The Presence Of The Benzimidazole System Biology Essay

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The presence of the benzimidazole system in a natural product is most striking in the case of vitamin B12 (cyanocobalamine). It was isolated from liver extracts and from the fungus Streptomyces griseus. It is an antipernicious anaemia factor. Benzimidazole is a ring fusion of Benzene to the 4,5- position of an imidazole ring result in benzimidazole. Benzimidazole nucleus is present in number of important naturally occurring product as amino acid e.g. Histidine (involve in biochemical living systems and purine, the reduced form of imidazole ring is also present in the Biotin ( Vitamin H). Like imidazoles they are attacked by benzoylchloride and caustic soda to formdibenzoylated o-diamines. They are extremely stable to oxidizing and reducing agents. Benzimidazole, pKa = 5.68, is less basic than imidazole, but with pKa = 12.75 is more strongly1 NH-acidic . Like imidazoles, benzimidazoles display annular tautomerism in solution, e.g.:

General Synthesis Types:

1.The standard synthesis for benzimidazoles is the cyclocondensation of o-phenylenediamineor substituted o-phenylenediamines with carboxylic acids or their derivatives.

2. The synthesis of benzimidazole also can be easily carried out by condensation of the O-phenylenediamine with the aromatic aldehydes

Reactions:

Reactivity:

Benzimidazole is considered to exibit properties of pyrrole as well as pyridine because of their presence of pyrrole-type and pyridine type nitrogen's in benzimidazole ring system.

Reaction with Electrophiles:

Electrophilic attack at nitrogen

Benzimidazole contains two nitrogen atoms, pyrrole type and pyridine type nitrogen, but the attack of Electrophile occurs at Pyridine type nitrogen containing lone pair of electrons in the ring because the attack of electrophile at pyrrole type nitrogendisrupts the aromaticity with the use of loan pair involved in aromatic sextet . If the attacking electrophile is a proton there will be simply a tautomeric interconversion.

Protonation (Basicity):

Benzimidazole , PKa 5.68, less basic than imidazole , but with PKa 12.75 is more strongly 1 NH acidic. Like imidazoles , Benzimidazoles display annular tautomerism in solution. Benzimidazole is the most basic ( PKa 5.68) among 1,3 azoles, oxazole (PKa 0.8) and Thiazole (PKa 2.5) , and forms salt with the acid. Benzimidazole is even stronger base than imidazole (PKa 5.2) ; The abnormally high basicity of Benzimidazole attributed to the relatively low electro negativity of nitrogen and the symmetrical structure of Benzimidazolinium cation which is resonance stabilised.

N- Alkylation:

Benzimidazole substituted at N-arre alkylated readily at N3 with the formation of quaternary salts But the alkylation of Benzimidazole ( with free -NH group) produces protonated N-alkyl benzimidazole which can be deprotonated by a base to provide N-alkyl Benzimidazole Benzimidazole substituted at N-arre alkylated readily at N3 with theformation of quaternary salts

N- Acylation :

Benzimidazole with free N-H group can be N- acylated by the reaction with acid chloride (2:1) in an inert solvent at room temperature with the formation of N-acylbenzimidazoles .

Electrophilic attack at carbon:

The reaction at carbon atoms in benzimidazole ring are expected to be similar to those in aromaric heterocycle which is less reactive than pyrrole and more reactive than pyridine towards electrophile. However, the reactivity of benzimidazole towards electrophile varies with reaction conditions.

Nitration:

Benzimidazole is nitrated with the mixture of concentrated Nitric acid and Sulphuric acid at 160oC with the formation of 5-nitrobenzimidazole.The reaction proceeds to involve the attack of electrophile (nitronium ion) at the position- 4 at the benzimidazolinium cation.

Sulfonation:

When Benzimidazole treated with the 50-60% Oleum at 160 oC ,the sulfonation occurs at the position-5 of the where the attack of electrophile on the benzimidazolinium cation.

Nucleophilic Reaction:

Nucleophiles react faster with benzimidazoles than with imidazoles, the attack occurring at the 2-position. For instance, on treatment with sodium amide in xylene,1alkylbenzimidazoles give the corresponding 2-amino compounds Chichibabin reaction.

The halogen in 2-halobenzimidazoles can be substituted by nucleophiles, e.g. alkoxides, thiolates or amines. However, the reactions proceed more slowly than with 2-halobenzoxazoles and 2-halobenzothiazoles.

Benzimidazoles substituted in position 1, e.g. 1-methylbenzimidazole, react with n- butyllithium at low temperature to give 2-lithio compounds. At room temperature, the reaction proceeds as follows.

By anology to imidazole, alkylation by haloalkanes by Benzimidazole on the N- atomoccurs in neutral and in basic media. 1-alkyl benzimidazloes are obtained fromBenzimidazole, Sodium Hydroxide and Bromoalkanes. Benzimidazoles unsubstituted at position-1 undergo the Mannich reaction.

Analytical Data:

The UV and 13C-NMR spectra of benzimidazole show the following characteristics:

UV (ethanol) 13C NMR (methanol-d4)

λ (nm) (ɛ) δ (ppm)

244 (3.74), 248 (3.73), 266 (3.69), C-2: 141.5, C-4: 115.4, C-5: 122.9, C-6: 122.9

272(3.71), 279(3.73) C-7: 115.4, C-3a: 137.9, C-7a: 137.9

The short wavelength bands at 244 and 248 nm are due to electronic excitation of the imidazole ring, the others to electronic transitions in the benzene ring.There is no detailed analysis of the A2B2 system of the two benzene-type protons in the 1H NMR spectrum. The H-2 signal is in the region of δ = 7.59 ± 0.58 (CDCl3), depending on the substituents in the benzene ring.

Benzimidazole Pharmacological and Biological Importance:

Antiinflammatory Action:

Inflammation is defined as the local response of living mammalian tissue to injury due to any agent. It is a body defence reaction in order to eliminate or the spread of injurious agent as well as to remove the necrosed cells and tissues.

The agents causing inflammation may be as under:

1) Physical agents like heat, cold radiation, mechanical trauma.

2) Chemical agents like organic and inorganic poisons.

3) Infective agents and their toxins from bacteria, viruses.

4) Immunological agents like cell-mediated and antigen antibody reactions.

