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Vol.04, Issue 01, January 2019 Available Online: www.ajeee.co.in/index.php/AJEEE

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REVIEW ON SYNTHESIS, CHARACTERIZATION AND BIOLOGICAL EVALUATION OF IMIDAZOLE DERIVATIVES FROM BENZOIN MOIETY

Mani Taneja

Research Scholar, Jayoti Vidyapeeth Women‟s University, Jaipur, (Rajasthan) Dr. Anurekha Jain

Guide, Jayoti Vidyapeeth Women‟s University, Jaipur (Rajasthan)

Imidazole is a monoacidic base in nature which possesses the ability to form crystalline salts with acids (John Wiley and Sons, 2006). Imidazole is a 5-membered planar ring, which is soluble in water and other polar solvents. It has two equivalents tautomers, ie. 1H- imidazole and 3H-imidazole, because the hydrogen atom can be located on either of the two nitrogen atoms. Imidazole is a highly polar molecule, as evidenced by knowing adipole of 3.61D, and is freely soluble in water. This compound is classified as aromatic due to the presence of a sextet of -electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.

1 CHEMISTRY OF IMIDAZOLE N

NH

(Basic)

(Acidic) (3)

Imidazoles have properties which are similar to both pyrrole as an acid and pyridine as a base (3). The electrophilic reagent would attack on the unshared electron pair on N-3 position, but not on the „pyrrole‟ nitrogen because it is the part of the aromatic 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 with drawing substituent‟s elsewhere in the ring. In the absence of such activation the position most probable site to nucleophilic attack is C-2. The fused benzene ring in benzimidazole provides sufficient electron withdrawl to allow a variety of nucleophilic substitution reaction at C-2.

The overall reactivity of imidazole 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.

1.1 Anti-Depressant Activity

Hadizadehet al, 2008 described that Moclobemide is a selective and reversible monoamine oxidase-A inhibitor, which is used as an antidepressant. Three moclobemide analogues were synthesized by replacing moclobemide phenyl ring with substituted imidazoles and studied for the antidepressant activity using forced swimming test in mice.

Synthesized compound were found to be more potent than moclobemide.

N

CONHCH₂CH₂ N O RS

R= CH₃, C₂H₅, CH₂C₆H₅

Volkeet al, 2003 studied and compare the behavioural effects of NOS inhibitor 7- nitroindazole with the more selective neuronal NOS inhibitor 1-(2- trifluoromethylphenyl) imidazole (TRIM) in animal models predictive of antidepressant- and anxiolytic-like activity in order to clarify the role of distinct isoforms of NOS in the regulation of depression and anxiety. The antidepressant-like effect of TRIM was counteracted by pretreatment with l- arginine (250 mg/kg). The systemic

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administration of TRIM (50 mg/kg), but not 7-NI (up to 50 mg/kg) increased the time spent in the light side of the apparatus in the light–dark compartment test. These motor side effects were more pronounced in the case of 7-NI and were not diminished by pretreatment with l- arginine. It was concluded that neuronal NOS seems to play the key role in the antidepressant- and anxiolytic-like effects of NOS inhibitors.

1-(2-trifluoromethylphenyl)imidazole N

N F

F

1.2 Anti-Viral Activity

Michele Tonelliet al, 2010 synthesized seventy six 2-phenylbenzimidazole derivatives and evaluated for cytotoxicity and antiviral activity against a panel of RNA and DNA viruses. Compound ([56- dichloro-2-(4-nitrophenyl) benzimidazole]) (85) exhibited a high activity resulting more potent than reference drugs smycophenolic acid and 6-azauridine.

NH N

NO₂ Cl

Cl

5,6-dichloro-2-(4-nitrophenyl)-1H-benzo[d]imidazole

1.3 Anti-Cancer Activity

Lakshmananet al, 2011 also reported the synthesis of 1-(4-substitutedphenyl)-2-(2- methyl-1H-imidazol-1-yl) ethanone and 1- (4-substituted phenyl)-2-(1H-imidazol-1- yl) ethanone by the reaction of para substituted phenacyl bromides with imidazoles which showed the significant antitumor activity.

