Syntesis, characterization and antimicobial activity of novel imidazoles


Doctoral Thesis / Dissertation, 2013
78 Pages, Grade: A-C

Excerpt

Table of contents

1 INTRODUCTION

2 REVIEW OF LITERATURE

3 OBJECTIVES

4 MATERIALS AND METHODS

5 RESULT AND DISCUSSIONS

6 SUMMARY AND CONCLUSIONS

7 REFRENCES

Acknowledgement

Today I am here because of almighty GOD. I am heartly thankful to him who gave me an opportunity to do something new and to meet such wonderful people.

It is a moment of gratification and pride to look back with a sense of contentment at the long traveled path, to be able to recapture some of the fine moments, to be thankful to several people, some who were with me from the beginning, some who joined me at different stages during this journey, whose kindness, love and blessings, who in some way or the other have brought me to this day. I wish to thank each and every one of them from the very bottom of my heart.

I offer flowers of gratitude to the GOD who has been the source of strength in my life.

Sant Kabir had once aptly said “if I have to choose between GURU and GOVIND I will undoubtedly choose my GURU by whose kind blessings I have attained the power of knowledge and freedom”. At this occasion I very humbly bow my head with utter respect and gratitude to all my teachers who at every stage have shaped my life and given me the power of knowledge.His valuable suggestions and support proved to be a boon during the work. Also his constant encouragement, remarkable guidance and enthusiastic discussion which always charged me up throughout my research work.

I bow my head with sheer respect and convey my pleasant regards to my most adorable Mummy-Papa Mrs. Meenaxi J. Shah and Mr. Jitendra R.Shah, and my elder brother Mr.Mehul,Bhabhi Mrs. Krupali and sweetest nephew Jaival.My Sister Unnati and Ankitjijaji and lovely nieces Vishruti and Jiya.The present work would have not been possible without their indispensable help, unlimited patience and emotional support.

My special grateful thanks to my wife Hemal J. Shah and her family members for their constant support in my endeavor.

I am also heartly thankful to my teachers for their never ending support.

At this moment how can I forgot my wonderful friends who gave me immense support during my research work and shared good and bad moments.

Last but not the least, I express my gratitude and apologize to everyone whose contribution I could not mention in this page.

Dr. PURVESH J. SHAH

2. Introduction:

Infection is a major category of human disease; skilled management of antimicrobial drugs is of the first importance. The term chemotherapy is used for the drug treatment of parasitic infections in which the parasites (viruses, bacteria, protozoa, fungi, and worms) are destroyed or removed without injuring the host.

Many substances that we now know to possess therapeutic efficacy were first used in the distant past. The Ancient Greeks used male fern, and the Aztecs chenopodium, as intestinal anthelmintic. The Ancient Hindus treated leprosy with chaulmoogra. For hundreds of years moulds have been applied to wounds, but, despite the introduction of mercury as a treatment for syphilis (16th century), and the use of cinchona bark against malaria (17th century), the history of modern rational chemotherapy did not begin until Paul Ehrlich developed the idea from his observation that aniline dyes selectively stained bacteria in tissue microscopic preparations and could selectively kill them. He invented the word ‘chemotherapy’ and in 1906 he wrote:

“In order to use chemotherapy successfully, we must search for substances which have an affinity for the cells of the parasites and a power of killing them greater than the damage such substances cause to the organism itself… This means… we must learn to aim, learn to aim with chemical substances.”

The antimalarial palanquin and mepacrine were developed from dyes and in 1935 the first sulphonamides, linked with a dye (Prontosil), was introduced as a result of systematic studies by Domagk. The results obtained with sulphonamides in puerperal sepsis, pneumonia and meningitis were dramatic and caused a revolution in scientific and medical thinking

In 1928, Fleming accidentally rediscovered the long-known ability of Penicillium fungi to suppress the growth of bacterial cultures but put the finding aside as a curiosity. In 1939, principally as an academic exercise, Florey and Chain undertook an investigation of antibiotics, i.e. substances produced by microorganisms that are antagonistic to the growth or life of other microorganisms. They prepared penicillin and confirmed its remarkable lack of toxicity.

