An Overview on Synthesis, Properties and Biological Activities of Imidazole and Its Derivatives

Nitrogen containing heterocyclic rings play a key role in development of pharmaceutical products. The main aim of a chemist is to develop the drugs with enhanced efficacy and duration of action and to decrease their toxicities and side effects. [1] Imidazole and its derivatives are the fundamental heterocyclic compounds in medicinal chemistry.  It was first synthesized by Heinrich Debus in the year 1858. Imidazole belongs to the class of five membered heterocyclic compound that possess two nitrogen atoms, three carbons, four hydrogen atoms and two double bonds in it. The term Imidazole was coined by Arthur Rudolf Hantzsch in 1887. It is also familiar as 1, 3-diazole. The current literature layout much information regarding the synthesis, physicochemical characteristics, biological role and functionalization of imidazole.  It acts as a catalyst in synthesis and process of new drug development and also included in chemical sciences, biological sciences and material sciences. Imidazole and its derivatives shows wide spectrum of biological activities such as antibacterial, anti-inflammatory, antifungal, anticancer, antidepressants, analgesic, antihistamine, antiprotozoal, antimalarial, antiviral, anthelmintic activity. It is amphoteric in nature, because it acts as both an acid and base. [2, 3, 4, 5]

Few examples of commercially available drugs in market which contains imidazole ring are Mebendazole (anthelmintic), nitroso-imidazole (bactericidal), Enviroxime (antiviral), Etonitazene (analgesic), Clemizole (antihistaminic), Tinidazole, Ornidazole (antiprotozoal and antibacterial), Astemizole (antihistaminic agents), Omeprazole, Pantoprazole (antiulcer), Nocodazole (antinematodal), Megazole (trypanocidal), azathioprine (anti-rheumatoid arthritis). [4]

aturally occurring imidazole derivatives:

Purines, histidine, histamine, etc. are the naturally occurring imidazole containing compounds. [6]

?Caffeine is a purine derivative which contains imidazole ring. It is one of the main chemical constituents extracted from tea plants and coffee. [7]

?Synthesis of caffeine from xanthosine: [8]

Histamine is primarily produced by mast cells, basophils, enterochromaffin-like cells (ECL) in the stomach and histaminergic neurons in the basal ganglia of the brain in mammals. It is a monoamine synthesized from Histidine, an amino acid catalyzed by the enzyme histidine decarboxylase. [9]

Properties of imidazole:

Imidazole is a colourless fluid having boiling point of 256 degrees Celsius. It has melting point at 90 degrees Celsius. In dioxane imidazole shows significant dipole moment of 4.8 D. They are the aromatic compounds having reverberation value of 14.2 Kcal/mol. It can form crystalline salts when treated with strong acids. Imidazole is soluble in water and other polar solvents. [10]

5. Synthetic methods of imidazole:

1) Synthesis of imidazole using glyoxal and formaldehyde in presence of ammonia:

Heinrich Debus was the first scientist to synthesize imidazole in the year 1858. It was synthesized from the compounds glyoxal and formaldehyde in presence of ammonia. Despite of producing low yields, this method is still used to create C-substituted imidazole compounds. [3]

Wallach synthesis:

According to Wallach, N, N-dimethyloxamide when reacts with phosphorus pentachloride, results in a chlorine containing compound, which on further reduction with hydroiodic acid gives N-methyl imidazole. Under the same conditions when N, N-diethyloxamide is converted into chlorine compound. On reduction it gives 1-ethyl-2-methyl imidazole. [11]

Dehydrogenation of Imidazoline: Barium manganate is a mild reagent which converts imidazolines into imidazole in the presence of Sulphur. Imidazolines obtained from 1,2 ethane diamine and alkyl nitriles are treated with BaMnO4 which yields 2-substituted imidazole. [11]

General van Leusen imidazole synthesis:

In the year 1997, van Leusen et al. first declared that TosMIC and aldimine undergoes a base-induced cycloaddition reaction in a proton solvent. They discovered that alpha-silylbenzyls isocyanate and alpha-tosylethyl isocyanate gives 1,4,5-trisubstituted imidazole. [2]

Biological activities:

1. Anti-tubercular activity:

Ramya ve t al synthesized a series of 5-[nitro/bromo)-styryl-2-benzeimdazoles derivatives and performed in-vitro anti-tubercular activity against mycobacterium tuberculosis. It resulted in effective anti-tubercular activity. The reference drug used is Streptomycin for this compound the following compounds may result in anti-tubercular activity.

A R=Br, R1=H

B R=Br, R1=3,4-OCH3

C R=Br, R1=4-CH3               

D R=Br, R1=2,4-Cl

Preeti Gupta et al explained the anti-tubercular activity of ring substituted-1H-imidazole-4-carboxylic acid derivatives and 3-(2-alkyl-1H-imidazole-4-yl)-propionic acid derivatives against drug-sensitive and drug-resistant Mycobacterium tuberculosis strains. As per the conclusion 2f and 2h compounds are more potent compounds.

Possible substitutions for this compound are 2f =R1=R2=c-C5H9 2h=R1=R2=C6H11 [12]

1. Anti-inflammatory:

Puratchikody A.et al studied on compound 2-substituted-4,5-diphenyl-1H-imidazole and checked its anti-inflammatory activity based on Carrageenan-induced paw edema method. He concluded that the compound shows maximum therapeutic activity and indomethacin is used as reference drug.

2-(benzyloxy)-4,5-diphenyl-1H-imidazole

1. Antimicrobial activity:

According to the research done by scientist Balasubramanian Narasimhan, Deepika Sharma, Pradeep Kumar, the antimicrobial activity was evaluated by using tube dilution method and performed against Gram-positive bacteria: S. aureus, B. subtilis, Gram-negative bacterium E. coli, and fungal strains: C. albicanas, and A. niger. Conclusion based on the results obtained is the synthesized compounds are two times more effective than the reference i.e. ciprofloxacin. [13]

1. Hypertensive activity:

Caffeine is used to treat orthostatic hypotension. It is also used for tiredness, and apnoea of prematurity in newborns. [14]

1. Antiulcer activity:

Pantoprazole is a proton pump inhibitor that provides a protection from ulcers in stomach.[14]

1. Anti-cancer activity:

Angiogenesis is an essential process that involves migration growth and differentiation of vascular endothelial cells. The vascular endothelial growth factor (VEGF) is a major angiogenic factor produced by the tumor cells. The anti-angiogenic drugs act by targeting the VEGF and thereby destroying VEGF pathway and tumor vasculature. Hansen et al. worked on series of levamisole derivatives i.e., 1-4i for in vitro inhibition of angiogenesis. Gopinath et al. reported series of imidazoles 5a-8f, they were screened in vitro for inhibition of KRAS/Wnt and their anti-angiogenesis properties. [15]