CHAPTER-1

INTRODUCTION
Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

INTRODUCTION

According to IUPAC specialized commission, “Medicinal chemistry concerns the discovery,

the development, the identification, and the interpretation of the mode of action of biologically
active compounds at the molecular level. Emphasis is put on drugs, but the interests of the
medicinal chemist are not restricted to drugs but include bioactive compounds in general.
Medicinal chemistry is also concerned with the study, identification and synthesis of the
metabolic products of these drugs and related compounds.
Drugs -natural and synthetic alike- are chemicals used for medicinal purposes. They interact
with complex chemical systems of humans or animals. Medicinal chemistry is concerned with
this interaction, focusing on the organic and biochemical reactions of drug substances with
their targets. This is one aspect of drug chemistry. Other important aspects are the synthesis
and analysis of drug substances. The two latter aspects together are sometimes called
pharmaceutical chemistry, but the synthesis of drugs is considered by some people- mainly
chemists- to be part of medicinal chemistry, denoting analytical aspects as pharmaceutical
chemistry. [Wermuth Georges Camille, 2009]

The discipline of medicinal chemistry is devoted to the discovery and development of new
agents for treating diseases. Most of this activity is directed to new natural or synthetic organic
compounds. Inorganic compounds continue to be important in therapy e.g. trace elements in
nutritional therapy, antacids, and radiopharmaceuticals, but organic molecules with
increasingly specific pharmacological activities are clearly dominant. The development
of organic compounds has grown beyond traditional synthetic methods. [Block H. John, et al, 1998]

Medicinal chemistry is central to modern drug discovery and development. For most of the
20th century, the majority of drugs were discovered either by identifying the active ingredient
in traditional natural remedies, by rational drug design, or by serendipity. It has advanced
during the recent decades from not only synthesizing new compounds but to
understanding the molecular basis of the disease and its control, identifying biomolecular

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 Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

targets implicated as disease-causing and ultimately inventing specific compounds called hits
that block the biomolecules from progressing to an illness or stop the disease in its track. [Lemke
L. Thomas, 2006 ]

Medicinal Chemistry is more narrowly concerned with the isolation, determination of structure,
and synthesis of compounds (mainly organic), which may be used in medicine. It also involves
the study of the metabolism and mechanism of action of drugs and the relationships between
structure and biological activity. [Bentlly, et al, 2004]

The primary objective of medicinal chemistry is the design and discovery of new compounds
that are suitable for use as drugs. This process involves a team of workers from a wide range
of disciplines such as chemistry, biology, biochemistry, pharmacology, mathematics, medicine
and computing, amongst others. [Thomas Gareth, 2009]

Medicinal chemistry is the field of pharmaceutical sciences that apply the principles of
chemistry and biology to the creation of knowledge leading to the introduction of new
therapeutic agents. Thus the medicinal chemist must not only be a competent organic chemist
but must have a basic background in biological sciences, particularly biochemistry and
[Korolkovas Andrejus, 2008]
pharmacology. The major drug targets are normally large molecules
(macromolecules) such as proteins and nucleic acids. Knowing the structures,
properties, and functions of these macromolecules are crucial if we are to design new drugs.
[Patrick L. Graham, 2009]

Medicinal chemistry covers the following stages-

1. In the first stage, new active substances or drugs are identified and prepared from natural
sources, organic chemical reactions or biotechnological processes. They are known as lead
molecules.
2. The second stage is the optimization of lead structure to improve potency, selectivity, and
lessen toxicity.
3. The third stage is the development stage involves the optimization of synthetic route for bulk
production and modification of pharmacokinetic and pharmaceutical properties of active
substance to render it chemically useful. [Nandela Rao Rama, 2008]

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

Heterocyclic Compounds

Heterocyclic compounds are those cyclic compounds in which one or more of the ring carbons
are replaced by another atom. The non-carbon atoms in such rings are referred to as
heteroatoms. The most common heteroatoms are nitrogen, oxygen, and sulfur, but other
[Bahl
atoms such as boron, phosphorous or silicon can also be members of heterocyclic rings.
Arun, et al, 2006]

