CHAPTER-I
AN OVERVIEW OF HETEROCYCLIC
COMPOUNDS AND THEIR
BIOLOGICAL SIGNIFICANCE
Chapter I; Introduction
An Overview of Heterocyclic compounds and their biological
significance
Introduction
Heterocyclic chemistry is a very important branch of organic chemistry
accounting for nearly one-third of modern publications. In fact two thirds of
organic compounds are heterocyclic compounds. A cyclic organic compound
containing all carbon atoms in ring formation is referred to as a carbocyclic
compound. If at least one atom other than carbon forms a part of the ring system
then it is designated as a heterocyclic compound1. Nitrogen, oxygen and sulfur are
the most common heteroatoms but heterocyclic rings containing other hetero
atoms are also widely known. An enormous number of heterocyclic compounds
are known and this number is increasing rapidly. Accordingly the literature on the
subject is very vast. Heterocyclic compounds may be classified into aliphatic and
aromatic. The aliphatic heterocyclics are the cyclic analogues of amines, ethers,
thio ethers, amides, etc. Their properties are particularly influenced by the
presence of strain in the ring. These compounds generally consist of small (3- and
4-membered) and common (5 to 7 membered) ring systems. The aromatic
heterocyclic compounds, in contrast, are those which have a heteroatom in the ring
and behave in a manner similar to benzene in some of their properties.
Furthermore, these compounds also comply with the general rule proposed by
Huckel. Besides the vast distribution of heterocycles in natural products, they are
also the major components of biological molecules such as DNA and RNA. DNA
is without doubt the most important macromolecule of life. Nucleotides, the
Page 1
Chapter I; Introduction
building blocks of our genes are derivatives of pyrimidine and purine ring
structures. Chlorophyll and heme, the oxygen carriers in plants and animals
respectively are derivatives of large porphyrin rings.
Heterocycles are an important class of compounds, making up more than
half of all known organic compounds. Heterocycles are present in a wide variety of
drugs, most vitamins, many natural products, biomolecules, and biologically active
compounds, including antitumor, antibiotic, anti-inflammatory, antidepressant,
antimalarial,
anti-HIV,
antimicrobial,
antibacterial,
antifungal,
antiviral,
antidiabetic, herbicidal, fungicidal, and insecticidal agents. Also, they have been
frequently found as a key structural unit in synthetic pharmaceuticals and
agrochemicals. Some of these compounds exhibit a significant solvatochromic,
photochromic, and biochemi-luminescence properties. Most of the heterocycles
possess important applications in materials science such as dyestuff, fluorescent
sensor, brightening agents, information storage, plastics, and analytical reagents. In
addition, they have applications in supra molecular and polymer chemistry,
especially in conjugated polymers. Moreover, they act as organic conductors,
semiconductors, molecular wires, photovoltaic cells, and organic light-emitting
diodes (OLEDs), light harvesting systems, optical data carriers, chemically
controllable switches, and liquid crystalline compounds. Heterocycles are also of
considerable interest because of their synthetic utility as synthetic intermediates,
protecting groups, chiral auxiliaries, organ catalysts, and metal ligands in
asymmetric catalysts inorganic synthesis. Therefore, substantial attention has been
paid to develop efficient new methods to synthesize heterocycles.
Page 2
Chapter I; Introduction
The alkaloids form a major group of naturally occurring heterocyclic
compounds having varied biological activity. Most alkaloids contain basic nitrogen
atoms. Ergotamine, the indole based alkaloid exhibits antimigraine activity2.
Cinchonine, a quinolone class of alkaloid shows antimalarial activity3.
Posaconazole is a triazole antifungal drug4.
It is active against the
following microorganism candida, asperigillus, Zygomycetes.
Page 3
Chapter I; Introduction
Anastrozole is an aromatase-inhibiting drug approved for the treatment of
breast cancer after surgery, as well as for metastasis in both pre and postmenopausal women. The severity of breast cancer is increased by estrogen, as sex
harmones cause hyperplasia, and differentiation at estrogen receptor sites5,6.
Anastrozole works by inhibiting the synthesis of estrogen.