The characteristics of inflammation are :

Rubor-Redness

Tumor-Swelling

Calor- Increased temperature

Dolor-Pain

Numbers of mediators have been identified which initiate certain experimentally induced inflammatory process. There is an initial release of Histamine and 5 HT followed by release of kinins and lastly the prostaglandin's and slow reacting substances. Inflammation is not one event, but series of events occurring in orderly sequence. The anti-inflammatory drugs usually act only on one component of the reaction or even on a single phase of one component, no drug is equally effective in suppressing all parts of the inflammatory response. Inflammation can be divided broadly into three separate tissue reactions (phases).

I. Dilation and increased permeability of small blood vessels resulting in edema or swelling.

II. Emigration of leucocytes from venules and capillaries.

III. Proliferation of fibroblasts and synthesis of new connective tissue to repair the injury.

The importance of anti-inflammatory agents cannot be exaggerated because of there utility, often as life saving drugs, in many diseases, such as arthritis and rheumatic fever. This utility and the equally extensive search for new drugs with this property have evoked much interest in the laboratory evaluation. The edema of an inflammed region or tissue depends partly on the volume of fluid exudates which inturn, is related to the quantity of plasma proteins leaving the vessels as a result of increased vascular permeability. Clinically anti-inflammatory drugs are judged by their effect on the pain, stiffness or swelling of the affected part, the action on swelling being the most objectively observable and therefore the most important.

Manifestations are as follows:

Inflammation may also be associated with general "flu" like symptoms including

ï‚· Fever

ï‚· Chills

ï‚· Fatigue/Loss of energy

ï‚· Headaches

ï‚· Loss of appetite

ï‚· Muscle stiffness

In the earlier days steroidal antiinflammatory drugs were in use. These drugs were found to be associated with undesired side effects. In order to avoid these side effects nonsteroidal antiinflammatory drugs were developed. Research is a never ending process, continuous efforts are being made to improve the potency of the present drug or to eliminate the side effects or discover thenew drugs. The present investigation is an effort to explore more effective nonsteroidal antiinflammatory drugs without any side effects. Literature survey as revealed that anthranilic acid derivatives are a class of nonsteroidal antiinflammatory agents. In the present investigation it is intended routeless the anthranilic acid moity by Benzimidazole analog. Traditional chemical methods are adopted for the synthesis of target molecules and then subjected to screening for antiinflammatory activity and other biological activities. The results are compared with the standard drugs. In conclusion we have found some of the compounds prepared in the course of this investigation are more effective than the standard drug and some of them are found to be as active as the standard drug.

Classical NSAIDs exhibit their action by inhibiting the prostaglandin biosynthesis and some of which by inhibiting the COX enzyme involved in the inflammatory. The heterocyclic synthetic moieties have shown the ability to act as anti-inflammatory substitute competing with the classical NSAIDs and have different mechanism with favoured less side effects as compared to the NSAIDs. Benzimidazole nucleus have too shown anti-inflammatory action by inhibiting the neutrophil enzyme release function. So further they are now developed as anti-inflammatory agents with different derivatives supporting to increase or decrease activity as compared to the standard drugs.

Antiinflammatory

Methods :

Anti-inflammatory drugs have been evaluated by studying inflammatory responses produced in the animals by injecting foreign or noxious agents. These responses mostly comprise of the development of edema and or the formation of exudates and granuloma. Drugs, which suppress any of these components, are designated as anti-inflammatory agents. On the basis of the different aspects of the inflammation, the following experimental methods can be selected to investigate the anti-inflammatory activity of a chemical compound.

I. Suppression of increased vascular permeability.

(a) Hind paw edema method.

(b) Experimental pleurisy.

(c) Isolated tissues

(d) Thermal injury.

(f) Arthus reaction.

(g) Ultra violet erythema.

II. Suppression of leucocyte emigration.

III. Suppression of granulation tissue formation.

Increased vascular permeability may be measured by determining the volume of fluid exuding from the injured vessels.

Hind paw oedema method:

It is based on measurement of oedema in the paw of the rat, induced by irritants or inflammagens for example carrageenan. The resultant swelling is then measured before and after administration of the test substance. If it is given locally, comparisons can be made on two feet of one animal.

Experimental pleurisy :

This method is based on measuring of the volume of the acute inflammatory exudates by inducing pleurisy in the rat through intrapleural injection of turpentine.

Isolated tissues :

This technique is based on oedema measurement of isolated perused tissues to the addition perfusate of plasma albumin or other colloids.

(d)Thermal injury :

Thermal injury to the skin can also be used as guide. Burns of standard duration and intensity are produced in anaesthetized rats, and the resultant inflammatory edema is measured by excising and weighing a standard area of the skin.

(e) Leakage of dye stuff :

Leakage of circulating protein-bound dye can also be used to measure ability of anti- inflammatory drugs. The permeability enhancing substance such as histamine or bradykinin, is injected intradermally in to the abdomen or flank, and the intensity or area of the patch of dye-staining is estimated.

(f) Arthus reaction :

Most of the inflammatory reactions are suspected to be the result of antigen antibody interaction. The animals may actively be sensitized by injections of antigen (egg albumin) or passively sensitized by injections of antibodies. An intradermal injection of antigen or antibody is then made and intensity of the vascular change (inflammatory reaction) with or without therapy may be measured by estimating the extent of oedema or dye leakage.

(g) Ultra violet erythma :

This is one of the most popular experimental systems, in which a standard ultra violet radiation exposure is given for 20 seconds to the developed skin and resultant erythma is graded by eye.

II. Suppression of leucocytes emigration :

An irritant substance or an antigen is injected in to a sensitized animal intradermally and after six hours the area is excised and tissue is examined as a histological section. The number of any particular type of leucocytes is then counted and the effects of the drug assessed.

III. Suppression of granulation tissue formation :

This method consists of injecting 25 ml of air into the dorsal subcutaneous tissues of the rat. The same site is then injected with a small volume of a chemical irritant (turpentine) resulting in the formation of a sterile abscess. The extent of inflammation is measured 04 to14 days later by estimating the thickness of the wall of granulation that forms around the abscess, the weight of the excised pouch the volume of the fluid exudate with in the abscess. Paw swelling, or footpad oedema, is a convenient method for assessing inflammatory responses to antigenic challenges and irritants. The protocol described in this unit uses carrageenan as the irritant to induce paw oedema. Typically, test compounds are assessed for acute anti-inflammatory activity by examining their ability to reduce or prevent the development of carrageenan-induced paw swelling. This model has long been used to assess the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin production.