1-(4-substitutedphenyl)-2-(2-methyl-1H-imidazol-1-yl) ethanone

O

N N CH₃ R

1-(4-substitutedphenyl)-2-(1H-imidazol-1-yl) ethanone O

N N

R

Refaat, 2010 synthesized various series of 2-substituted benzimidazole. Several of the analogues products were subjected for anticancer screening which revealed that all the tested compounds exhibited antitumor activity against human hepatocellular carcinoma, breast, adenocarcinoma, and human colon carcinoma. Given compounds showed the highest potency against human hepatocellular carcinoma.

N HN

S HN

O HOOC

N HN Cl

F CN

(Z)-2-(6-chloro-1H-benzo[d]imidazol-2-yl)-3-(4-fluorophenyl)acrylonitrile 2-((4-oxothiazolidin-2-yl)methyl)-3H-benzo[d]imidazole-5-

carboxylic acid

2 REVIEW OF LITERATURE

A. Yasodha et. al. [1] presented a series of 1-substituted 2, 4, 5 triphenyl imidazoles were synthesized by the reaction equimolar mixture of 2, 4, 5 triphenyl imidazole with chloro compound in the presence of anhydrous potassium

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carbonate. The newly synthesized compounds were characterized on the basis of UV, IR and H1 NMR spectra. The synthesized compounds were screened for anti inflammatory, antimicrobial activities. Anti inflammatory activity was screened by carrageen an induced rat paw oedema method. Compounds T4 & T5 showed highly significant activity.

Antimicrobial activity was screened by disc-plate method. All the compounds showed mild to moderate activities.

Shailesh P. Zala et. al. [2]

proposed all the synthesized compounds were characterized by IR and some of by Mass and 1H-NMR spectroscopy. When increases in aromaticity while substitution showed decrease in activity.

Results of substituted compounds containing electron donating groups like methyl and methoxy functional group are showed more active than electron withdrawing nitro functional group. From the obtained results, we can conclude that compound 6b will be the better candidate. In future study, further investigation on the mechanism of action of some of our compound may reveal new compounds with potent anti-inflammatory action and antimicrobial Activity.

R. Rajkumar et. al. [3] revealed in conclusion a novel series of 1-(2-(4,5- dimethyl-2-phenyl-1Himidazol-1 yl) ethyl) piperazine (5a–m) was synthesized and their structures were confirmed by IR, LC–MS, 1 H and 13C NMR spectra.

Synthesized compounds were subjected to antimicrobial studies and the results revealed that the introduction of thiophene moiety and halo substitution in the imidazole ring surprisingly enhanced their antibacterial and antifungal activities.

Rana S. Ahmed et. al. [4]

indicated new 2, 4, 5-triphenyl imidazole derivatives were synthesized from benzoin. All of the prepared products have been studied their biological activities toward two kinds of bacteria. These products showed good efficacy to moderate toward these bacteria.

Nannapaneni DT et. al. [5]

presented the present study describes a simple, inexpensive, and easy method for synthesis of benzimidazole derivatives in a stipulated time, without using any drastic conditions. The yield of all benzimidazole derivatives were found to be in the range of 75 – 94%. The purity of the compounds

were ascertained by a melting point and TLC. The assigned structure was further established by IR, 1 HNMR, and MS spectral studies. The acute and chronic studies for anti-anxiety activity of the synthesized compounds were screened using elevated plus maze method in Wistar rats. Diazepam was used as the reference drug. In the prepared benzimidazole derivatives, it seemed that the compounds ZB [4-(1H-benzimidazol- 2- yl) phenol], ZE [2-(4-methylphenyl)-1H- benzimidazole], ZF [4-(6-nitro-1H- benzimidazol-2-yl) phenol], ZG [2-(4- methylphenyl)-6-nitro-1H-benzimidazole], and ZH [4-(6-methyl-1H-benzimidazol-2- yl) phenol] showed potent activity when compared to the standard drug diazepam.