Three out of twenty natural amino acids are heterocyclic, as are many
essential vitamins. The range of application of heterocyclic compounds is very
wide. They are of specific importance as they are associated with a wide variety of
physiological activities.
Significant number of compounds synthesized in the industrial sector is
heterocyclic in nature. A large number of synthetic heterocyclic compounds are
predominant among all types of pharmaceuticals, agrochemicals veterinary
products. Some of the synthetic heterocyclics are used in photography and as
rocket propellants.
Heterocyclics are able to get involved in an extraordinarily wide range of
reaction types. Depending upon pH of the medium, they may behave as acids or
bases, forming anions or cations. Some interact readily with electrophilic reagents,
Page 4
Chapter I; Introduction
other with nucleophiles, yet others with both. Some are readily oxidized, but resist
reduction, while others can be readily hydrogenated but are stable toward the
action of oxidizing agents. The ability of many heterocyclics to produce stable
complexes with metal ions has great biochemical significance.
Sumatriptan, a heterocyclic compound is the first antimigrain drug7,
replacement of sulfonamide moiety in sumatriptan with 1, 2,4-triazole (A), which
is also a potent 5-HT1D receptor agonist8.
The practical application of indole and pyrroles are heavily centered in the
pharmaceutical area. Many analogues of indole derivatives have been synthesized
in an effort to find substances with useful central nervous systems (CNS) activity9.
The furan ring is common in many naturally occurring terpenoid compounds. The
cardiac active steroidal lactones are important class of naturally occurring 2(5H)furanones and because of their pharmaceutical importance and many synthetic
routes for the 2(5H)-furanones have been developed10. A number of relatively
simple pyridine is used in the treatment of muscular rheumatism11. Compounds
which have unsaturated ∂-lactone rings are reported to have carcinogenic and
Page 5
Chapter I; Introduction
antitumor activity as well as other biological property12. The fusions of a five
membered rings with six membered heterocyclic rings are interesting and
pharmacologically active.
The rich activity of heterocyclic compounds in biological systems is
important for pharmaceuticals, agricultural, and natural products.
Heterocyclic compounds have provided a platform for the rapid exchange
of research in the areas of organic, pharmaceutical, analytical, and medicinal
chemistry. In the pharmaceutical industry over 75% of the top two hundred
branded drugs have heterocyclic fragments in their structures.
Biological efficacy and Therapeutic utility of Heterocyclic Compounds:
Isoxazole is an azole with an oxygen atom next to the nitrogen. It is also the
class of compounds containing this ring. Isoxazolyl is the univalent radical derived
from isoxazole.
Isoxazole derivatives have served as versatile building blocks in organic
synthesis13. The isoxazole nucleus is a prominent structural motif found in
numerous natural products and synthetic compounds with vital medicinal value14.
Also, isoxazoles have applications in functional materials15, such as liquid
crystalline
compounds16
antibacterial19,
and
exhibit
anti-inflammatory20,
GABAA
antagonist17,
hypoglycemic21,
COX-2
analgesic18,
inhibitory22,
antinociceptive23 and anticancer activity24.
Isoxazole rings are found in some natural products, such as ibotenic acid.
Isoxazoles also form the basis for a number of drugs, including the COX-2
Page 6
Chapter I; Introduction
inhibitor viz; veldecoxib (Bextra). A derivative, furoxan, is a nitric oxide donor.
An isoxazolyl group is found in many betalactamase-resistant antibiotics, such as
cloxacillin, dicloxacillin and flucloxacillin. The synthetic androgenic steroid
danazol also possess an isoxazole ring25.
Quinoxaline 1-4-di-N-Oxide derivatives:
Quinoxalines
pharmacological27
display
activities
a
broad
such
as
spectrum
insecticides,
of
biological26
fungicides,
and
herbcides,
anthelmintics, antibacterial28, antimycobacterial, antiprotozoal, anticancerand
antibiotic properties29. Quinoxaline derivatives have found applications in dyes30
electron luminescent materials31 and chemically controllable switches32 as building
blocks for the synthesis of anion receptors33, cavitands34, dehydro annulenes35 and
organic semiconductors36 and as electron transport materials in multilayer
OLEDs37. A number of synthetic strategies have been developed for the
preparation of substituted quinoxalines, including condensation of aryl-1,2diamines with α-functionalized ketones, usually dicarbonyl compounds or their
equivalents38, 39.