Paw swelling, or footpad oedema, is a convenient method for assessing inflammatory responses to antigenic challenges and irritants. The protocol described in this unit uses carrageenan as the irritant to induce paw edema. Typically, test compounds are assessed for acute anti-inflammatory activity by examining their ability to reduce or prevent the development of carrageenan-induced paw swelling. This model has long been used to assess the anti-inflammatory properties of agents such as nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit prostaglandin production.

Antimicrobial Action:

Antibiotics are microbial metabolites or their synthetic analogs produced by various species of micro-organism (bacteria, fungi, actinomycetes), which in small doses suppress the growth of other microorganisms and may eventually destroy them without serious toxicity to the host. However common usage often extends the term antibiotics to include synthetic antibacterial agents, such as sulfonamides and quinolones, which are not the product of microbes. The number of antibiotics that has been identified now extends into hundreds and many of these have developed to therapy of infectious disease antibiotics differ markedly in physical, chemical and pharmacological properties, antibacterial spectra and mechanism of action. Synthetic antibacterial compounds are divided into two major groups,

- Topical agents

- Systemic agents.

The topical agents or local anti-infective agents may be classified into antiseptics and disinfectants. They are termed as antiseptics disinfectants and preservatives on how they are used.

Mechanism:

1.Agents that inhibits synthesis of or activate enzymes that disrupt bacterial cell wall to cause loss of viability and often cell lysis; these include the penicillins and cephalosporins which are structurally similar, and dissimilar agents such a cyclosporins, vancomycins and the imidazole antifungal agents.

2. Agents that affect the function of bacterial ribosome to cause a reversible inhibition of protein synthesis. Egg., Chloramphenicol, Tetracycline, Erythromycin, and Clindamycin.

3. Agents that bind to the 30S ribosomal subunit and alter protein synthetic, which eventually leads to cell death including aminoglycosides.

4. Chelating agents like EDTA forms chelates with cation in the outer membrane of the cell wall and this process induces the release of lipopolysaccharides.

5. Phenols, quaternary ammonium compounds, biguanides and parabens cause leakage of low molecular weight compounds from the cell and interfere with normal proton flux.

6. Agents that effect nucleic acid metabolism such as rifampicin, which inhibit DNA dependent RNA polymerase and the quinolones, which inhibit DNA super-coiling and DNA synthesis.

7. Nucleic acid analogs, such as zidovudine, ganciclovir, vidarabine etc.

8.Ergosterol Biosynthesis inhibitors by antifungal agents Such as Grisivofulvin ,Amphotericin B.

Almost all the major classes of antibiotics have encountered resistance in clinical

applications.The emergence of bacterial resistance to ß-lactam antibiotics, macrolides, quinolones, and vancomycin is becoming a major worldwide health problem. In particular, antibiotic resistance among Gram-positive bacteria (staphylococci, enterococci, and streptococci) is becoming increasingly serious. Entercococci, which are frequently resistant to most antibiotics including penicillin, cephalosporin and aminoglycosides, are often treated with either a combination of two antibiotics or vancomycin.

Benzimidazoles benzimidazoles are two or more folds more effective against S. aureus than E. coli. All benzimidazoles were also screened for their ability to inhibit bacterial translation and transcription using a coupled assay.These has potent antifungal activity against Candida albicans and Crytococcus neoformans, provide a very favourable and flexible DNA recognition module. Hence the involvement of Benzimidazoles as novel antibacterial agents now has been proved and even being developed in better approach further. Although a variety of benzimidazole derivatives are known, the development of new and convenient strategies to synthesize new biologically active benzimidazoles is of considerable interest.

Literature Review :

Sandeep Gupta et al., Synthesis and antimicrobial screening of some acid chloride derivatives of 2-substituted benzimidazoles.The synthesized compounds were tested for antimicrobial activity against E.coli, P.aeruginosa and S.aureus .

Michele Weidner- Wells et al., Amidino Benzimidazole Inhibitors of bacterial two component systems .The synthesized compounds shown good in vitro antibacterial activity against a variety of susceptible and resistant Gram-positive organisms.

Rohini Ram et al., synthesis and antimicrobial activity of azetedinone thiazolidine of benzimidazolo(1,2)quinazoline,.The synthesized compounds were screened for their their antimicrobial activity against B.subtilis, staphylococcus, E.coli

Suroor Ahmad Khan et al., Synthesis of 2-substituted benzimidazole as anti-inflammatory analgesic agents. The synthesized compounds were screened for their anti-inflammatory acitivity.

Canan et al., Synthesis and antioxidant properties of some novel benzimidazole derivatives on lipid peroxidation in the rat liver. The synthesized compounds were screened for their assay of lipid peroxidation activity.

Hiroyuki Nakano et al., Synthesis of benzimidazole as antiallergic with 5-lipoxygenase inhibiting action.The synthesized compounds were screened for their anti-allergic activity.

Abdel Hafez et al., Synthesis benzimidazole condensed ring systems new synthesis and antineoplastic activity of substituted 3,4-dihydro and 1,2,3,4-tetrahydro-benz(4,5)imidazol(1,2a) pyrimidine derivatives.the synthesized compounds were screened for their antineoplastic activity.

Raquel Jacob et al., Synthesis of 1, 2 -disubstituted Benzimidazoles using SiO2/ZnCl2.They have presented the improved methodology for selective synthesis of 1, 2-disubstituted benzimidazoles by the condensation of o-phenylenediamine and aldehydes using solid supported catalyst.

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Zhan-Hui Zang et al., An expeditious synthesis of Benzimidazole derivatives catalyzed by Lewis Acids. The synthesis of Benzimidazole derivatives by the reaction of O-phenylenediamine with ortho esters in the presence of Lewis acids was described

Rui Wang et al., Acid catalysed solvent free synthesis of 2-arylbenzimidazoles under microwave irradiation .The solvent free synthesis was carried out to get 2-arylbenzimidazoles which then were characterised.

Chhanda Mukhopadhyay et al., PEG-mediated catalyst-free expeditious synthesis of 2-substituted benzimidazoles and Bis-benzimidazoles under solvent less conditions. The Benzimidazoles and bis-Benzimidazoles were synthsesized under solventless conditions giving excellent yields with low as well as high molecular weight PEGs.