The compound ZH [4-(6-methyl-1H- benzimidazol-2-yl) phenol] exhibited the highest anti-anxiety activity when compared to the other prepared benzimidazole compounds. From the present study, it can be concluded that the benzimidazole derivatives can potentially be developed into useful anti- anxiety agents, which can prompt future researchers to synthesize a series of benzimidazole derivatives containing a wide variety of substituent‟s, with the aim of producing a novel heterocyclic system, with enhanced activity.

Pratik G. Shobhashana et. al. [6]

proposed in conclusion, we have established a convenient method for the synthesis of imidazole based quinoline derivatives by applying a three-component reaction in the presence of an inexpensive, nontoxic, commercially available ceric ammonium nitrate. The simplicity of the reaction, easy workup, excellent yields of the products, and short reaction time make it an efficient route for synthesizing imidazole based quinoline heterocycles. Among the compounds, 5c and 5d were emerged as potentially active antimicrobial agents. In molecular docking studies, compound 5a, 5c and 5d exhibited least binding energy. The compounds with least binding energy are responsible for more active antimicrobial agent with respect to standard drugs. The best dock conformation is one with minimum binding energy has the maximum affinity.

R. H. Parab et. al. [7] revealed the present study showed that the antimicrobial activity of newly synthesized compounds may change by introduction

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or elimination of a specific group. Thus, the imidazole derivatives could be powerful and elegant factor to stimulate major advances in chemotherapeutic agents of remarkable significance in medicine, biology and pharmacy.

Sami Ullah Bhat et. al. [8]

indicated H-ZSM-22 has been introduced as an efficient catalyst for the synthesis of tetra-substituted imidazoles. This catalyst provides an alternate way for the above synthesis in terms of small reaction time, better product yield, minimum waste production, reusability of the catalyst as compared to other catalysts. In conclusion, we have demonstrated a simple method for the synthesis of tetra- substituted imidazoles using H-ZSM-22 as an eco-friendly, inexpensive and efficient catalyst.

M. Smitha et. al. [9] presented the vibrational spectra of two imidazole derivatives are reported theoretically and experimentally. The vibrational wave numbers are assigned with the help of potential energy distribution analysis.

Using frontier molecular orbital analysis the charge transfer within the molecules are discussed. Both MEP and ALIE descriptors identified nitrogen atom belonging to imidazole ring to be sensitive towards electrophilic attacks.

Additionally, ALIE descriptor identified region above imidazole ring to be sensitive towards electrophilic attacks. According to Fukui functions, benzene ring could also be important reactive site, to the change in electron density after addition and removal of charge. Hydrogen atoms of one methyl group connected to imidazole ring have H-BDE values higher than, but very close to, 90 kcal/mol, indicating that these derivatives might be sensitive towards the autoxidation mechanism. MD simulations revealed very similar g(r) curves, with nitrogen atom of imidazole ring having the strongest interactions with water molecules. The docked ligands form stable complexes with dehydrogenase inhibitor and exhibits inhibitory activity against APO-liver alcohol dehydrogenase inhibitor.

Vikas Chaudhary et. al. [10]

proposed in conclusion, we designed a new series of analogues of combretastatin A-4, comprising 2-aminoimidazole as a bridging skeleton replacing a double bond in CA-4, 3,4,5-trimethoxyphenyl in ring A and various relevant (hetero) arenes in