When the preparation was administered to a policeman with combined staphylococcal and streptococcal septicemia there was dramatic improvement; unfortunately the manufacture of penicillin (in the local Pathology Laboratory) could not keep pace with the requirements (it was also extracted from the patient’s urine and re-injected); it ran out and the patient later succumbed to infection. Subsequent development amply demonstrated the remarkable therapeutic efficacy of penicillin.

- Classification of Antimicrobial Drugs

Antimicrobial agents may be classified according to the type of organism against which they are active.

- Antibacterial drugs
- Antiviral drugs
- Antifungal drugs
- Antiprotozoal drugs
- Anthelmintic drugs.

A few antimicrobials have useful activity across several of these groups. Few examples, metronidazole inhibits obligate anaerobic bacteria (such as Clostridium perfringens) as well as some protozoa that rely on anabolic pathways (such as Trichomonasvaginalis).

Antimicrobial drugs have also been classified broadly into:

- Bacteriostatic, i.e. those that act primarily by arresting bacterial multiplication, such as sulphonamides, tetracycline and chloramphenicol.
- Bactericidal, i.e. those which act primarily by killing bacteria, such as penicillins, cephalosporins, aminoglycosides, isoniazid and rifampicin.

- Bacteria

In 1928, a German scientist C.E. Ehrenberg used the term “ bacterium ”. Bacteria are the microscopic organisms of plant kingdom and are devoid of chlorophyll. They are relatively simple and primitive form of cellular organisms known as “Prokaryotes”. Bacteriology is the science that deals with the study of bacteria. The Danish physician Christian Gram in 1884, discovered a strain known as Gram strain, which can divide all bacteria into two classes “ Gram positive ” and “ Gram negative ”. The Gram-positive bacteria resist decolouration with acetone, alcohol and remain strained (methyl violet) as dark blue color, while Gram-negative bacteria are decolorized.

Bacteria can be classified according to their morphological characteristics as lower and higher bacteria. The lower bacteria have generally unicellular structures, never in the form of mycelium or sheathed filaments, e.g., cocci, bacilli, etc. The higher bacteria are filamentous organisms, few being sheathed having certain cells specialized for producing diseases in animal or human, are known as “ Pathogens ”.

- Classification of Organisms

- Staphylococcus Aureus is species of schizomycetes class; having Eubacteria’s order, micrococeaceac family and staphylococcus genus.
- Escherichia Coli is species of schizomycetes class; having Eubacteria order, Enterobacteriaceae family and Escherichia genus.
- Bacillus Subtillis is species of schizomycetes class; having Eubacterials order, Bacteriodaceac family and fusobacterium streptobacillus and sphaerophorus genus.
- Pseudomonas Aeruginosa is species of schizomycetes class; having pseudominodales order, pseudominadaceac family and pseudomonas genus.

- An introduction of various microorganism used in the present work:

1. Escherichia coli :

Domain - Bacteria

Phylum - Proteobacteria

Class - grammaproteobacteria

Order - Enterobacterias

Family - Enterobacteriaceae

Genus - Escherichia

Species - coli

Binominal name: Escherichia coli

illustration not visible in this excerpt

Figure 1: Escherichia coli

E.coli strains are harmless,but some ,causes serious food poisoning in humans .E.coli was discovered by German pediatrician & bacteriologist . Theodor Escherich in 1885 and is now classified as part of Enterobacteriaceae family of grammaproteobacteria.

E.coli is gram negative,facultative anaerobic and nonsporulating . Cells are rod shaped & 2 micrometer long & 0.5 micrometer in diameter. Optimal growth of E.coli occurs at37[0] C (98.6 F ) but some laboratory strains can multiply at temperature of up to 49[0] C(120.2 F) .