Ansari et al., Synthesis Physicochemical properties and antimicrobial activity of some new benzimidazole derivatives. All synthesized compounds were screened for their antimicrobial activity ,showing good activity towards Gram-positive bacteria and negligible activity towards Gram-negative bacteria.

Shweta Sharma et al., Convenient one-spot synthesis of novel 2-substituted benzimidazoles tetrahydrobenzimidazoles and imidazoles and evaluation of their in vitro antibacterial and antifungal activities.The synthesized compounds were tested for antibacterial activity against two Gram- positive ,two Gram- negative bacteria and inhibitory action against five strains of fungus.

Yun He et al., 2- Piperidin-4-yl-benzimidazoles with Broad Spectrum Antibacterial Activities.he synthesized compounds were shown effective against Gram-positive and Gram-negative bacteria of clinical importance, particularly enterococci.

Sham et al., Anti-inflammatory, analgesic and antiamoebic activity evaluation pyrimido[1,6-a]benzimidazole derivatives synthesized by the reaction of ketoisothiocyanates with mono and diamines.The synthesized compounds have shown good anti-inflammatory ,mild analgesic and good antiamoebic activity agains Entamoeba-histolytica in vitro.

Kavitha et al., In-vivo analgesic and anti-inflammatory activities of newly synthesized benzimidazole derivatives.The synthesized compounds have shown potent analgesic and anti-inflammatory activities compared with the standard drug Nimesulide.

Hanan et al., Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives. The synthesized products were subjected to in vitro anticancer screening that revealed that all the tested compounds exhibited antitumor activity against human hepatocellular carcinoma (HEPG2), human breast adenocarcinoma (MCF7) and human colon carcinoma (HCT 116).

Jat Rakesh Kumar et al., Synthesis of Benzimidazole Derivatives as Anti-hypertensive Agents.The synthesized compounds were shown to have affinity for AII receptor and oral antihypertensive potency.

Rajesh Bahekar et al., New Bronchodialators -3:synthesis of benzimidazo[1,2-c]-quinazolin-6(5H)-ones and their thio analogues .The bronchodialatory activity of compounds IIIa and IVa was reported using in vitro and in vivo animal models.

Chandrasekhare et al., Synthesis of derivatives of Oxine and Benzimidazole for antiamoebic and other biological profile. The synthesized compounds were screened for antiamoebic and other biological activites showing good antimicrobial and antiamoebic activity.

Dubey et al., Studies on syntheses of 1-aryl/2-aralkyl-2-cinnamoylbenzimidazoles.The structure of the products were supported by their spectral and analytical data

Ramaiah et al., Mass spectral studies of some two substituted Benzimidazoles.The compounds were purified by recrystallisation and coloumn chromatography and mass spectral analysis was carried out.

Gupta et al.,Synthesis and Biological Evaluation Of Some 2-Substituted Derivatives Of Benzimidazoles.Journal of pharmaceutical Science and research, These N-substituted benzimidazoles were tested for antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus.

Chonnekar et al., Synthesis and Pharmacological Evaluation of Some New 2-Phenyl benzimidazoles Derivatives and their Schiff's Bases. The compounds synthesised were nidentified by 1H NMR, FAB Mass and FT-IR spectroscopic techniques. All compounds studied in this work were screened for their in vitro antimicrobial activities .

Rajesh Kumar et al., Mild and Efficient One Pot Synthesis of Imidazolines and Benzimidazoles from Aldehydes. A series of some imidazolines and benzimidazoles were synthesized from various aldehydes and 1,2-diamines in the presence of ceric ammonium nitrate.

Mehmet Alp et al., Synthesis and antiparasitic and antifungal evaluation of 2-arylsubstituted 1H-[2,5]bisbenzimidazolyl-5-carboxamidines. The antiparasitic activity against Trypanosoma brucei rhodesiense ,Plasmodium falciparum , Leishmania donovani and Trypanosoma cruzi and antifungal activity against Candida albicans and Candida krusei were evaluated in vitro.

Thimmegowda et al., Synthesis, characterization and evaluation of benzimidazole derivative and its precursors as inhibitors of MDA-MB-231 human breast cancer cell proliferation. The title compounds were evaluated for inhibition against MDA-MB-231 breast cancer cell proliferation.

Ansari et al., Synthesis and evaluation of some new benzimidazole derivatives as potential antimicrobial agents. Structures of the synthesized compounds have been elucidated on the basis of their elemental analyses and spectral data. All the synthesized compounds were screened for their antimicrobial activity.

Prabodh Chander Sharma et al., Synthesis and in-vitro antibacterial activity of some novel N-nicotinoyl-1-ethyl-6-fluoro-1, 4-dihydro-7-piperazin-1-yl-4-oxoquinoline-3-carboxylates. The structures of synthesized compounds were established on the basis of analytical and spectral studies. All the synthesized compounds were evaluated for antibacterial activity against four different strains of bacteria.

El kihel et al., 1H and 13C spectra of condensed benzimidazole and imidazobenzodiazepines. The 1H and 13CNMR spectra of new imidazobenzodiazepines were investigated.

Ramya et al., Derivatives of benzimidazole pharmacophore: Synthesis, anticonvulsant, antidiabetic and DNA cleavage studies. synthesized and screened for in vivo anticonvulsant activity by Maximal Electroshock (MES) model and antidiabetic activity using Oral Glucose Tolerance Test (OGTT).

Xiangming et al., A simple and efficient synthesis of 2-aryl-substituted benzimidazoles. The procedure was simple and convenient, and it implied inexpensive promoter and was characterized by short reaction time and easy purification of the final products.

Characterization of Benzimidazole Derivatives

COMPOUND: A

Molecular weight : 299.33

Molecular formula : C19H13N3O

Chemical name : (2-phenyl-benzimidazol-1-yl)-pyridin-3-yl-

methanone

Melting Point : 288

Colour : Pale brown

State : Powder

Solubility : Freely soluble in Ethanol, Methanol and Chloroform.

