as a technology for rapid reaction organization,
efficient synthesis of new chemical entities and for exploring chemical
reactivity.

18
1.2.1.Mechanism of microwave heating:
There are three specific mechanisms of interaction between
materials and microwaves: [1] dipole interactions [2] ionic conditions
and [3] ohmic heating. All mechanisms require effective coupling
between components of the target material and the rapidly oscillating
electrical field of the microwaves.
Dipole interactions occur with polar molecules. The polar ends
of the molecule tend to align themselves and oscillate with oscillating
electrical field of the microwaves. Collisions and friction between the
moving molecules results in heating. Broadly, the more polar a
molecule, the more effectively it will couple with the microwave field.
Ionic

condition

is

only

minimally

different

from

dipole

interactions. Obviously, ions in solution do not have a dipole moment.

They are charged species that are distributed and can couple with the
oscillating electrical field of the microwaves. The effectiveness or rate
of microwave heating of an ionic solution is a function of the
concentration of the ions in solution26-32. The behavior of any material
in a microwave field can be explained by studying its physical
parameters like the dissipation factor, often called the loss tangent.
The dissipation factor is a ratio of dielectric loss [loss factor] to the
dielectric constant.33 In ohmic heating conducting materials, the
conducting

species,

electrons,

ions

etc.,

are

moved

through

(microwave) field, causing polarization34. These induced currents will

cause heating through electrical (ohmic) resistance.35

19
1.2.2.Advantages of Microwave Synthesis36 :
01.

Higher reaction temperatures can be obtained by combining

rapid

microwave

heating

with

sealed-vessel

(autoclave)

technology.
02.

In many instances significantly reduced reaction times,

higher

yields

and

cleaner

reaction

profiles

will

be

experienced, allowing for more rapid reaction optimization

and library synthesis.
03.

Solvents with lower boiling points can be used under

pressure (closed vessel conditions) and

be heated at

temperatures considerably highr than their boiling point.

04.

Microwave heating allows direct in core heating of the

reaction mixture, which results in a faster and more even
heating of the reaction mixture.

05.

Specific microwave effects that cannot be reproduced

conventional heating can be exploited-for

by

example, the

selective heating of strongly microwave-absorbing catalysts.

06.

Easy on-line control of temperature and pressure profiles is

possible,

which

leads

to

more

reproducible

reaction

conditions.
07.

Microwave heating is more energy efficient than classical oilbath heating because of direct molecular heating and
inverted temperature gradients.

08.

It can easily be adapted to automated sequential or parallel

synthesis.

20
09.

The introduction of microwave energy into a chemical

reaction which has at least one component which is capable
of coupling strongly with microwaves can lead to much
higher

heating

rates

than

those

which

are

achieved

conventionally.
10.

Chemicals and the container materials for chemical reactions

do not interact equally with the commonly used microwave
frequenciesd for dielectric heating and consequently selective
heating

may

be

achieved.

Specifically

the

container

materials for a chemical reaction may be chosen in such a

way that the microwave energy passes thorugh the walls of
the vessel and heats only the reactants.

The very high

temperatures which result when metal powders are exposed

to microwave fields have been used to create hot spots
which accelerate the reactions of the metals with gases, other
inorganic solids and organic substrates.
11.

These selective interactions mean that microwave dielectric

heating is an ideal method for accelerating chemical
reactions under increased pressure conditions. Using quite
simple apparatus based either on transparent plastics, e.g.
Teflon or glass, it is possible to increase the temperature of a
reaction in common organic solvents up to 100 degree
centrigrade above the conventional boiling point of the
solvent.

For example,

ethanol has a conventional boiling

point of 79 degree centrigrade, microwave dielectric heating

21
in a closed vessel can rapidly lead to temperatures of 164
degree centrigrade and a pressure of 12 atmospheres. This
higher temperature leads to a thousand-fold acceleration of
the

reaction rate, for reactions which are studied in this

solvent.
12.

Microwave assisted organic synthesis facilitates more rapid

synthesis and screening of chemical substances to identify
compounds with appropriate qualities.

13.

It is useful in the discovery of novel reaction pathways due to

the extreme reaction conditions attainable by microwave
heating.

14.

Microwave synthesis is useful in drug discovery process by

generation of a discovery lilbrary, hit-to-lead efforts, and lead
optimization.