IJMPR 2021, 5(3), 167-197 ISSN: 2319-5878 IJMPR Rohit et al. International Journal of Modern Pharmaceutical Research 167 International Journal of Modern Review Article Pharmaceutical Research SJIF Impact Factor: 5.273 www.ijmpronline.com CHEMISTRY OF BENZIMIDAZOLE AND THEIR DERIVATIVES: MINI REVIEW Rohit Verma1*, Chitra Gupta2, Ali Mohd Ganie2, Vaibhav Kumar3, Sanjay Singh1 and P.K. Singh4 1Department of Chemistry, T.R.S. P.G College, Rewa (M.P.) 486001, India. 2Department of Chemistry, Bundelkhand University, Jhansi (U.P.) 248124, India. 3Bundelkhand University, Jhansi (U.P.) 248124, India. 4Department of Chemistry, P.G College, Sidhi (M.P.) 486661, India. Received on: 29/04/2021 ABSTRACT Revised on: 19/05/2021 Benzimidazole is a heterocyclic aromatic organic compound containing nitrogen. This Accepted on: 09/06/2021 bicyclic compound is formed by the fusion of benzene with imidazole ring. It is a vital Pharmacophore and privileged structure in medicinal chemistry which exhibits various *Corresponding Author therapeutic activities like antiulcer, antihypertensive, analgesic, antiviral, antifungal, Rohit Verma anticancer and antihistaminic. The disease conditions targeted by these activities are discussed. The present article extensively covers various procedures of synthesis of 2- Department of Chemistry, substituted benzimidazole and its analogs by utilizing different catalysts, solvent T.R.S. P.G College, Rewa conditions, reactants and microwave irradiation with the aim to obtain an inexpensive, (M.P.) 486001, India. eco-friendly, less time-consuming procedure which ensures good yield and quick isolation of the pure product. Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. This review is summarized to know about the chemistry of benzimidazole and their derivatives of substituted benzimidazole along with their physical and chemical properties. We demonstrate the change in properties of benzimidazole with change in their structure, their isomers, uses and their pharmacological activity. KEYWORDS: Benzimidazole derivatives, Synthesis, Physical and Chemical Properties and its Therapeutic Drugs. INTRODUCTION aliphatic or aromatic in nature. Both these types of compound differ in their properties due to the presence The publication, many new strategies for the synthesis of of ring strain. benzimidazole derivatives are discovered and reportedabl.[1,2] A literature.[3-5] survey has uncovered Among different Homoazoles Benzimidazole,[8] is that the various derivatives of benzimidazole have been bicyclic in nature which consists of the structure of synthesized for their pharmalogical activities and many Benzimidazole is as follows: of them supported the finding that benzimidazole derivatives are potent against various microorganism N strains. NH The aim of object of this paper is to review the discovery and the synthesis of benzimidazole containing nucleus The Benzimidazole ring system can be theoretically derivatives by using different routes for obtaining good derived,[9] by fusion of aromatic compound Benzene and yield of them, mainly drugs for screening various Imidazole ring (containing two Nitrogen atoms at non therapeutic classes few of them are discussed below. adjacent positions) as indicated in the numbering system through its 1-2 bond to a benzene ring.[10] The Heterocyclic compound,[6] is a Carbocyclic compound in which at least one atom other than Carbon 3 3 atom forms a part of the ring system. Besides the most 2 N 5 1 N common atoms like N,O and S the other Heteroatoms are 5 1 4 7 5 8 known widely.[7] Furthermore there is rapid rise in + 6 number of Heterocyclic compound which may be 6 2 1 NH 2 NH 3 4 9 4 Volume 5, Issue 3. 2021 │ ISO 9001:2015 Certified Journal │ 167 Rohit et al. International Journal of Modern Pharmaceutical Research 168 The numbering system for the Benzimidazole is as 4 follows: Occasionally 2- positions is designated as the 5- 5 N position. 3 6 2 4 4 N NH N 7 1 3 3 2 The Benzimidazole are also known as Benziminazolones 5 2 NH 5 NH or Benzoglyoxalines. They are also known as the 1 1 derivative of o-phenylenediamines. The numbering in the benzimidazole ring system is done as shown below. Some are the nucleobases (purines biomolecules derivatives) in the Nucleic acid of DNA and RNA. Also it is a 4,5 nitrogen containing compounds. NH2 O N N N HN NH N NH N H2N N Adenine N Guanine N NH Purine O CH3 O H3C NH N HN N O O NH NH O N N Uric acid CH3 Caffeine Fig. Common biomolecules with a “6+5” heterocyclic structure. Isomerism Tautomerism N NH Tautomerism is a cyclic analogous to that found in Imidazoles and Amidines, the two Nitrogens present in the Imidazole ring are different from one another in their NH N nature and this makes the properties of the ring system Acidic Basic diverse in character. The Nitrogen bearing Hydrogen atom is sp2 in character and is often referred as Pyrole Benzimidazole structure with its tautomer. 