2. Bacillus subtilis :

Kingdom - Bacteria

Phylum - Firmicutes

Class - Bacilli

Family - Bacillaceae

Genus - Bacillus

Species - Subtilis

Binomial name : Bacillus subtilis

illustration not visible in this excerpt

Figure 2: Bacillus subtilis

B.subtilis known also as the hay bacillus or grass bacillus, is a gram positive bacterium commonly found in soli. A member of the genus Bacillus, B. subtilis is rod shape and the ability to form a tough, protective endospore,allowing the organism to tolerate extreme environmental condition.

B.subtilis has proven highly amenable to generic manipulation and has become widely adopted as a model organism for laboratory studies,especially of sporulation , which is a simplified example of cellular differentiation. It is also heavily flagellated which gives B.subtilis the ability to move quickly in liquid.

B.subtilis has approximately 4,100 genes. Of these only 192 were shown to be indispensable; another 79 were predicted to be essential as well. It is used to produce amylase. In 1835,the bacterium was oginally named vibrio subtilis by Christian Gottfried Ehrenberg, and renamed Bacillus subtilis by Ferdinand Cohn in 1872.

3 . Aspergillus Niger:

Division - Eukaryote

Kingdom - Fungi

Phylum - Ascomycota

Class - Eurotiomycetes

Order - Eurotiales

Family - Trichocomaceae

Genus - Aspergillus

Binomial name: Aspergillusniger

illustration not visible in this excerpt

Figure 3:Aspergillusniger

A. niger is a fungus and one of the most common species of the genus Aspergillus. It is discovered in 1867 by Van Tieghem .Variosstrain of A.niger are used in the industrial preparation of citric acid and glucomic acid and have been assessed as acceptable for daily intake by the World Health Organization .A.niger causes black mold of onions. A.niger is one of the most common cause of otomycosis( fungal ear infection ), which can cause pain, temporary hearing loss and in severe causes, damage to the ear canal and tympanic membrane.

4. Penicilium:

Division - Eukaryota

Kingdom - Fung

Phylum - Ascomycota

Class - Eurotiomycetes

Order - Eurotiales

Family - Trichocomaceae

Genus - Penicillium

Binominal name : Penicillium

illustration not visible in this excerpt

Figure 4:Penicillium

Penicillium is placed in class Ascomycetes, because they form the ascus,a sac-like cell containing a usually definite numbers of ascospores. Colonies are small (5-7 mm),circular ,flat & compact. The color of colony is white when the young but on aging it appears dark green or blue,hence it is also known as blue mold.

Some species are responsible for production of mycotoxins in food Penicillium damage lather,fabrics& furniture also spoils food like pickles and sauerkraunt.P.notatum produce the antibiotic penicillin.

- Identification Techniques of the Organisms

The organisms were identified by using the following strains [ 1,2 ]. - Schiff technique periodic acid

- Gram strains

- ZeilNelsonm acid fast strains

- Evaluation Techniques

The following condition must be met for the screening of antimicrobial activity.

- There should be an intimate contact between test organisms and substance to be evaluated.
- Required conditions should be provided for the growth of microorganisms. 7
- Condition should be same throughout the study.
- Aseptic/sterile environment should be maintained.

Various methods have been used from time to time by several workers to evaluate the antimicrobial activity [3,4]. The evaluation can be done by the following methods [ 5 ].

1. Turbidometric method,
2. Agar streak dilution method,
3. Serial dilution method, and
4. Agar diffusion method.

Agar diffusion method is again of three types:

- Agar cup method,
- Agar ditch method, and
- Paper disc Method.

In present work Agar cup method is used.

- Factors Affecting Zone of Inhibition

- Ingredient of culture media

Many substances are present in culture media, which may affect the zone of inhibition. Common ingredients such as peptone, agar, etc. may vary in their contents and many of these minerals may influence the activity of some antimicrobials. It is well known that Ca, Mg, Fe, etc. ions affect the sensitivity of zone produced by the tetracycline, gentamycin, NaCl reduce the activity of amino glycosides and enhances the effect of fucidin.