Rf Value : 0.92

Percentage yield : 65.76 % w/w

IR Interpretation (cm-1) of the compound-A:

Aro. C-H stretching

3047.63 cm-1

Aro. C=C stretching

1410.01 cm-1

Aro. C-C stretching

1118.75 cm-1

C=N stretching

1543.10 cm-1

C=O stretching

1622.19 cm-1

C-N stretching

1276.92 cm-1

NMR Interpretation (ppm) of the compound-A:

4H (Benzimidazole)

7.4537-7.5443

5H (Aromatic C-H)

7.1803-7.2100

4H (Pyridine C-H)

7.5680-8.1938

Mass Spectra Interpretation of compound- A:

M/Z

Other Ions

299.1880

249.3073, 191.8543, 117.3626, 103.4753

IR Spectra of Compound-A:

D:\print\my thesis\IR\IR-A.jpg

NMR Spectra of Compound-A:

D:\print\my thesis\NMR modf\NMR-A.png

Mass Spectra of Compound-A:

D:\print\my thesis\mass\mass-struct-A.bmp

COMPOUND: B

Molecular weight : 333.77

Molecular formula : C19H12 ClN3O

Chemical name : [ 2-(2chlorophenyl)-benzimidazol-1-yl]-(pyridin-3-yl)

methanone.

Melting Point : 294

Colour : Pale yellow

State : Powder

Solubility : Freely soluble in Ethanol, Methanol.

Rf Value : 0.72

Percentage yield : 67.56 % w/w

IR Interpretation (cm-1) of the compound-B:

Aro. C-H stretching

2916.47 cm-1

Aro. C=C stretching

1442.80 cm-1

Aro. C-C stretching

1053.17 cm-1

C=N stretching

1591.33 cm-1

C=O stretching

1622.19 cm-1

C-N stretching

1274.99 cm-1

C-Cl stretching

1317.43 cm-1

NMR Interpretation (ppm) of the compound-B:

4H (Benzimidazole)

7.7072-7.7578

5H (Aromatic C-H)

7.3757-7.6581

4H (Pyridine C-H)

7.9311-7.9611

Mass Spectra Interpretation of compound-B:

M/Z

Other Ions

333.2929

224.5421, 189.8792, 87.6176

IR Spectra of Compound-B:

D:\print\my thesis\IR\IR-B.jpg

NMR Spectra of Compound-B:

D:\print\my thesis\NMR modf\NMR-B.png

Mass Spectra of Compound-B

D:\print\my thesis\mass\mass-stru-B.png

COMPOUND: C

Molecular weight : 329.35

Molecular formula : C20H15 N3O2

Chemical name : [ 2-(4-chlorophenyl)-benzimidazol-1-yl]-(pyridin-3-yl)

methanone.

Melting Point : 291

Colour : White

State : Powder

Solubility : Freely soluble in DMSO and DMF, moderately soluble in

Ethanol

Rf Value : 0.60

Percentage yield : 58.33% w/w

IR Interpretation (cm-1) of the compound-C:

Aro. C-H stretching

3049.56

Aro. C=C stretching

1437.02

Aro. C-C stretching

1030.02

Aro C=N stretching

1502.60

Aro C=O stretching

1610.61

Aro C-N stretching

1249.91

Aro O-CH3 stretching

1030.02

NMR Interpretation (ppm) of the compound-C:

4H (Benzimidazole)

7.4079-7.5984

5H (Aromatic C-H)

6.8162-7.2388

4H (Pyridine C-H)

7.6240-8.3117

3H (Ar-OCH3)

3.3516-3.8272

Mass Spectra Interpretation of compound-C:

M/Z

Other Ions

329.1204

221.8690, 206.5503, 119.5625, 58.2516

IR Spectra of Compound-C:

D:\print\my thesis\IR\IR-C.jpg

NMR Spectra of Compound-C:

D:\print\my thesis\NMR modf\NMR-C.png

Mass Spectra of Compound-C:

D:\print\my thesis\mass\mass- struc-c.bmp.png

COMPOUND: D

Molecular weight : 342.39

Molecular formula : C21H18N4O

Chemical name : [ 2-(4-dimethylaminophenyl)-benzimidazol-1-yl]-

(Pyridin-3-yl)- methanone.

Melting Point : 298

Colour : yellowish Orange

State : Powder

Solubility : Freely soluble in Ethanol, Methanol and Chloroform.

Rf Value : 0.69

Percentage yield : 57.63% w/w

IR Interpretation (cm-1) of the compound-D:

Aro. C-H stretching

3051.49

Aro. C=C stretching

1438.94

Aro. C-C stretching

1064.74

Aro C=N stretching

1556.61

N-H stretching

1373.36

C=O stretching

1610.61

C-N stretching

1276.69

NMR Interpretation (ppm) of the compound-D:

4H (Benzimidazole)

7.1348-7.4956

4H (Aromatic C-H)

6.8101-7.1243

4H (Pyridine C-H)

7.5062-8.0260

6H [Ar-N-(CH3)2]

2.4893-2.9847

Mass Spectra Interpretation of compound-D:

M/Z

Other Ions

342.1415

235.6366, 219.9474, 192.1019,117.6391

IR Spectra of Compound-D:

D:\print\my thesis\IR\IR-D.jpg

NMR Spectra of Compound-D:

D:\print\my thesis\NMR modf\NMR-D.png

Mass Spectra of Compound-D:

D:\print\my thesis\mass\mass-struct-D.png

COMPOUND: E

Molecular weight : 289.29

Molecular formula : C17H11N3O2

Chemical name : [ 2-(furan-2-yl)-benzimidazol-1-yl]-

(Pyridin-3-yl)- methanone.

Melting Point : 263

Colour : Brownish Black

State : Powder

Solubility : Freely soluble in Methanol and Chloroform.