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Chapter I; Introduction
Heterocyclic compounds as antimalarial:
Malaria is one of the most serious, complex and refractory malady facing
humanity this century. Some 300-500 million of world’s population are infected by
the disease, presenting 120 million clinical cases annually.
Quinine may be claimed, without exaggeration, as the drug to have relieved
more human suffering than any other inhibitors40. Chloroquinine, the main drug
among the 4-aminoquinoline class, is one of the most successful antimalarial
agents ever produced.
Primaquinine is the drug of 8-aminoquinoline class, which is connected to
amino acids by forming peptide bond to the amino group. These amino acid
derivatives are known for higher activity and lower toxicity41.
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Chapter I; Introduction
Heterocyclic compounds as Diuretic agents:
Diuretics are medicines that help reduce the amount of water in the body.
Acetazolamide is a potent carbonic anhydrase inhibitor, effect in the control of
fluid secretion in the treatment of certain Convulsive disorders and in the
promotion of diuresis in instances of abnormal fluid retention. Acetazolamide is
not a mercurial diuretic. Rather, it is non-bacteriostatic sulfonamide possessing a
chemical structure and pharmacological activity distinctly different from the
bacteriostatic sulfonamides. The anticonvulsant activity of acetazolamide may
depend on a direct inhibition of carbonic anhydrase in the CNS, which decreases
carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen
tension. The diuretic effect depends on the inhibition of carbonic anhydrase,
causing a reduction in the availability of hydrogen ions for active transport in the
renal tubule lumen42-44. This leads to alkaline urine and increase in the excretion of
bicarbonate, sodium, potassium, and water.
Heterocyclic compounds as anthelmintic:
Helminthes are parasitic worms, which infect an estimated two billion
people worldwide, nearly all in poor developing tropical or semitropical countries.
Helminthic infections contribute to malnutrition, anemia, stunted growth, cognitive
impairment, and increased susceptibility to other diseases.
Page 9
Chapter I; Introduction
Benzimidazole, pyrazine, isoquinoline, tetrahydropyramidine, tetrahydro
quinolone, piperidine, piperazine, triazoles, indoleisoxazole derivatives are the
different types of heterocyclic used as anthelmintics. Albendazole is the most
active benzamidazole anthelminitic drug45.
Heterocyclic compounds as antineoplastic agents:
Cancer is a major human health problem worldwide and is the second
leading cause of death in United States46. Systematic chemotherapy began in the
1940’s and 1950’s with nitrogen mustards developed from war gases and with
antimetabolites developed from early knowledge of DNA metabolism. Compounds
that alkylated DNA have long been of interest as anticancer drugs. Different types
of antineoplastic agents are developed, which include nitrogen mustards
(Bendamustine), tyrosine kinase inhibitors, 26S proteasome inhibitors etc.
Page 10
Chapter I; Introduction
Quinozoline and pyrimidine derivatives are used as tyrosine kinase
inhibitors. A series of substituted 2-(aminopyridyl)-and 2-(aminopyrimidinyl)
thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with
excellent antiproliferative activity against hematological and solid tumor cell
lines47. Chronic Myelogenous Leukemia (CML) is a myeloproliferative disorder
that is characterized by hyper proliferation of stem cells, followed by their
subsequent differentiation into peripheral white blood cells. Imatinib, is the block
buster drug used for the treatment of Chronic Myelogenous Leukemial (CML)48.
Imatinibmysilate is marketed under brand name Gleevec.
The quinazoline
derivative drugs like erlotinib, and lapatinib are also important tyrosine kinase
inhibitors.
Page 11
Chapter I; Introduction
Heterocyclic compounds as antidepressants:
An antidepressant is a psychiatric medication used to alleviate mood
disorders, such as major depression, and dysthymia. Drugs including the
monoamine oxidase inhibitors (MAOIS), tricyclic antidepressants (TCAs),
tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors
(SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) are most commonly associated with
them.