Heterocyclic compounds are very widely distributed in nature and are essential to life in
various ways. Most of the sugars and their derivatives, including Vitamin C, for instance, exist
largely in the form of five-membered (furan) or six-membered (pyran) rings containing one
oxygen atom. Most members of the vitamin B group possess heterocyclic rings containing
nitrogen. One example is Vitamin B6 (Pyridoxin), which is a derivative of pyridine essential
in amino acid metabolism. Many other examples of the importance of heterocyclic compounds
in biological systems can be given. Most of the alkaloids, which are nitrogenous bases
occurring in plants and many antibiotics, including penicillin also contain heterocyclic ring
systems. A large number of heterocyclic compounds, obtained only by laboratory synthesis
have valuable properties as chemotherapeutic agents, drugs, dyes, dyestuffs, copolymers etc.

Heterocyclic compounds can be aliphatic or aromatic in character, depending on their

electronic constitution. In general, the aliphatic heterocyclics, where specific effects due to the
constitution of the compound are excluded, are very similar chemically to their open-chain
aliphatic analogs. For instance, tetrahydrofuran (1) has many properties characteristic of
diethyl ether (2). In a similar way, the aromatic heterocyclic compounds have many properties
resembling their aromatic carbocyclic analogues, a specific example being a comparison of
pyridine (3) and benzene (4). [Acheson R. Morrin, 2008]

CH3 CH3

CH2 CH2
O O N
2 3 4
1

Fig 1.1 Heterocyclic Compounds

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

The chemistry of heterocyclic compounds has been an interesting field of study for a long
[Patel Navin B., et al, 2010]
time. Heterocyclic compounds having five-membered rings containing
two carbon atom, one oxygen, two nitrogen & two double bonds such as oxadiazole. These
compounds are structurally similar to cyclic organic hydrocarbons, but their properties can
vary widely from those of their hydrocarbon counterparts and are largely governed by the
identity, location and number of heteroatoms present in the molecule. It is this rich diversity of
physical and biological properties that has to lead to an intense study of heterocyclic
[Castle W. Lyle, et al, 2009]
compounds. Synthesis of such heterocyclic compounds are of
pharmaceutical importance and a foremost task of chemists due to its vast pharmacological
and industrial applications. Nitrogen and oxygen-containing five-member heterocyclic
compounds have been used as a scaffold to synthesize numerous therapeutic molecules.
[Shridhar A. H, et al, 2011]

Classification of Heterocyclic Compounds

Heterocyclic chemistry is the chemistry branch dealing exclusively with synthesis, properties
[Fromm R. James, 1997]
and applications of heterocyclics especially vital to drug design.
Heterocyclic compounds may be given name after the hetero atoms present in the ring. Thus
we have oxygen heterocyclics like furan, pyran etc., nitrogen heterocyclics like pyrrole,
pyridine, piperidine etc. Sulfur heterocyclics like thiophene, thiopyran etc. for single
heteroatom-containing compounds. They may also be classified on the basis of the size of the
heterocyclic ring present. We have for example, 5-membered heterocyclics (Furan, Pyrrole,
thiophene etc.); 6-membered heterocyclics(pyridine, piperidine, pyran, thiopyran etc.)
containing single heteroatom in their heterocyclic rings.

5- Member-

H2 C CH2 H2 C CH 2

H2 C CH2 H2 C CH2
N S O O N
H H

Pyrrole Thiophene Furan Tetrahydrofuran Pyrrolidine

(Azole) (Thiole) (Oxole) (Oxolane) (Azolidine)

Fig. 1.2 Five member heterocyclic rings

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

6- Member-

H H H H

N O S O
N
H

Pyridine Piperidine Y-Pyran Y-Thiopyran Tetrahydropyran

(Azine) (Perhydrazine) (4H-Oxane) (4H-Thiane) (Oxane)

Fig. 1.3 Six member heterocyclic rings

Five membered heterocyclics containing two or more heteroatoms( e.g. imidazole, oxazole,
pyrazole, thiazole, etc.) and six-membered heterocyclics containing 2 or more heteroatoms are
e.g. pyrimidine, pyridazine, pyrazine etc.