- Choice of media

Consistent and reproducible results are obtained in media prepared especially for sensitivity testing, the plates must be poured flat with an even depth.

- Effect of pH

The activity of amino glycosides is enhanced in alkaline media and reduced in acidic media, the reverses is shown by tetracycline.

- Size of inoculums

Although large numbers of organisms do not markedly affect many antibiotics, all inhibition zones are diminished by heavy inoculate. The ideal inoculum is one, which gives an even dense growth without being confluent. Overnight broth cultures of organisms and suitable suspensions from solid media can be diluted accurately to give optimum inoculate for sensitivity testing.

Along with globalization many new diseases are arising in the world, infection caused by the microorganisms render a major contribution to it. Some of the infections are acute and some are chronic which may be air born, water born or food born. Unhygienic conditions are determined to be the root cause for these infections. In addition to it the development of resistance in microorganisms against current antimicrobial therapy continues to drive the search for more effective antimicrobial drugs.[1]

Antimicrobial drugs are the greatest contribution of the 20th century to therapeutics as their advent changed the outwork of physician about the power drugs. Their importance is magnified in the developing countries, where infective diseases predominate. Drugs in this class differ from all others in that they are designed to inhibit/kill the infecting organism and to have no/minimal effect on the recipient such type of therapy is generally called “chemotherapy ”. The basis of selective microbial toxicity is the action of drug on a component of the microbe (e.g. bacterial cell wall) or metabolic process (e.g. Folate synthesis) that is not found in the host, or high affinity for certain microbial bio-molecules (e.g. trimethoprim for bacterial dihydrofolatereductase). Due to analogy between the malignant cell and the pathogenic microbes, treatment of neoplastic diseases with drugs is also called ‘ chemotherapy.’[2]

Since microorganisms develop rapid resistance, there is an ample scope for the development of antimicrobial agents that are active against resistant microorganism. There is a great need to synthesize the compounds, which are capable of treating both acute and chronic pain.

In order to combat the microbial infections, antimicrobial drugs are frequently used concurrently i.e. the combined use of antimicrobial with following objectives,

- To prevent emergence of resistance.
- To lower the adverse or side effects.
- To have a synergetic effect. 9
- To broaden the anti-microbial spectrum.

Heterocyclic compounds are of challenging interest in therapeutic chemistry, and this has catalyzed the innovation and development of much new heterocyclic chemistry and methods. It is equally interesting for its theoretical implication for the diversity of its synthetic procedure and for the physiological and industrial significances. Synthetic heterocyclic drugs are used as hypnotics, anticonvulsants, antiseptics, antineoplastics, antiviral, antihistaminics, antitumor etc. Majority of the drugs being introduced in pharmacopeias every year are heterocyclic compounds. Sulphar and nitrogen containing heterocyclic compounds and their fused analogs represent an important class of drugs in the therapeutic chemistry and also contributed to the society from biological and industrial point which helps to understand life processes.[3] They exist in numerous natural products,[4] displaying wide range of biological and pharmaceutical activities. [5-7].

During the last decades, chemistry, synthesis and transformations of five membered heterocyclic compounds have received considerable attention and importance due to their remarkable and wide variety of applications. The development of simple, facile and efficient synthetic methods for the synthesis of five membered heterocyclic from readily available reagents is one of the major challenges in organic synthesis. Among them, Imidazole and their derivatives have long been used as precursors for the synthesis of biologically active molecules. Because of their wide spectrum of activity shown by the Imidazole moiety, numerous Imidazole substituted with different groups at various positions have been prepared. In recent years several new methods for the preparation of Imidazole derivatives and reaction have been reported. Due to wide spectrum of biological activity of these derivatives inspired us to undertake the aspect on Imidazole derivatives.