Rf Value : 0.59

Percentage yield : 61.11% w/w

IR Interpretation (cm-1) of the compound-E:

Aro. C-H stretching

3059.20

Aro. C=C stretching

1452.45

Aro. C-C stretching

1074.39

Aro C=N stretching

1523.82

Aro C=O stretching

1631.83

Aro C-N stretching

1278.85

Aro C-O-C stretching

1232.55

NMR Interpretation (ppm) of the compound-E:

4H (Benzimidazole)

7.1720-7.2598

3H (Aromatic Furan C-H)

6.7115-7.7155

4H (Pyridine C-H)

7.5321-8.3101

Mass Spectra Interpretation of compound-E:

M/Z

Other Ions

289.3758

267.4203, 181.8807, 153.1433,116.4163

IR Spectra of Compound-E:

D:\print\my thesis\IR\IR-E.jpg

NMR Spectra of Compound-E:

D:\print\my thesis\NMR modf\NMR-E.png

Mass Spectra of Compound-E:

D:\print\my thesis\mass\mass-struc-E.png

COMPOUND: F

Molecular weight : 345.35

Molecular formula : C20H15N3O3

Chemical name : [ 2-(4-hydroxy-3-methoxyphenyl)-benzimidazol-1-yl]-

(Pyridin-3-yl)- methanone

Melting Point : 318-320

Colour : Redish pink

State : Powder

Solubility : Freely soluble in Methanol and Chloroform.

Rf Value : 0.63

Percentage yield : 54.17% w/w

IR Interpretation (cm-1) of the compound-F:

Aro. C-H stretching

3063.06

Aro. C=C stretching

1437.02

Aro. C-C stretching

1031.95

C=N stretching

1500.67

C=O stretching

1600.97

C-N stretching

1271.13

C-OH stretching

3319.60

NMR Interpretation (ppm) of the compound-F:

4H (Benzimidazole)

7.4211-7.6510

3H (Aromatic C-H)

6.7535-7.7155

4H (Pyridine C-H)

7.6810-8.3451

1H(Aromatic O-H)

5.2153

3H(Aromatic O-CH3)

3.7814

Mass Spectra Interpretation compound-F:

M/Z

Other Ions

345.6521

264.2165, 240.0504, 117.6391

IR Spectra of Compound-F:

D:\print\my thesis\IR\Ir -F.jpg

NMR Spectra of compound-F

D:\print\my thesis\NMR modf\NMR-F.png

Mass Spectra of compound-F:

D:\print\my thesis\mass\mass-str-F.png

COMPOUND: G

Molecular weight : 333.77

Molecular formula : C19H12 ClN3O

Chemical name : [ 2-(4-chlorophenyl)-benzimidazol-1-yl]-

(Pyridin-3-yl)- methanone

Melting Point : 292-294

Colour : yellow

State : Powder

Solubility : Freely soluble in Methanol andEthanol.

Rf Value : 0.68

Percentage yield : 72.28% w/w

IR Interpretation (cm-1) of the compound-G:

Aro. C-H stretching

3061.13

Aro. C=C stretching

1442.80

Aro. C-C stretching

1053.17

C=N stretching

1591.33

C=O stretching

1622.91

C-N stretching

1274.99

C-Cl stretching

1317.43

NMR Interpretation (ppm) of the compound-G:

4H (Benzimidazole)

7.1829-7.4312

H (Aromatic C-H)

6.9201 -6.9510

4H (Pyridine C-H)

7.5123 -8.1817

Mass Spectra Interpretation of compound-G:

M/Z

Other Ions

332.2491

253.2950, 228.7923, 189.3648,120.3135

IR Spectra of Compound-G:

D:\print\my thesis\IR\Ir G.jpg

NMR Spectra of Compound-G:

D:\print\my thesis\NMR modf\NMR-G.png

Mass Spectra of Compound-G:

D:\print\my thesis\mass\mass-str-G.png

COMPOUND: H

Molecular weight : 315.33

Molecular formula : C19H13 N3O2

Chemical name : [ 2-(2-hydroxyphenyl)-benzimidazol-1-yl]-

(Pyridin-3-yl)- methanone

Melting Point : 313-315

Colour : Orange

State : Powder

Solubility : Freely soluble in DMSO and Ethanol.

Rf Value : 0.56

Percentage yield : 70.53% w/w

IR Interpretation (cm-1) of the compound-H:

Aro. C-H stretching

3057.27

Aro. C=C stretching

1492.95

Aro. C-C stretching

1037.74

Aro C=N stretching

1589.40

Aro C=O stretching

1631.83

Aro C-N stretching

1261.49

Aro C-OH stretching

3327.32

NMR Interpretation (ppm) of the compound-H:

4H (Benzimidazole)

7.4102-7.6718

5H (Aromatic C-H)

6.6823-7.2214

4H (Pyridine C-H)

7.7215-8.2214

Mass Spectra Interpretationof compound H:

M/Z

Other Ions

315.4431

118.6391, 211.8120, 240.0165

IR Spectra of Compound-H:

D:\print\my thesis\IR\IR-H.jpg

NMR Spectra of Compound-H:

D:\print\my thesis\NMR modf\nmr-H.png

Mass Spectra of Compound-:H

D:\print\my thesis\mass\mass-stru-H.png

Anti-inflammatory Activity

CARRAGEENIN INDUCED RAT HIND PAW EDEMA METHOD:

Principle

The inflammatory reaction is readily produced in rats in the form of paw Oedema with the help of irritants or inflammagens. Carrageenin induced paw edema is the most commonly used method in experimental pharmacology.Carrageenin is a sulfated polysaccharide obtained from sea weed (rhodophyceae) causing the release of Histamine, 5-HT, Bradykinin and Prostaglandins.It produces inflammation and oedema.

Requirements

Animals: Albino rats of both sex (weighing 140-190 g) 40 Nos.

Carrageenin: 1% w/v solution injected 0.05 ml under plantar region to induce foot

edema.

c) Drug: Indomethacin (dose 25 mg/kg) prepared in 2% gum acacia solution and

administered orally according to the body weight of the animals.

d) Sample: Compounds physical data prepared and administered similar to the Std drug.

e) Equipment: Plethysmograph.

Working Procedure:

The inhibitory activity of synthesized compound on carrageenean induced rat paw edema will be determined according to mercury displacement method by using plethismograph. Groups of albino rates (140-190gm) of both sexes four animals in each were orally dosed with synthesized compounds one hour before carrageenan challenge, foot paw edema was induced by sub planter injection of 0.05ml of 1% suspension of carrageenan in saline in to the planter tissue of one hind paw. The equal vol. of saline will be injected serve as a control group. The standard group of indomethacin (25mg/kg) s.c. given. The test drugs i.e Benzimidazole derivatives of 50mg/kg as dose were given in respective groups. The mercury displacement was compared with standard for evaluation of anti-inflammatory activity of synthesized compound. The percentage inhibition of all compounds were determined according to following formula.