5- Member Rings

The suffix –azole is used for five-membered rings containing two or more heteroatoms with at
least one nitrogen atom.

N N N N

N N

N N N O S
H H H

Pyrazole Imidazole 1,2,3-Triazole Oxazole Thiazole

(1,2-Diazole) (1,3-Diazole) (1,3-Oxazole) (1,3-Thiazole)

Fig. 1.4 various five-member rings

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

6- Member Rings

The suffix –azine is used for 6 member rings containing 2 or more heteroatoms. For example,

N
N

N
N N N

Pyridazine Pyrimidine Pyrazine

(1,2-Diazine) (1,3-Diazine) (1,4-Diazine)

Fig. 1.5 various six-member rings

Nomenclature of Heterocyclic Compounds

1. The systematic names for monocyclic compounds are given by using prefixes for the nature
of the heteroatom(s) present and dropping ‘a’ whenever necessary e.g. oxa-(for oxygen); thia-
(sulfur); aza-(nitrogen), sila-(silicon) and phospha-(phosphorous), etc. If two or more similar
heteroatoms are present, the prefixes di- tri- etc. are used e.g. triaza, trioxa etc. If heteroatoms
are different the order of citation starts from heteroatom of the highest group in the periodic
table and as low an atomic number when in the same group. Thus the order of naming will be
O, S, N, P, Si etc e.g. oxaza (O then N).

2. The size of the monoheterocyclics is indicated by the suffix –ole for 5-membered and –ine
for 6-membered.

3. In monoheterocyclics numbering is given such a way that the heteroatom gets the lowest
number and it proceeds anticlockwise around the ring.

4. When the heteroatoms are different, the numbering starts according to the order (given
above in rule-1) and proceeds around the ring in order of precedence.

5. In common names, Greek. letters denote the position of the substituents.

Systematic names are given in italics for comparison. [Jain M.K., et al, 2008]

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

CH3 N N

N O
N N O
H

Pyridine β-Methyl pyridine Furan Imidazole Oxazole

(Azine) (3-Methylazine) (Oxole) (1,3-Diazole) (1,3-Oxazole)

Fig. 1.6 various heterocyclic compounds

Importance of Heterocyclic Compounds

Heterocyclic compounds are very widely distributed in nature and are particularly important
because of the wide variety of physiological activities associated with this class of substances.
Several of the important compounds contain heterocyclic rings, e.g. heterocyclic rings are
present in most of the members of the vitamin B complex, most of the alkaloids, antibiotics,
chlorophyll, haemin, other plant pigments, amino acids, dyes, drugs, enzymes, the genetic
material, DNA etc. A great deal of research is carried out to prepare new heterocyclic molecules
having therapeutic uses. [Agrawal O.P., 2008 ] During past decades, compounds bearing heterocyclic
nuclei have received much attention due to their chemotherapeutic value in the development of
novel antimicrobials and anthelmintics. [Srinivas Kantham, et al, 2010] In recent scenario heterocycles
play a major role in drug synthesis. In recent years, a significant portion of the research in
heterocyclic chemistry has been devoted to sydnones containing different moieties. [Kamble
Ravindra R., et al, 2008]
In that respect oxadiazole plays a significant role among other
heterocycles.[Parikh Palak K, et al, 2011]

About Oxadiazole

The oxadiazole chemistry has been developed extensively and is still developing. Presently
there are a number of drugs used clinically, which comprise oxadiazole moiety in association
[Frank Priya V., et al, 2007]
with various heterocyclic rings. Oxadiazole is a cyclic compound
containing one oxygen and two nitrogen atoms in a five-membered ring. There are four
possible isomers of oxadiazole depending on the position of the nitrogen atom in the ring. The

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

electrophilic substitution, nucleophilic substitution, thermal and photochemical which made it

[Panda
medicinal backbone on which a number of potential molecules can be constructed.
Jnyanaranjan, et al, 2011]
Oxadiazole is the parent compound for a vast class of heterocyclic
[Singh Poonam, et al, 2010]
compounds. These are azoles with oxygen and nitrogen. Oxadiazole
moiety and its various derivatives studied frequently in the past few decades and found potent in
various pharmacological and pathological conditions. Oxadiazole derivatives have been found
to possess broad-spectrum antimicrobial activity and therefore are useful substructures for
further molecular exploration. Furamizole (Figure 1.2) is a compound that is based upon 1, 3, 4-
oxadiazole ring and has strong antibacterial activity.

