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Ramesh Dhani et al. / International Journal of Advances in Pharmaceutical Research
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Review Article
ISSN: 2230 – 7583
CHEMISTRY AND REACTIVITY OF IMIDAZOLE DERIVATIVES
Ramesh Dhani*1
Department of Pharmaceutical Chemistry, Oil Technological Research Institute, Jawaharlal Nehru Technological
University, Anantapur, A.P, India. [email protected] , +91-9290623231
Received on 22 – 07 - 2012
Revised on 18 – 08- 2012
Accepted on 25– 08 – 2012
ABSTRACT
In the past two decades, a wide variety of bioactive peptides have been discovered. Condensation of heterocyclic
moieties viz nicotinic acid, thiazole, coumarin, quinoline, furan, imidazole etc. with amino acids and peptides
resulted in compounds with potent biological activities. Many of the heterocyclic found to exhibit antifungal,
antibacterial, cytotoxic, antineoplastic, insecticidal, anti-inflammatory, tyrosinase inhibitory and melanin
production inhibitory activities. Imidazole has been drawn as promising structural units in the field of medicinal
chemistry. Metronidazole, serconidazole, fluconazole are well known marketed drugs. Introduction of D-amino
acids and N-methylation of amino acids like tyrosine, valine, alanine etc enhanced antimicrobial activity
Key words: Thiazole, Coumarin, Quinoline, Furan, Imidazole, Valine.
INTRODUCTION
Discovery of newer and more potent analogs of
molecules with already established activities form a
key part of research in the pharmaceutical field.
Bringing about modifications in the parent
compound serves to enhance the activity of the
compound and also in most cases, eliminates
adverse effects or toxicity associated with the
parent drug.A great number of drugs are heterocyclic
compounds, mostly are of synthetic origin, few have
obtained from natural resources which include
alkaloids, xanthines, cardiac glycosides, vitamins
and several antibiotics. Heterocyclic derivatives
having two nitrogen atoms oriented in, 1-3 position
are endowed with wide spectrum of biological
activities. Number of organo-sulphur and nitrogen
containing compounds are present in living and
non living system. Among the heterocyclic
compounds containing sulphur and nitrogen, the six
and five membered heterocyclic compounds
containing sulphur and nitrogen has maximum
attention, as they have many biological and
industrial applications [1, 2].
Compound containing the imidazole ring
are very important in living system, such as vitamin
B12 and several pilocarpin alkaloids. Imidazole
occurs in the essential amino acid histidine;
histidines within enzymes are intimately involved in
catalysis requiring protein transfer. 1-Histidine and
its derivative carnosine which is a di-peptide and is
a constituent o f mu s c le . The structurally r e lat ed
ho r mo ne , histamine is a vasodilator and is a major
factor in allergic reaction such as hay fever [3, 4].
CHEMISTRY OF IMIDAZOLES
Imidazole ring has attracted considerable attention in
the last 30 years. i.e industry started in the year 1970,
regarding its chemistry structure, physical properties
and application of its various derivatives. Imidazole
or imidazoline is an azapyrrole, the nitrogen atoms
being separated by one carbon atom.
This
compound was earlier also called as glyoxaline as
it was first prepared in 1858 from glyoxal and
ammonia [2, 3].
The imino nitrogen is assigned position 1 while the
tertiary nitrogen atom position3. Imidazoles is very
stable compounds which do not autoxidise, but it is
attacked by potassium permagnate. Imidazole also
exists in tautomeric forms; either of the nitrogen
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atoms can bear the hydrogen atom. As a
consequences of this 4-methyl imidazole is identical
with 5-methyl imidazole and depending on the
position of the amino hydrogen such a compound
may
be
designated
either
4or
5methylimidazole11.All such tautomeric pairs are in
spereable.
The contribution of charged structures of imidazole
are important than those of benzene. For this reason
imidazole possesses increased reactivity towards
electrophilic attack.
REACTIVITY OF IMIDAZOLES
4.1 Electrophilic Substitution
The behavior of the imidazole and its derivatives
towards the electrophillic reagents can be explained
efficiently considering the resonance structures.C- 2
if this position is occupied then it occurs at 4(5)
position. In imidazole the electrophilic substitution
take place at 4(5) position but the reverse is true for
deuteration.Imidazole
undergoes
halogenation,
nitration and sulphonation. Imidazole is much more
reactive nitration than thiazole, substitution taking
place via the salt, as doe’s nitration of alkylthiazoles.
The typical regioselutivity being for formation of
nd
more 5-nitro than 4-nitro derivatives, the 2 position
is not attacked, 4, 5-dimethylimidazole is resistant to
nitration. Diazo coupling take place at position C- 2
if this position is occupied then it occurs at 4(5)
position. In imidazole the electrophilic substitution
take place at 4(5) position but the reverse is true for
deuteration. Amino imidazoles are unstable owing to
hydrolytic cleavage and quaternary imidazolium
salts decompose to primary amines in presence of
alkali.
Hydrogen bonding in imidazoles
Imidazole is both a good donor and a good acceptor
of hydrogen bonds; the imine nitrogen donates an
electron pair and the N-hydrogen, being appreciably
acidic, is an acceptor. This property is central to the
mode of action of several enzymes which utilize the
imidazole ring of a histidine. These include the
digestive enzyme chymotrypsin, which bring about
amide hydrolysis of peptides in the small intestine;
the enzyme provides a proton at one site, while it
accepts a proton at another making use of the
ambivalent character of the imidazole ring to achieve
this.
In the work an attempt is made to synthesize some 4[2'-(5'-nitro)imidazolylbenzoyl(N-methyl)
Amino acids and to study the variations in
activity.Selection of amino acid units were done by
considering following considerations.Amino acids
like proline, valine and tyrosine were seen to be
present in almost all cyclic peptides that exhibited
antimicrobial activity in their structure. Moreover
compounds containing proline units showed
antimicrobial activity. It was observed that Nmethylation of amino acids increased the
antimicrobial activity to a great extent in enzyme
during the bacterial cell wall synthesis D-alanine
was especially selected in an attempt to mislead the
transpeptidase enzyme.
CONCLUSION
The present study concludes that compound
containing the imidazole ring is very important in
living system, such as vitamin B12 and several
pilocarpin alkaloids.Imidazole occurs in the essential
amino acid histidine; histidines within enzymes are
intimately involved in catalysis requiring protein
transfer. The contribution of charged structures of
imidazole are important than those of benzene. For
this reason imidazole possesses increased reactivity
towards electrophillic attack.
ACKNOWLEDGEMENT
I am indebted to my parents for their inspiration and
encouragement given to me during this work with
deep appreciation for their determination and
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Ramesh Dhani et al. / International Journal of Advances in Pharmaceutical Research
enthusiasm at each and every front of my life to
transform my dreams into reality.
I am very thankful and prevail age to my deep sense
of gratitude to Abdul Mohammed Bari, M.pharm,
Ph.D, Director of Bright laboratories, Hyderabad.
5.
6.
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