(Vt-Vo) control - (Vt-Vo) treated

% Inhibition of Paw edema = -------------------------------------------------- x 100

(Vt-Vo) control

Compounds treated

Edema induced by

carrageenan (mm)

at 4 th hr

% Inhibition of Paw

Edema

Control (Vehicle)

5.06 ±0.03

_

Standard drug

(Indomethacin)

3.77±0.02

88.65

A

4.11±0.02

73.04

B

4.21±0.02

64.13

C

4.26±0.02

65.24

D

3.11±0.02

74.46

E

4.36±0.02

66.66

F

3.04±0.02

70.21

G

3.13±0.02

58.86

H

4.018±0.02

68.79

Table: Antiinflammatory activity shown by Benzimidazole derivatives

(Vt-Vo) control - (Vt-Vo) treated

% Inhibition of Paw edema = -------------------------------------------------- x 100

(Vt-Vo) control

Graph: Percentage of Inhibition of Paw edema shown by Benzimidazole derivatives

Sy3.4 Result and Descussion

Carrageenan-induced paw oedema is a commonly used primary test for the screening of new anti-inflammatory agents and is believed to be biphasic. The first phase (1-2 hr) is due to the release of histamine or serotonin and the second phase of oedema is due to the release of prostaglandin and cyclo-oxygenase. These mediators take part in inflammatory response and able to stimulate nociceptor and induce pain. It has been reported that the second phase edema is sensitive to most clinically effective anti-inflammatory drugs which have been frequently in use .

The significant inhibitory activity shown by the most of Benzimidazole derivatives 50mg/kg over a period of 4 h in carragenan-induced inflammation was quite similar to that exhibited by the group treated with Indomethacin 25 mg/kg. The derivatives A and D have shown maximum percentage of inhibition of paw edema than other Benzimidazole derivatives as compared to the Indomethacin as Standard drug.

Experimental Procedure:

Step I:

An Adduct formed by stirring (0.01 mole) of aromatic aldehyde with the 40% of NaHSO3. O-phenylenediamine (0.01 mole) was dissolved in 50 ml of warm Ethanol 80. The NaHSO3 adduct of the aldehyde is added slowly with constant stirring in the warm solution of O-phenylenediamine stirred for 20-30 min still solid product obtained, then added 100 ml of Distilled water and filtered . Now the product was recrystallised by using Ethanol.

Step II: Nicotinoyl Cloride

0.1 mole of Nicotinic Acid was refluxed for 6 hrs with the 20 ml of Thionyl Chloride. After this the excess of Thionyl Chloride was distilled off and separated from the product and dried it.

Step III:

0.01 mole of 2-phenylbenzimidazole solution in 100 ml Pyridine and 10% NaOH stirred for 8 hrs constantly with the 0.01 mole of Nicotinoyl Chloride ,then the water added 50 ml to get a solid product. The product was filtered, dried and recrystallised using Ethanol.

Experimental Scheme : Synthesis of Benzimidazole Derivatives

AIM AND OBJECTIVES

Molecular modification of a promising lead compound is still a major line of approach for the discovery of new drug. Molecular modification involves substituting, elimination, or adding new moieties to a parent lead compound, there by making gradual changes in the physico-chemical properties of the parent compound and thus biological activity of the compound.

It is clear from the literature review that a number of Benzimidazole derivatives are known for the, antibacterial, antifungal and ant-inflammatory activities properties.

The present studies were performed with the following objectives:

Synthesis of new series of 1,2-substituted benzimidazole derivatives.

Characterization of newly synthesized compounds by spectra methods viz.,infrared spectra (IR spectra), Nuclear magnetic resonance spectra (¹H NMR spectra) and (Mass spectra).

Screening of the antibacterial and Antifungal of the newly synthesized compounds using various strains of bacteria and fungi by determining their MIC.

Screening of anti-inflammatory action of Benzimidazole derivatives.

Scope and Plan of work:

Literature survey revealed that Benzimidazole nucleus is a part numerous class of reported molecules exhibiting diverse range of biological activities like antibacterial, antifungal, antiviral, anticancer, analgesic ,anti-inflammatory activity, antihyperlipidemic, antihistaminic, antiulcer, anti-arrhythmic , HIV-RT inhibitor. Considering the reported data about Benzimidazole nucleus we have tried to synthesize some Nicotinoyl derivatives of Benzimidazole. The Benzimidazole derivatives of all above mentioned activities are mostly of 2-substituted type .The synthesis of 2-(substituted phenyl)-benzimidazolyl-1-pyridinyl-3-methanone was carried out and screened for antibacterial, antifungal, and anti-inflammatory activity.

The present work was divided in to three sections:

Synthesis of 1,2-substituted derivatives of Benzimidazole .

Chemical Characterisation of the synthesized compounds.

Biological evaluation of synthesized compounds.

Pharmacological screening of the synthesized compounds.

ANTIMICROBIAL SCREENING

An antibiotic is a chemical compound that in high dilution hinders the growth and the survival of one or more species of microorganism.A drug is considered to have bacteriostatic or fungistatic activity when it inhibits the growth of bacteria or fungi respectively and bactericidal or fungicidal activity when it kills the bacteria or fungi. In vitro tests are used as screening procedure for new agents and for testing the susceptibility of individual isolates from infection to determine which of the available drug might be useful therapeutically.

Important factors for antimicrobial activity are size of the inoculums, metabolic state of microorganism, pH, temperature, and duration of interaction, concentration of the inhibitor and presence of interfering substance.

Antibacterial activity studies:

Literature survey reveals that the synthesis and evaluation of antibacterial activity of various 2-substituted benzimidazole derivatives. The development of resistant among various pathogenic microorganisms towards the antibiotics has increased the impetus for investigating new antimicrobial agent. When a compound are synthesized in the hope that one of them would be more effective than the existing one. The antimicrobial effectiveness of a compound can be evaluated by serial dilution method and cup plate method. Dilution susceptibility tests are used to determine the Minimum Inhibitory Concentration (MIC).

MIC is the lowest concentration of a drug that inhibits the growth of a particular organism under specific condition. The sensitivity of a compound against a particular organism can be studied by cup plate method.Initially the zone of inhibition method was carried out to evaluate the sensitivity of the organism were selected for determination of MIC.

CUP PLATE METHOD:

Cultivation of Microorganism for Antibacterial activity:

The following microorganisms were used to study the antibacterial activity.