N N

O
O2N NH2
O

Fig 1.7 Furamizole

The first monosubstituted 1, 3, 4-Oxadiazoles were reported in 1955 by two independent

laboratories. Since 1955 other workers have extended this reaction 1, 3, 4-Oxadiazole
boils at 150° C. Oxadiazole exist in four isomeric forms as shown in Figure 1.3. [Bhatia Shivi, et
al, 2011]

N N N N

N N N N
O O O O

Fig. 1.8 Four isomers of Oxadiazole

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

Oxadiazole is an important heterocyclic ring present in a large number of biologically active

molecules of different pharmacological classes.[Mishra Manish Kumar, et al, 2010]
Oxadiazole
derivatives have been the subject of numerous reports highlighting their chemistry and use in
the recent past. Oxadiazole ring has been shown to impart anti-inflammatory properties in
compounds designed as orally-active nonulcerogenic agents or in products formulated as
analogs of fenamates for the inhibition of cyclooxygenase and 5-lipooxygenase.[Roman Gheorghe, et
al, 2007]
Oxadiazole is the major compound of the heterocyclic nucleus for the development of
new drugs and the drugs of oxadiazole were the first effective chemotherapeutic agent to be
employed systemically for the prevention & cure of bacterial infection.[Singh Harkishan, et al, 2008]

Some oxadiazoles with different substituents, especially with a 4-hydroxyphenyl moiety at

different locations on the five-membered heterocyclic ring produced fungicidal and bactericidal
agents of various potencies.[Sadek Bassem, et al, 2011]

About 1, 3, 4-Oxadiazole
The widespread use of 1, 3, 4-oxadiazoles as a scaffold in medicinal chemistry renders this
moiety as an important bioactive class of heterocycles. These molecules are also utilized as
pharmacophores due to their favorable metabolic profile and ability to engage in hydrogen
bonding. In particular, marketed antihypertensive agents such as tiodazosin and nesapidil, as
well as antibiotics such as furamizole contain the oxadiazole nucleus. They are also useful as
HIV integrase inhibitors and the angiogenesis inhibitors. Moreover, 1, 3, 4-oxadiazole
derivatives are among the most widely employed electron-transporting and hole-blocking
materials in the development of organic light-emitting diodes (OLEDs), which are used in
[Aryanasab F., et al, 2011]
energy-efficient, full-color and fiat-panel displays. From the literature
survey, 1, 3, the 4-oxadiazole nucleus has been found to possess diverse pharmacologica
activities such as antibacterial, anti-inflammatory, analgesic, antitubercular[Dewangan Dhansay, et al,

2010], [Bharathi D., et al,2010], [Almasirada Ali, et al,

anthelmintic anticonvulsant, muscle relaxant activity
2007]
and anticancer activity. [Srinivas Kantham, et al, 2010]

Synthesis of 1, 3, 4-Oxadiazole

1, 3, 4-oxadiazole is thermally stable and this stability is increased on substitution, particularly

by aryl and perfluoroalkyl groups.1, 3, 4-oxadiazole is a liquid, which boils at 150°C.
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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

Ainsworth first prepared it in 1965 by the thermolysis of ethyl formate formally hydrazone at
atmospheric pressure. [Sharma S., et al, 2010]
In the present study, a new series of oxadiazole derivatives were synthesized from different
substituted anilines The first step in which the substituted anilines were reacted with sodium
cyanate in presence of glacial acetic acid to form aryl urea. The reaction is based on the
synthesis of urea by vital force theory. In the second step, the substituted aryl ureas were treated
with hydrazine hydrate in a basic condition to form substituted phenylsemicarbazide by a
nucleophilic substitution reaction. In the third step, the substituted phenylsemicarbazide
undergoes reaction with substituted benzoic acid in pyridine to form 1, 3, 4oxadiazole
derivatives. The reaction is taking place at 170-200 °C in an oil bath through
cyclization.[Ilangovan Ponnilavarasan, et al, 2011]