Paroxetine, reboxetine, are some of most useful antidepressants containing
heterocyclic moiety in their structure. Some piperidine and pyrimidine derivatives
also possess antidepressant activity. A variety of small molecule nano-peptide
antagonist heterocyclics have been discovered and shown to possess antidepressant
activity in animal behavioral tests49, 50.
Heterocyclic compounds as antiulcer agents:
Pyridine ring plays an important role in human metabolism due to its
interaction with amino acids. Many of the active drugs in the market contain
pyridine
moiety51,52.
Benzamidazoles
also
are
well
known
for
their
Page 12
Chapter I; Introduction
pharmacological properties in particular, they are widely used as anthelmintic
agents.
It
is
interesting
pyridylsulfinylbenzimidazole
to
note
molecules
that
like
a
series
omeprazole
of
substituted
possess
gastric
antisecretary and consequently anti-ulcerative activity53.
Later several omprazole analogues like lanoprazole54, pantoprazole55 have been
introduced in the market successfully.
Page 13
Chapter I; Introduction
Heterocyclic compounds as antipsychotic agents:
Antipsychotic agents constitute a diverse class of heterocyclic drugs that are
effective in the treatment of major psychosis, including those associated with
schizophrenia. Which is a severe, life-long, idiopathic psychiatric disorder with a
polygenic component. Schizophrenia is a disorder afflicting approximately 1% of
human of most population.
Benzisoxazole derivatives are found to have antipsychotic properties and
are more potent. 3-(piperidin-4-yl)-1,2-benzisoxazole possess anti-psychotic
properties and helpful in the treatment of variety of disorders in which serotonin
release is of predominant importance56.
Apart from the above significant classes of heterocyclic compounds useful
as therapeutic agents, some indole derivatives as antiosteoporotic agents57, and
triazole compounds (fluconazole, Isavuconazole, Hexaconazole, epoxiconazole,
difenoconazole, tebuconazole etc.,) are used as a fungicides58, Indole derivatives
are used as antimigraines; Quinoline/Isoquinoline drugs are used as antimalarial,
and drugs for asthma & allergies, hypertension 59.
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Chapter I; Introduction
Page 15
Chapter I; Introduction
Page 16
Chapter I; Introduction
Triazoles
1,2,3-Triazole has become one of the most important heterocycles in current
chemistry research60, due to its important industrial, agrochemical, and
pharmaceutical applications61, especially in biological science62, material
chemistry63, and medicinal chemistry64. One of the most attractive ways to prepare
these compounds involves thermal 1,3-dipolar cyclo addition of azides with
alkynes65. Additionally, the chemistry of the tetrazole ring is gaining increasing
attention due to its importance in a variety of synthetic and industrial processes 66
and excellent properties as a metabolically stable isosteric replacement for the
carboxylic acid moiety67and as a cis-peptide bond mimetic68. Tetrazoles have also
been used as precursors to other heterocycles and in high energy compounds69,70.
The synthesis of tetrazoles from a cycloaddition reaction between a nitrile and an
azide is well documented71.
Heterocyclic chemistry is vastly expanding, because of the enormous
amount of research work being done in this area. The majority of known molecules
are heterocyclics. Heterocyclic compounds dominate the field of biochemistry,
medicinal chemistry, dyestuff, photographic sciences and are of increasing
importance in many other areas includingpolymers, adhesives and molecular
engineering. Among the heterocyclic compounds, Quinoxalines, Oxoindolines,
Triazoles and Isooxazoles are important chemotherapeutic agents and have found
wide clinical applications as antimicrobial, anticancer, antiviral and anti-AIDS,
antitubercular,
sedative/hypnotic/antiepileptic,
cardiac
agents,
as well as
analgetics, diuretics, antibiotics and metabolic electrolytes etc.
Page 17
Chapter I; Introduction
On continuation of our interest to synthesis the heterocyclic compounds, the
present work is focused on synthesis of some novel Quinoxaline 1-4-di-N-Oxide
derivatives, Oxoindoline derivatives, triazole derivatives and isooxazoles
derivatives
and
to
evaluate
for
their
antimicrobial,
anticancer
and
anti-inflammatory activities.
Page 18
Chapter I; References
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