Review of literature

3. Review of literature:

- Brief review about Imidazole Derivatives:

Imidazole (1,3-diaza-2,4-cyclopentadiene) is a planar five-member ring system with 3C and 2N atom in 1 and 3 positions The simplest member of the imidazole family is imidazole itself, a compound with molecular formula C3H4N2. The systemic name for the compound is 1, 3-diazole, one of the annular N bears a H atom and can be regarded as a pyrole type N. It is soluble in water and other polar solvents. It exists in two equivalent tautomeric forms 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 π-electrons, consisting of a pair of electrons from the protonated nitrogen atom and one from each of the remaining four atoms of the ring.Imidazole is amphoteric, i.e. it can function as both an acid and as a base. As an acid, the p K a of imidazole is 14.5, making it less acidic than carboxylic acids, phenols, and imides, but slightly more acidic than alcohols. The acidic proton is located on N-1. As a base, the p K a of the conjugate acid (cited above as p K BH + to avoid confusion between the two) is approximately 7, making imidazole approximately sixty times more basic than pyridine. The basic site is N-3.

Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid“histidine” which has an imidazole side chain. Histidine is present in many proteins and enzymes and plays a vitalpart in the structure and binding functions of hemoglobin. Histidine can be decarboxylase to histamine, which is also a common biological compound. One of the applications of imidazole is in the purification of His tagged proteins in immobilized metal affinity chromatography (IMAC). Imidazole has become an important part of many pharmaceuticals. Synthetic imidazole is present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea

Review of literature

leaves and coffee beans, which stimulates the central nervous system. Apart of its use for pharmaceutical purpose it also have varying applications in industries, the imidazole has been used extensively as a corrosion inhibitor on certain transition metals, such as copper. Preventing copper corrosion is important, especially in aqueous systems, where the conductivity of the copper decreases due to corrosion. Many compounds of industrial and technological importance contain imidazole derivatives. The thermostablepolybenzimidazole (PBI) contains imidazole fused to a benzene ring and linked to benzene, and acts as a fire retardant. Imidazole can also be found in various compounds which are used for photography and electronics. This review mainly enlights the pharmaceutical importance of the imidazole moiety.

- CHEMICAL ASPECTS OF IMIDAZOLE

Imidazoles were prepared in 1858 from glyoxal and ammonia. Several approaches are available for synthesis of imidazoles as, Radiszewski synthesis, dehydrogenation of imidazolines, from alpha halo ketones, Wallach synthesis, from aminonitrile and aldehyde and Marckwald synthesis. Details of the synthetic procedures are given below:

1) RADISZEWSKI SYNTHESIS [8-10]

It consist of condensing a dicarbonyl compound such as glyoxal, aketo aldehyde or a- diketones with an aldehyde in the presence of ammonia, benzyl for instance, with benzaldehyde and two molecule of ammonia react to yield 2,4,5-triphenylimidazole. Formamide often proves a convenient substitute for ammonia.

2) DEHYDROGENATION OF IMIDAZOLINE[11]

Knapp and coworkers have reported a milder reagent barium managanate for the conversion of imidazolines to imidazoles in presence of sulphur. Imidazolines obtained from alkyl nitriles and 1, 2-ethanediamine on reaction with BaMnO4 yield 2-substituted imidazoles.

Review of literature

3) FROM α-HALO KETONE

This reaction involves an interaction between an imidine and alpha halo ketones. This method has been applied successfully for the synthesis of 2, 4- or 2, 5- biphenyl imidazole phenacyl bromide and benzimidine according to this method afford 2,4-diphenyl imidazole. Similarly, amidine reacts with acyloin or alpha halo ketones to yield imidazoles.

4) WALLACH SYNTHESIS [11 - 15]

When N, N′-dimethyloxamide is treated with phosphorus pentachloride, a chlorine containing compound is obtained which on reduction with hydroiodic acid give N- methyl imidazole. Under the same condition N, N′-diethyloxamide is converted to a chlorine compound, which on reduction gives 1-ethyl-2-methyl imidazole. Thechlorine compound has been shown to be 5- chloral imidazole.