ring B. Fifteen compounds were synthesized by a diversity feasible and atom-economical route involving arene C−H bond arylation. Four compounds exhibited anti-proliferative activities in nanomolar concentrations. 5-Quinolin-3- yl and 4-(3,4,5-trimethoxyphenyl) substituted imidazol-2-amine (compound 12) was most potent. Compound 12 showed higher anti-proliferative activity than CA-4 against five different cancer cell lines including a drug resistant cell line. In addition, compound 12 exerted stronger inhibitory effect on the migration of highly metastatic MDA-MB-231 than CA-4, indicating its strong anti-metastatic potential. Compound 12 was found to cause a significant depolymerization and perturbation of the interphase and mitotic microtubule network and induced mitotic arrest in MCF-7 cells. Like CA-4, compound 12 inhibited the rate and extent of an in vitro assembly of purified tubulin with an IC50 of 1.6 μM. A dissociation constant of 1.9 μM is indicative of a strong binding affinity of compound 12 to tubulin. Importantly, compound 12 when bound to tubulin showed an increase in the fluorescence intensity, indicating its potential use as a probe in the characterization of new antitubulin agents. Competition studies with CA-4 and podophyllotoxin for tubulin-binding signified that compound 12 binds at the colchicine site on tubulin.

The results indicated the importance of 2- aminoimidazole as bridging skeleton and quinoline motif in ring B in the structural modulation of CA-4 for generating a new class of antitubulin agents.

Varun Bhardwaj et. al. [11]

revealed conclusively, the synthesis of pyrrole analogs is still an active field in medicinal research and development industries. Various new methods are being employed for its preparation and it will continue to be an important area for research in future. By presenting this review, we hope that the scientific community will be beneficial in developing new synthetic routes for the preparation of this resourceful heterocyclic system with better biological outcomes.

Prakash P. Neelakandan et. al.

[12] indicated the chemistry of cyclophanes has been an area of interest because of the potential applications of functionalized cyclophanes in supramolecular chemistry,[1] in

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molecular recognition,[2] in molecular electronics and machines,[3, 4] as drug carriers,[5] and as catalysts in organic synthesis.[6] These systems are associated with a high degree of structural rigidity and are known to form unusually strained structures.[7] By virtue of having a rigid structure with a defined cavity, these systems encapsulate and stabilize a large number of guest molecules through noncovalent interactions.[8] Even though several cyclophane derivatives have been effectively utilized for host–guest complexation,[9] the design of functional cyclophanes that are soluble in aqueous media and undergo specific interactions with biomacromolecules such as oligonucleotides, DNA, and proteins has been challenging in recent years.[10]

A Babul Reddy et. al. [13]

presented in this work, we have reported a new class of multisubstituted oxazole derivatives which are characterized by FT- IR, PMR and 13C NMR spectral analysis.

Synthesized compounds are screened for their antifungal and antibacterial activity.

These compounds show good activity against Gram +ve and Gram -ve bacteria and fungal species.

Prakash T. Parvatkar et. al. [14]

proposed Iodine is a non-metal under Group VII A of the periodic table. Though relatively a rare element, the high solubility of its compounds in water has contributed to its enrichment in the oceans. It is the heaviest micronutrient element essential for all living organisms, with its deficiency known to cause severe health problems in animals and human beings. Iodine provides the substrate for synthesis of the thyroid hormones, thyroxine and triiodothyronine, which are crucial for normal growth and development. Deficiency of this element is known to cause goiter and even mental retardation.

Santhivardhana Reddy Yetra et.

al. [15] revealed the N-heterocyclic carbene (NHC)-organ catalyzed enantios elective annulation reaction of pyrazolones with α, β-unsaturated aldehydes proceeding via the chiral α,β- unsaturated acyl azolium intermediates under oxidative conditions is presented.

The reaction afforded dihydropyranone- fused pyrazoles in moderate to good yields and good er values under operationally simple and base-free conditions.