NH2 NHCONH 2 NHCONHNH 2

Sodium Cyanate Hydrazine hydrate

CH3 COOH
3 hrs reflux
R R
R

Substituted aniline substituted phenyl urea Substituted phenyl semicarbazide

Substituted Pyridine
Benzoic acid 4 hrs oil bath

H O
N

R1
N N

2-(substituted aniline)-5-(substituted phenyl)-1, 3, 4-oxadiazole

Fig.1.10 Synthesis of 2-(substituted aniline)-5-(substituted phenyl)-1, 3, 4-oxadiazole

Literature survey reveals that the 1, 3, 4 oxadiazole undergoes number of reactions such as
Electrophilic substitution, Nucleophilic substitution, Thermal and Photochemical. This has been
exploited in the preparation of 1, 3, 4 oxadiazole therapeutic molecules for various
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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

applications.[Nagaraj, et al, 2011]

Combining biphenyltetrazole with substituted 1, 3, 4-
oxadiazole by –SCH2- moiety is expected to give novel heterocyclic compounds with
better biological activities. [Chaoa Shu-Jun, et al, 2005]

Among the methods employed in synthesis of 1, 3, 4-oxadiazole, condensation of hydrazide

and its derivatives with variety of substituted acids and bases are commonly used. 2,5-
disubstituted 1, 3, 4-oxadiazole can be conveniently synthesized by the treatment of pyridine-
4-carbohydrazide with different acids and bases and carbon disulfide in basic and acidic
media. It was anticipated that the 1, 3, 4-oxadiazole ring 2,5-disubstituted with the potential
drug molecules containing pyridine, piperidine and indole rings will enhance the activity of
[Hemavathi S.N, et al, 2011]
the molecule. 1, 3, 4-oxadiazole-2-thiones are biologically active
compounds, information about their three dimensional structures may be of great interest for
rational drug design. 1, 3, 4-Oxadiazole-2-thiones consist of an equilibrium mixture of its
thione and thiol forms.[Aydogan Feray, et al, 2002] The interesting properties of the metal chelates of
chromen-2-one carboxy hydrazide and 1, 3, 4-oxadiazole derivatives have stimulated research
in these compounds that find a variety of laboratory uses and many industrial
.[Mathew Glory, et al, 2011]
applications

Applications of 1, 3, 4-Oxadiazole

1, 3, 4-oxadiazoles are biologically active, synthetically useful and important heterocyclic

compounds for these reasons the chemistry of 1, 3, 4-oxadiazoles have been the subject of
many investigations. Cerric ammonium nitrate has received considerable attention as an
inexpensive and easily available catalyst for various organic reactions such as Oxidation,
Oxidative addition, Nitration, Photo-oxidation, Polymerization etc. [Dabholkar Vijay V., et al, 2011]
Some material applications of 1, 3, 4-oxadiazole derivatives lie in the field of liquid crystals
and photosensitizer. Many seed oils, fatty acids and their derivatives are known for their
pesticidal, antimicrobial and antifungal activities. Thus fatty acids on derivatization to the
heterocyclic compounds can be used as valuable oleo-chemicals. [Banday Mudasir R, et al, 2010]

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Synthesis, Characterization and Pharmacological Evaluation of 2, 5-Disubstituted 1, 3, 4- Oxadiazole Derivatives

Marketed Drugs containing 1, 3, 4-Oxadiazole nucleus

Nesapidil, 1-[4-(2-methoxyphenyl)piperazin-1-yl]-3-[3-(5-methyl-1, 3, 4-oxadiazol-2

yl)phenoxy]propan-2-ol, a well established vasodilating agent also contains 1, 3, 4 oxadiazole nucleus.
It is calcium channel blocker.

N
OMe
N
N N

O Me
O
HO

Fig 1.11 Nesapidil

Tiodazosin, is an antihypertensive drug. It produced a noncompetitive antagonism of α

adrenergic receptors in the portal vein. [Bala Suman, et al, 2010]

NH2

MeO

N N N N
MeO
N
SMe
O

Fig. 1.12 Tiodazosin

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