2 Nitrogen and the other is sp in character and is often referred as Pyridine Nitrogen. Our target molecules were based on benzimidazole derivatives. It is possible to design a wide range of Benzimidazole possesses each acidic also as basic potential microbial inhibitors by replacing the hydrogen nature. The NH cluster present in benzimidazole is at various positions of the benzimidazole ring with relatively powerful acidic and frail basic extra different functional groups. However, the most characteristic of benzimidazole is that they need the accessible derivatives are those with substituents at the capability to make salts. Benzimidazoles with 1-, 2- and 5-positions. Retro synthesis analysis of a 2,5- unsubstituted NH teams show quick prototropic disubstituted benzimidazole identified two fragments, tautomerism that ends up in balance mixtures of which explain why these particular substitute asymmetrically substituted compounds. Benzimidazole benzimidazoles are easy to prepare. that embrace an atom connected to the Nitrogen in the 1- position promptly tautomerize this could be delineating 5-Position N as follows.[9,11,12] 2-Position NH 1-Position Volume 5, Issue 3. 2021 │ ISO 9001:2015 Certified Journal │ 168 Rohit et al. International Journal of Modern Pharmaceutical Research 169 4 7 Due to this tautomerism, certain Benzimidazole H C H C 3 N 3 NH derivatives that appear as the first isomers in reality the 5 3 6 1 tautomers 4- and 5- positions are equivalent to 6- and 7- 2 2 5 positions because of this phenomenon. For example, 5- 6 NH N 7 1 4 3 Methyl Benzimidazole is a tautomer of 6-Methyl Acidic Basic Benzimidazole. Although two non-equivalent structures can be written, the two structures are tautomers and both Benzimidazole structure with its tautomer. structures represent the same compound known. To prevent any confusion between the two tautomers, both the designating structures are written with the This may be illustrated with 5- or 6-methyl second one in parenthesis, e.g., 5-or 6-Methyl benzimidazole. Benzimidazole. When 5- group attached to the Nitrogen in the 1-position is other than Hydrogen, such tautomerism is prevented and only isomeric forms exist. Thus, 1,5-dimethylbenzimidazole and 1,6- dimethylbenzimidazole exist as distinct, isomeric compounds. H C 4 7 CH 3 H C 3 N 3 N 5 3 6 1 2 2 6 N 5 1 N 7 4 3 Acidic CH3 Basic 1,5-dimethyl benzimidazole 1,6-dimethyl benzimidazole H2C CH 3 Fig. Isomeric structure of 1,5- and 1,6-dimethyl benzimidazole. Due to clinical and pharmacological activities of Historically the first benzimidazole was prepared in 1872 benzimidazoles chemists tried to synthesize the by Hoebrecker,[13] who obtained 2,5- or 2,6-dimethyle benzimidazole in the laboratory. benzimidazole by the reduction of 2-nitro-4- methylaacetanilide. H C H C 3 CH3 3 NH2 NO2 Sn HCl NH COCH NCH3COCH3 2 3 -H O 2 H C N 3 N or CH3 CH3 H C NH NH 3 2,6- dimethylbenzimidazole 2,5- dimethylbenzimidazole Synthesis of Benzimidazole[5,8,14-17] Weidenhagen. Weidenhagen’s method,[21] consists in A) By reaction with Carbonyl compound[18] reacting the diamine and aldehyde in water or alcoholic 1. Reaction with Aldehyde[19-20] solution in the presence of Cupric acetate or a similar Since an oxidation is involved, the reaction is best Cupric salt. The Cuprous salt of the benzimidazole carried out under oxidative conditions. This oxidation separates and by means of Hydrogen sulfide it may be may be brought about by the air or more conveniently, readily decomposed to the free benzimidazole and by the use of other oxidizing agents such as Cupric Cuprous sulfide. The sulfide may be removed readily by acetate. This latter reagent was first introduced by filtration. By means of Weidenhagen’s method,[21] Volume 5, Issue 3. 2021 │ ISO 9001:2015 Certified Journal │ 169 Rohit et al. International Journal of Modern Pharmaceutical Research 170 excellent yields of 2-substituted benzimidazole may be oxidizing agents such as Cupric acetate (Weidenhagen obtained. procedure)[9,21] Mercuric oxide.[24] (for 2-NHCOOMe), Chloranil (for 2-furyl),[25] Lead tetraacetate,[26] The reaction between o-phenylenediamine and aldehydes Manganese dioxide,[27] Nickel peroxide,[28] and as a method to synthesize benzimidazoles has been Nitrobenzene.[29] An improvement in the conventional reviewed independently by Rao and Ratnam,[22] and method is the use of the sodium bisulfite addition Smith and Ho.[23] Various 2-substituted benzimidazoles product of the aldehyde,[30] which in boiling ethanol (R = alkyl or aryl) were synthesized by condensing o- often results in good yields.