Nitesh Kumar Nandwana et. al. [16]

indicated in conclusion, a metal-free method has been developed for the synthesis of symmetrical and

unsymmetrical dicarbonyl

imidazoheterocycles using glyoxals as the carbonyl source. The present method demonstrated practical and green reaction conditions to afford unexplored symmetrical dicarbonyl imidazohetero cycles in good yields. More importantly, unsymmetrical dicarbonyl imidazohetero cycles were also obtained in high yields as compared to the previously reported methodologies under metal-free conditions. The method is amenable for a scale-up reaction which has been demonstrated through the gram scale reaction. Mechanistic investigation revealed that glyoxal has a dual role in this transformation both as a dicarbonyl source as well as an oxidant.

REFERENCES

1. A.Yasodha1, A. Sivakumar, G. Arunachalam, A. Puratchikody2, “SYNTHESIS AND BIOLOGICAL EVALUATION OF SOME 2, 4, 5 TRIPHENYL IMIDAZOLE DERIVATIVES”, Journal of Pharmaceutical Science and Research, ISSN: 0975-1459 Vol. 1 (4), 2009, pp.- 127-130.

2. Shailesh P. Zala, Badmanaban R., Dhrubo Jyoti Sen and Chhaganbhai N. Patel,

“SYNTHESIS AND BIOLOGICAL EVALUATION OF 2,4,5- TRIPHENYL-1H-IMIDAZOLE-1-YL DERIVATIVES”, Journal of Applied Pharmaceutical Science, ISSN: 2231-3354, 02 (07); 2012, pp.- 202-208.

3. R. Rajkumar, A. Kamaraj, K. Krishnasamy,

“SYNTHESIS, SPECTRAL

CHARACTERIZATION AND BIOLOGICAL EVALUATION OF NOVEL 1-(2-(4,5- DIMETHYL-2-PHENYL1H-IMIDAZOL-1- YL)ETHYL) PIPERAZINE DERIVATIVES”

Journal of Saudi Chemical Society, ISSN:

1319-6103,

http://dx.doi.org/10.1016/j.jscs.2014.08.00 1, pp.- 1-9.

4. Rana S. Ahmed1, Rana Abid Ali 2, Luma S.

Ahamed2, “SYNTHESIS OF NEW 2, 4, 5- TRIPHENYL IMIDAZOLE DERIVATIVES DERIVED FROM BENZOIN AND STUDYING THEIR BIOLOGICAL ACTIVITY” Journal of Global Pharma Technology, 2019, ISSN: 0975 -8542, Vol. 11, Issue 07, pp.- 437-444.

5. Nannapaneni DT, Gupta Atyam VSSS1, Reddy MI, Sarva Raidu Ch1, “SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL EVALUATION OF BENZIMIDAZOLE DERIVATIVES AS POTENTIAL ANXIOLYTICS”, Pharm Chemistry, 2010, 2,(3), DOI: 10.4103/0975-1483.66809, pp.- 273-279.

6. Pratik G. Shobhashana, Pratibha Prasad, Anirudhdha G. Kalola, Manish. P. Patel,

“SYNTHESIS OF IMIDAZOLE DERIVATIVES BEARING QUINOLINE NUCLEUS CATALYSED BY CAN AND THEIR

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ANTIMICROBIAL, ANTITUBERCULAR AND MOLECULAR DOCKING STUDIES” Life Science Informatics Publications, 2018 May – June RJLBPCS 4(3), DOI - 10.26479/2018.0403.15, Page No.175-186.

7. R. H. PARAB* and B. C. DIXIT, “SYNTHESIS, CHARACTERIZATION AND ANTIMICROBIAL ACTIVITY OF IMIDAZOLE DERIVATIVES BASED ON 2-CHLORO-7- METHYL-3- FORMYLQUINOLINE” E-Journal of Chemistry 2012, ISSN: 0973-4945, 9(3), http://www.ejchem.net, pp.- 1188-1195.