5) MARKWALD SYNTHESIS

The preparation of 2-mercaptoimidazoles from α-amino ketones or aldehyde and potassium thiocyanate or alkyl isothiocyanates is a common method for the synthesis of imidazoles. The sulfur can readily be removed by a variety of oxidative method to give the desired imidazoles. The starting compounds, a- amino aldehyde or ketone, are not readily available, and this is probably the chief limitation of the Markwald synthesis.

Review of literature

Benzimidazole is more important than imidazole as the former occur in Vit B12 and has been prepared by a number of methods, 1,2-diaminobenzene condenses with a carboxylic acid on heating in an acidic medium to give benzimidazole.

- 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 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 withdrawing substituents 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 benzimidazoles provides sufficient electron withdrawal to allow a variety of nucleophilic substitution reaction at C-2.

The overall reactivity of imidazole and benzimidazole is referred from sets of resonance structure in which thedipolar 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[16].

- PHYSICAL PROPERTIES

Review of literature

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. Imidazole shows a large value of dipole moment of 4.8 D in dioxane. Imidazole show amphoteric properties andhas 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 substitutionhappens in the presence of electron withdrawing group in its nucleus. Imidazoles have m.p. 90[0] C, it is a weak base and tautomeric substance, since position 4 and 5 are equivalent.It’s spectroscopic parameters are λmax of 207 nm, I.R.=1550, 1492, 1451(cm-[1] ), τ = 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[17].

- CHEMICAL REACTION

- REACTION WITH ACIDS

Imidazole is a monoacidic base and form crystalline salt with acid. It also possesses weakly acidic properties (pseudo acidic) and is even more acidic than pyrroles and thus forms salts of the following type with Grignard reagent or metal ions. With ammonical silver nitrate imidazole form a silver salt, which is sparingly soluble in water.

- REACTION WITH OXIDISING AND REDUCING AGENTS

Imidazole itself is stable to auto oxidation and to the action of chromic acid but is attacked by potassium permanganate. However imidazole readily opens the ring to form oxamide with H2O2. Oxygen in the presence of a sensitizer (single oxygen) reaction gives an imidazolidine derivative. Imidazolium dichromate, a mild oxidizing agent has been employed for the oxidation of allylic and benzylic alcohol to the corresponding carbonyl compound.

- ELECTROPHILLIC SUBSTITUTION

Imidazolesposses increased reactivity towards electrophillic attack. It is more susceptible to electrophillic attack than pyrazole or thiazole and more so than from furan and thiophene also. From the following resonance structure of the intermediate ion; it is evident that the attack takes place at the 4th and 5th position in imidazole ring. It may benoticed that the attack at C-2 involves a canonical form which is highly unflavored at positive N at position 3.Halogenations of imidazole are very complex and vary considerably depending on the substrate, reagents and reaction condition.

Review of literature

- PHARMACOLOGICAL ACTIVITIES OF IMIDAZOLES

Imidazole derivatives have a wide range of pharmacological activity, literature survey revealed that imidazole and its derivative are reported to have, analgesic and anti-inflammatory activity [18-21], cardiovascular activity[22,23], anti-neoplastic activity[24], anti- fungal activity [24-25], enzyme inhibition activity [26-28], anti-anthelmintic activity[29], anti-filarial agent, anti- viral activity and anti- ulcer activity.Other than their pharmacological actions they also function as dyestuffs catalysts and polymerizing agents. 2-nitroimidazole (azomycin) and 1-(2- hydroxyethyl)-2-methyl-5-nitroimidazole(metronidazole) are antibacterial agent with particular applications as trichomonacide. Along with metronidazole other nitroimidazoles (misonidazole,metrazole and clotrimazole) are important anti cancer drugs.Two imidazolines, priscol and privine are valuable vasodialating and vasoconstriction drugs. 2-aminoimidazolines are among the class which are known for fungicidal action. The modern scientific searches aim at discovering more effective and better-tolerated imidazole derivatives.

