You are hereIMIDAZOLE: SYNTHESIS, PROPERTIES AND BIOLOGICAL ACTIVITY

IMIDAZOLE: SYNTHESIS, PROPERTIES AND BIOLOGICAL ACTIVITY


ABOUT AUTHORS:
Sarthak B. Dave*, Dipen K. Sureja
Department of Pharmaceutical Chemistry
Shree H. N. Shukla Institute of Pharmaceutical Education & Research,
B/H Marketing Yard, Near Lalpari Lake,
Amargadh (Bhichari), Rajkot-360002
davesarthak@ymail.com

ABSTRACT
Imidazole derivatives have occupied a unique place in the field of medicinal chemistry. It is the constituent of several natural compounds like histamine, histamine, biotin, alkaloids and nucleic acid and a very important class among the medicinal compounds. Large number of imidazole derivatives have been are being developed for different therapeutic actions, therefore this article aims to review the work reported on the synthesis of Imidazole derivatives using microwave reactions as a modern method for synthesis, to get better yield, economic and environment friendly reaction. Imidazole is an entity which is being synthesized in many of its derivative form from past few years; the entity is major source of interest for many of medicinal chemist to explore its various pharmacological potentials.

REFERENCE ID: PHARMATUTOR-ART-1938

INTRODUCTION:-
During the past decade, the concept of Imidazolines (I) receptors has been developed and gained consensus. Different rank order of affinity of ligands indicates the existence of at least two major classes of Imidazolines receptors I1 and I2.[1] Findings from different laboratories have been shown that they are widely distributed in different tissues and species and may participate in the regulation of various physiological functions. Therefore a more definite knowledge of the structure and function of this receptor system could help to the search for therapeutic agents useful for treating efficaciously a variety of disorders such as hypertension, diabetes mellitus, gastric ulcer, endogenous depression and stroke. Some Imidazole containing compounds like clonidine, guanfacine and newly synthesize lofexidine hydrochloride also act as α2agonists and clinically useful for the treatment of hypertension. α2 –adrenergic agonist also exhibit activity in human platelets and peripherally act in Ocular hypertension (glaucoma). [2]

Medicinal chemistry is the discipline concerned with determing the influence of chemical structure on biological activity and in the practice of medicinal chemistry developed from an empirical one involving organic synthesis of new compound based largely on the modification of structure and then identifies their biological activity.[3,4] Medicinal chemistry concerns with the discovery, development, interpretation and the identification of mechanism of action of biologically active compounds at the molecular level.[5] Various biologically active synthetic compounds have five-membered nitrogen-containing heterocyclic ring in their structures.[6]

Imidazole is an organic compound with the formula C3H4N. This aromatic heterocyclic is a “1, 3-diazole” and is classified as an alkaloid. Imidazole (1) refers to the parent compound,whereas imidazoles are a class of heterocyclic with similar ring structure, but varying substituents. This ring system is present in important biological building blocks, such as histidine (2), and the related hormone histamine (3). Imidazole can serve as a base and as a weak acid. Many drugs contain an imidazole ring, such as antifungal drugs and Nitroimidazole (4). [7-11]


STRUCTURE AND PROPERTIES:-
Imidazole is a monoacidic base having the ability to form crystalline salts with acids. The melting point of number of characteristic imidazolium salts [12]. Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It exists in two equivalents Tautomeric forms, 1H-imidazole and 3H-imidazole, because the hydrogen atom can be located on either of the two nitrogen atoms. Imidazole is a highly polar compound, as evidenced by a calculated dipole of 3.61D, and is entirely soluble in water. The compound is classified as aromatic due to the presence of a sextet of p-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring. [13]


REACTIVITY:-
Imidazole can be considered as having properties similar to both pyrrole and pyridine. The electrophilic reagent would attack the unshared electron pair on N-3, but not that on the ‘pyrrole’ nitrogen since it is the part of thearomatic sextet. While the imidazole ring is rather susceptible to electrophilic attack on an annular carbon, it is much less likely to become involved in nucleophilic substitution reaction unless there is a strongly electron withdrawing substituent’s elsewhere in the ring. In the absence of such activation the position most prone to nucleophilic attack is C-2. The fused benzene ring in Benzimidazole provides sufficient electron with drawl to allow a variety of nucleophilic substitution reaction at C-2.


The overall reactivity of imidazoles and Benzimidazole is referred from sets of resonance structure in which the dipolar contributors have finite importance. These predict electrophilic attack in imidazole at N-3 or any ring carbon atom, nucleophilic attack at C-2 or C-1 and also the amphoteric nature of the molecule. In Benzimidazole the nucleophilic attack is predicted at C-2. The reactivity of Benzimidazole ion at the C-2 position with nucleophiles is enhanced compared with the neutral molecule. [14]

PHYSICAL PROPERTIES:-
It is colourless liquid having a high B.P. of 256oC than all other 5- membered heterocyclic compounds due to the intermolecular H-bonding, where there is linear association of molecule.


Imidazoles shows a large value of dipole moment of 4.8 D in dioxane. Imidazole show amphoteric properties and has pKa of 7.2 more than pyrazole and pyridine. Imidazoles are an aromatic compound possessing a resonance value of 14.2 K cal/ mol, which is almost half the value for pyrazole. The electrophillic substitution occurs frequently in imidazole and nucleophillic substitution happens in the presence of electron withdrawing group in its nucleus. Imidazoles have M.P. 90ºC, it is a weak base and tautomeric substance, since position 4 and 5 are equivalent. [15]


It’s spectroscopic parameters are λmax of 207 nm, I.R.=1550, 1492, 1451(cm-1), t = 2.30, 2.86, mass spectroscopy is studied for heterocyclic compounds containing one hetero-atom, in detail, not in case containing two or more heteroatom.

General Methods of Preparation:-
Imidazole can be synthesized by numerous methods. Many of these synthesis can also be applied to different substituted imidazoles and imidazole derivatives simply by varying the functional groups on the reactants. Several approaches are available for synthesis of imidazoles as, Debus synthesis, Radiszewski synthesis, dehydrogenation of imidazolines, from alpha halo ketones, Wallach synthesis, from aminonitrile and aldehyde and Marckwald synthesis [16]. Details of the synthetic procedures are given below.

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