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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.
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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,
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bioavailability, pharmacokinetics and finally its capacity to establish
direct interactions between the substituent and the receptor or the
enzyme.
Solubility, Electronic M H M X 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
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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
C-F
C-Cl
C-Br
C-I
93
114
72
59
45
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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
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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:
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Table 1.1: Therapeutic agents with Fluorine
S.No. Name Structure Activity
01
Flucloxacillin
Antibiotic
02
5-
Fluorocytosine
Antibiotic
03
Mefloquine
Antibiotic
04 Bicalutamide NH C C CH2
CH3
OH
O2N
CF3
SO2 F
O
Antineoplastic agent
05 Flumazenil N
NF
CH3O
N
C O
O
C2H
5
CNS depresent
06 Midazolan
Cl
F
N
N
NCH3
CNS depressant
07 Haloperidol F C CH2CH2CH2 N
OH
Cl
O
Anti psychotic
08 Penfluridol
N
CF3
ClOH
F
F
Antipsychotic
09 Fluoxetine
O
CF3
NHCH3
CNS stimulant
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10 Atorvastatin F
N
NH
OH
OHOH
O
O
Cardiovascular
agent (for inhibition of HMG-CoA
reductase)
11 Sulindac CH2COOHFCH
3
CH
SCH3
O
Analgesic agent
12 Progabide
C NCH2CH
2CH
2CONH
2
OH
Cl
F
Antiepileptic
13 Diflunisal
F
OH
COOH
F
Analgesic Antiinflammatory agent
14 Enoxacin NHN
F
N
CH2CH
3
COOH
O
In the treatment of Urinary tract inflections
15 Flutrimazole
CF
N
N
F
Antifungal
16 Fluconazole
CH2
CH2COH
F
F
N
N
N
NN
N
Antifungal
17 Fluorouracil
N
N
O
OF
H
H
Antineoplastic
agent
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Table 1.2: Therapeutic agents with Chlorine
S.No. Name Structure Activity
01
Chloroquine
NCl
N
H CH
CH3
CH2
CH2
CH2
N
CH2CH
3
CH2CH
3
Antimalarial
02 Amodiaquine
NCl
N
OH
CH2H
N
C2H
5
C2H
5
Antimalarial
03 Pyrimethamine CH3
N
NH2
CH2
N
Cl
NH2
Antimalarial
04 Proguanil
NH
NH
NH
NH
NH
CH3
CH3
Cl
Antimalarial
05 Dicloxacillin
ON
Cl
Cl
NH
N
O
CH3
S
CH3
COOHO
CH3
Antibacterial
06 Cefachlor O
CH
NH2
NH
NO
S
Cl
COOH
Antibacterial
07 Mitotane CH Cl
Cl
CHCl2
Antineoplastic
agent
08 Clonidine
NH
Cl
Cl
N
N
H
H
Antihypertensive
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09 Ticlopidine Cl
CH2 N
S
Cardiovascular
agents (Anti
Angina)
10 Diuril Cl
SO2 S
NH
N
NH2
O O
Diuretic
11 Mefruside Cl
SO2 SO
2
OCH
3NH
2
N
CH3
CH2
Diuretic
12 Dichloroisoproterenol Cl
Cl
OH
NHCH(CH3)2
Adrenergic
agent
13 Guanabenz
CH NNHCNH2
NHCl
Cl
Antihypertensive
agent
14 Diazepam
Cl
N
N
OCH3
CNS depressant
15 Oxazepam
Cl
N
CHOH
N
OH
CNS depresents
16 R=NH2 ,
Aproclonidine,
R=H, Clonidine,
R=OH,
4-hydroxyclonidine
N
Cl
Cl
R
N
NH
H
Antihypertensive
agent
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17 Chloropheniramine
maleate CH CH
2CH
2N(CH
3)2
Cl
N CHCOOH
CHCOOH
Antihistaminic
agent
18 Niclosamide
CONH
Cl
NO2
OH
Cl
Anthelmintic
19 Zomepirac
CClN CH
2COONa
OCH
3
CH3
Analgesic
20 Chlorcyclizine
CH N N
Cl
CH3
Antihistamine
21 Lamotrigine
Cl
ClN
NN
NH2NH
2
Antiepileptic
22 Chloroquine Cl N
NHCHCH2CH
2CH
2N
CH3
CH2CH
3
CH2CH
3
Antimalarial
23 Miconazole
Cl
Cl
CH2
OCH
Cl
Cl
CH2
N
N
Antifungal
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Table 1.3: Therapeutic agents with Bromine
S.No. Name Structure Activity
01 Sulphobromoph
thalein
Br
Br
BrO
SO3Na
OH
SO3Na
OH
OBr
Diognastic
agaent
02 Remoxipride
Br
MeO OMe
NH
CH2
NC
2H
5
O
D2 recedptor
blocker (CNS
depressant)
03 Bretylium
Torsylate
CH
2
N
Br
CH2CH
3
CH3
CH3
SO3- CH
3.
Adrenergic agent
(Antiarrhythmic)
04 Pyridostigmine
Bromide N
O N
CH3
CH3
O
CH3
Br+
Treating in
Myastheniagravis
05 Demecarium
Bromide N
O N (CH2)10
N
CH3
CH3
CH3
CH3
CH3
O
NCH
3
CH3
CH3
O O
BrBr+
+
To treat wide
angle glaucoma
06 Bromodiphenly
dramine
Hydrochloride
Br
CHOCH2CH
2N(CH
3)2 . HCL
Antihistaminic
agent
07 Bromophnirami
ne Maleate NCH
Br
CH2CH
2N(CH
3)2 .
CHCOOH
CHCOOH
Antihistaminic
agent
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08 Bromhexine
Br NH2
Br
CH
2
N
CH3
Antitussive
09 Bromperidol F CH
2CH
2CH
2
O
NOH
Br
In the
treatament of
Schizophrenia
10 Bromazepam
Br
NH
N
N
O
Anxiolytic
11 Temelastine N
CH3
CH
2
NH
NHCH2CH
2CH
2CH
2
O
N
CH3
Br
Antihistamine
12 Benzbromarone OCH
2CH
3
Br
OH
Br
O
Antiinflammatory
and analgesic
antipyretic
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Table 1.4: Therapeutic agents with Iodine
S.No. Name Structure Activity
01 Idoxuridine
I
NO
OH
O
NH
O
OH
Antiviral
02 Haloprogin
Cl
Cl
Cl
O
I
For the treatment of
superficial tinea inflections
03 Clioquinol
N
OH
I
Cl
Used in atopic dermatitis, eczema,
psoriasis and impetigo
04 Idoquinol N
I
I
Anti-infective
05 Loxaglate
I
II
COO-
OHCH2CH
2NHOC NHOCCH
2NHOC
I
II
CONHCH3
NCH
3CH
3CO
Diagnostic agent
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06 Lopanoic
acid
I
II
NH2
CH2
CH
COOHC
2H
5
Diagnostic agent
07 Locetamic
acid
I
II
NH2
N CH
2
CH
CH3
COOH
CH3
O
Diagnostic agent
08 Propyliodone
I
O
N
I
CH2CO
2C
3H
7
Diagnostic agent
09 Lav
othyroxine
sodium
O
I
II
I
OH CH
2
CH
NH2
COO-.Na+
Hypothyroidism
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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
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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.
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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
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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 by
conventional heating can be exploited-for 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 oil-
bath heating because of direct molecular heating and
inverted temperature gradients.
08. It can easily be adapted to automated sequential or parallel
synthesis.
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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
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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.
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