8. SAMI ULLAH BHAT*, RAWOOF AHMAD NAIKOO, MUZZAFFAR AHMAD MIR, RADHA TOMAR, “SYNTHESIS OF TETRA- SUBSTITUTED IMIDAZOLE DERIVATIVES BY CONDENSATION REACTION USING ZEOLITE H-ZSM 22 AS A HETEROGENEOUS SOLID ACID CATALYST”, International Journal of Current Pharmaceutical Research, ISSN- 0975-7066, Vol 8, Issue 1, 2016, pp.- 36-39.

9. M. Smitha a , Y. Sheena Mary b, Mossaraf Hossain c , K.S. Resmi b , Stevan Armakovic d , Sanja J. Armakovic e , Rani Pavithran a , Ashis Kumar Nanda c , C. Van Alsenoy f,

“TWO NOVEL IMIDAZOLE DERIVATIVES E COMBINED EXPERIMENTAL AND COMPUTATIONAL STUDY”, Journal of Molecular Structure 1173, 2018, ISSN: 0022- 2860,

http://www.elsevier.com/locate/molstruc, pp.- 221-239.

10. Vikas Chaudhary,†,∥ Jubina B.

Venghateri,‡,∥ Hemendra P. S. Dhaked,§ Anil S. Bhoyar,† Sankar K. Guchhait,*,† and Dulal Panda*,§, “NOVEL COMBRETASTATIN-2- AMINOIMIDAZOLE ANALOGUES AS POTENT TUBULIN ASSEMBLY INHIBITORS:

EXPLORATION OF UNIQUE

PHARMACOPHORIC IMPACT OF BRIDGING SKELETON AND ARYL MOIETY”, Journal of Medicinal Chemistry, DOI:

10.1021/acs.jmedchem.6b00101,pp.- 3439−3451.

11. Varun Bhardwaj a, Divya Gumber b, Vikrant Abbot a, Saurabh Dhiman a, Poonam Sharma a, “PYRROLE: A RESOURCEFUL SMALL MOLECULE IN KEY MEDICINAL HETERO- AROMATICS” RSC Advances, www.rsc.org/advances, Page 1-84.

12. Prakash P. Neelakandan and Danaboyina Ramaiah, “DNA-ASSISTED LONG-LIVED EXCIMER FORMATION IN A CYCLOPHANE”, Biomolecular Recognition, 2008, DOI:

10.1002/ange.200803162, pp.-8535-8539.

13. A BABUL REDDYa,c, R V HYMAVATHIb and G NARAYANA SWAMYa, “A NEW CLASS OF MULTI-SUBSTITUTED OXAZOLE DERIVATIVES: SYNTHESIS AND ANTIMICROBIAL ACTIVITY”, Indian Academy of Sciences, Vol. 125, No. 3, May 2013, pp.- 495–509.

14. Prakash T. Parvatkar,[a,b] Perunninakulath S. Parameswaran,*[c] and Santosh G.

Tilve*[b], “RECENT DEVELOPMENTS IN THE SYNTHESIS OF FIVE- AND SIXMEMBERED HETEROCYCLES USING MOLECULAR IODINE”, ISSN:- 5460 -5489, vol.18; 2012, pp.- 1-31.

15. Santhivardhana Reddy Yetra,† Santigopal Mondal,† Eringathodi Suresh,‡ and Akkattu T. Biju, “ENANTIOSELECTIVE SYNTHESIS OF FUNCTIONALIZED PYRAZOLES BY NHCCATALYZED REACTION OF PYRAZOLONES WITH Α,Β-UNSATURATED

ALDEHYDES”, DOI:

10.1021/acs.orglett.5b00293, pp.- 1-4.

16. Nitesh Kumar Nandwana, Om P. S. Patel, Manu R. Srivathsa, and Anil Kumar*, “DUAL ROLE OF GLYOXAL IN METAL-FREE DICARBONYLATION REACTION: SYNTHESIS OF SYMMETRICAL AND UNSYMMETRICAL DICARBONYL IMIDAZOHETEROCYCLES”, ACS Omega 2019, 4, DOI:

10.1021/acsomega.9b00716, pp.- 10140−10150.