Bacillus subtilis - Gram positive bacteria

Staphylococcus aureous - Gram positive bacteria

Escherichia coli - Gram negative bacteria

Salmonella typhi - Gram negative bacteria

Standard: Streptomycin (1000µg)

Solvent: DMF

All the test compounds were tested at 250 µg, 500 µg , and 1000 µg.

Preparation of the medium:

Composition of nutrient agar medium

Beef extract………..10g

Peptone……………..10g

Sodium chloride……..5g

Agar………………….20g

Purified water………1000ml

pH...............................7.2± 0.2

The medium was prepared by dissolving the specified quantity of the dehydrated medium in purified water by heating on a water bath and were dispensed in 100 ml volume conical flasks. The conical flasks were closed with cotton plugs and were sterilized by autoclaving at 121°C (15 lb psig) for 15 minutes.

The contents of the conical flasks were poured aseptically into sterile Petridishes are allowed to solidify. These sterilized Medias were used to subculture the bacterial culture.

Procedure:

Each Petridish was filled to a depth of 4-5 mm with a nutrient agar medium that was previously inoculated with suitable inoculums of suitable test organism, and then allowed to solidify. The petridish were specially selected with flat bottom and were placed on level surface so as to ensure that the layer of medium is in uniform thickness. The petridishes were sterilized at 160-170°C in hot air oven for 30 mins before use. Small sterile borer of uniform size was placed approximately at 10 cm height, having an internal diameter of approximately 6-8 mm and made of aluminium (or) stainless steel. Each plate was divided in to four equal portions along the diameter. To each portion one cylindrical cavity was made in medium with the help of sterile borer. Three cavities for test compounds and one cavity for the standard. The petridishes were incubated at 37°C for 18 hours. Diameter of the zone of inhibition was measured and the average diameter for each sample was calculated. The diameter obtained by the test sample was compared with that produced by standard Streptomycin.

Antifungal Activity Studies:

CUP PLATE METHOD:

Cultivation of Microorganism for Antifungal activity:

The following fungal strains were used to study the antibacterial activity.

1. C.raphigera

2. A.polytricha

Standard: Ketocanazole (1000mcg)

Solvent: DMF

All the test compounds were tested at 250 µg, 500 µg , and 1000 µg.

Preparation of the medium:

Composition of nutrient agar medium

Sabraoud Dextrose broth...........64gm

Distilled water............................1000ml

pH...............................................7.2± 0.2

The medium was prepared by dissolving the specified quantity of the dehydrated medium in purified water by heating on a water bath and were dispensed in 100 ml volume conical flasks. The conical flasks were closed with cotton plugs and were sterilized by autoclaving at 121°C (15 lb psig) for 15 minutes.

The contents of the conical flasks were poured aseptically into sterile Petri dishes are allowed to solidify. These sterilized medias were used to subculture the fungal culture.

ROCEDURE:

Each Petridish was filled to a depth of 4-5 mm with a nutrient agar medium that was previously inoculated with suitable inoculums of suitable test organism, and then allowed to solidify. The petridish were specially selected with flat bottom and were placed on level surface so as to ensure that the layer of medium is in uniform thickness. The petridishes were sterilized at 160-170°C in hot air oven for 30 mins before use. Small sterile borer of uniform size was placed approximately at 10 cm height, having an internal diameter of approximately 6-8 mm and made of aluminium (or) stainless steel. Each plate was divided in to four equal portions along the diameter. To each portion one cylindrical cavity was made in medium with the help of sterile borer. Three cavities for test compounds and one cavity for the standard. The petridishes were incubated at 37°C for 18 hours. Diameter of the zone of inhibition was measured and the average diameter for each sample was calculated. The diameter obtained by the test sample was compared with that produced by standard Ketocanazole.

Table: Antifungal activity of Benzimidazole Derivatives

Compound

Concentration

(µg)

Zone of Inhibition

C.raphigera

A.polytricha

A

250

500

1000

23

24

25

24

25

26

B

250

500

1000

22

24

24

24

26

28

C

250

500

1000

24

26

28

19

22

27

D

250

500

1000

21

23

24

21

22

25

E

250

500

1000

23

25

26

20

22

24

F

250

50

1000

23

24

26

25

26

27

G

250

500

1000

23

24

27

19

22

25

H

250

500

1000

22

23

24

16

20

24

Std

Ketocanazole

1000

26

30

Introduction to Medicinal Chemistry

The subject of medicinal chemistry explains the design and production of compounds that can be used for the prevention, treatment or cure of human and animal diseases. Medicinal chemistry includes the study of already existing drugs, of their biological properties and their structure-activity relationships. Medicinal chemistry was defined by IUPAC specified commission as "it concerns the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds at the molecular level".Medicinal chemistry covers the following stages:

(i) In the first stage new active substances or drugs are identified and prepared from natural sources, organic chemical reactions or biotechnological processes. They are known as lead molecules.

(ii) The second stage is optimization of lead structure to improve potency, selectivity and

to reduce toxicity.

(iii) Third stage is development stage, which involves optimization of synthetic route for bulk production and modification of pharmacokinetic and pharmaceutical properties of active substance to render it clinically useful. Medicinal chemistry is the application of chemical research techniques to the synthesis of pharmaceuticals. During the early stages of medicinal chemistry development, scientists were primarily concerned with the isolation of medicinal agents found in plants. Today, scientists in this field are also equally concerned with the creation of new synthetic compounds as drugs. Medicinal chemistry is almost always geared toward drug discovery and development. Medicinal chemists apply their chemistry training to the process of synthesizing new pharmaceuticals. They also work on improving the process by which other pharmaceuticals are made. Most chemists work with a team of scientists from different disciplines, including biologists, toxicologists, pharmacologists, theoretical chemists, microbiologists, and bio pharmacists. Together this team uses sophisticated analytical techniques to synthesize and test new drug products and to develop the most cost-effective and eco-friendly means of production.

Medicinal

Chemistry

The focus on development of new synthetic drug compounds has resulted in the Incorporation of many other disciplines, such as biochemistry and molecular biology, into medicinal chemistry.These areas include biology, computer aided drug design , X-ray crystallography metabolism and pharmacokinetics, legal and regulatory affairs, clinical, franchise management, pharmaceutics and process research chemistry.

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