- IMIDAZOLES AS ANTHELMINTICS

It was found that imidazole is less sensitive in extra intestinal parasites particularly intravascular and intestinaldwelling parasites than gastrointestinal parasites.The activity against developing stages is superior to that against arrested or adult stages in comparable habitats.The hatching and larval development are inhibited at doses which are sub- efficacious against adult in vivo.They required to achieve efficacy against nematodes are lower than those used for cestode and trematode control.For cestode or trematode control higher dose of drug or multiple treatments is needed.The member of class (2-alkyl benzimidazole) has been found to remove various species of nematodes andtrematodes from different hosts. 4, 5, 6, 7-tetra chloro-2-trifluoromethyl benzimidazole show high activity againstthe nematodes Ancylostomacaninum, Haemonchuscontrtus, ascarissuum and trimatodes Fasciola hepatica several 2 disubstitutedbenzimidazole, with proven potentials to kill various species of intestinal nematodes havealso been found to posses activity against cestodiasis of man and animal. Mebendazole at the dose of 100 mg/kgcure patient suffering with T. Soliumand T. Saginata.

- The pharmacological principle affecting in vivo efficacy are -

1. Host toxicity is low at efficacious anthelmintics doses, however adverse reactions at higher doses are observed.
2. Benzimidazoles are extensively metabolized in host species usually to less potent anthelmintics. The rate ofmetabolism for each benzimidazole is similar for all hosts. First pass metabolism by soluble liver enzyme(reductase& oxidase) constitutes a rapid pathway for deactivation for several benzimidazoles notablyMebendazole&Albendazole.
3. Benzimidazoles are hydrophobic and water insoluble and therefore bioavailability and pharmacodynamics andthus efficacy can be altered by formulation and presentation. Thus there are three aspect of benzimidazole pharmacology in vivo, the role of host pharmacodynamics,hostparasiteinteraction and biochemical pharmacology of benzimidazole. For maximum efficacyof the drug itsbioavailability is also to be considered.

The factors that influence the bioavailability of anthelmintic include host biology (e.g. site and kinetics ofabsorption, drug metabolism, and disease state), parasite biology (e.g. site of predilection, absorption kinetics) andphysicochemical properties of the drug (e.g. lipophilicity, pKa, molecular size).

- IMIDAZOLES AS ANTI-INFLAMMATORY AGENTS

The search for the new and better drug in anti-inflammatory therapy is never ending process. The search for anti-inflammatory agent to relieve the swelling, redness, pain and fever associated with rheumatism dates back toantiquity. The synthetic studies include work on a variety of heterocyclic system, in isolation or fused with othersystem.

Amino acids are reported to posses’ anti-inflammatory activity [30-31] and bearing this in mind Kumar et al [32] prepared various heterocyclic derivatives having both carboxylic and amino group. The structure activityrelationship studies indicated the conversion of the carboxylic group into a heterocyclic ring usually potentiated theinhibition of edema. Conversion into benzimidazole and 1, 2, 3, 4-tetrahydroquinoline ring resulted in compoundspossessing better activity then that formed by the conversion of the carboxylic group into imidazole ring.

Though imidazole and benzimidazole derivative are associated with a broad spectrum of biological activities theyalso have anti inflammatory activity, various N-substituted imidazoles [33] and substituted imidazolone[34] havebeen found to be active. Among a series of 3- [substituted phenyl methylene] amino-5-(substituted phenyl methylene-2 -thioxo- imidazolidinone) compound (I) was found to be most potent inflammation inhibitor and superior to phenyl butazone[35]. Activity has also been observed among some 1-(thiadiazolyl substituted phenyl)-2-methyl-4-(substituted) methylene imidazol-5-ones[36].

[...]

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Title
Syntesis, characterization and antimicobial activity of novel imidazoles
College
Sardar Patel University
Grade
A-C
Author
Year
2013
Pages
78
Catalog Number
V270251
ISBN (eBook)
9783656613503
ISBN (Book)
9783656613497
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1963 KB
Language
English
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syntesis
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Purvesh Shah (Author), 2013, Syntesis, characterization and antimicobial activity of novel imidazoles, Munich, GRIN Verlag, https://www.grin.com/document/270251

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