chapter 1 general introduction -...

CHAPTER 1

General

Introduction

Chapter 1 General introduction

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Ph.D. Thesis (2013) – Deepkumar S. Joshi, DST-JRF (INSPIRE fellow), MNSC-HNGU, Patan

1. General introduction

1.1 Introduction to Organic chemistry

Organic chemistry erupted as an important branch in chemical science around

1900, until which the subject, chemistry remained undivided. The unprecedented

number of factual research enforced a progressive segmentation of the subject into sub

disciplines. Organic chemistry is one of a special branch in chemistry and is concerned

with the synthesis of organic compounds via use of several reactions and reagents.

Organic synthesis has emerged as a subject of interest and centre of attraction for many

scientists because of its ability to produce several beneficial products artificially, for the

smooth functioning of human life.

Organic chemistry has helped to construct many different useful drugs and also

in synthesizing other compounds, what a basic human needs. A keen investigation in the

organic chemistry has helped to serve the mankind with life saving molecules – drugs

and medicines and other basic necessities. Along with the development of organic

chemistry, the advances in the interdisciplinary knowledge of relationship between

biological activity and chemical structures has made a remarkable appearance in the

support of synthesizing novel and useful organic molecules, thus ensuring a limitless

scope for the development of structurally novel organic compounds with wide range of

biological applicability.

Along with the development of organic chemistry; a great improvement in

structural and functional development occurred, which helped the researchers to

undertake their research and reach the conclusions more effectively. The instruments

developed for characterizing organic molecules were much advanced technologically and

were able to produce high quality results in less time span.


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1.2 Introduction and importance of Medicinal Chemistry

The treatment of pain and disease is one of humanity‘s most vital tasks to serve

mankind, to accomplish their fundamental rights towards health. It is inevitable for the

scientific fraternity and medicinal chemists to create equitable access to essential

medicines for the priority diseases. This demanding activity for the betterment of

humans requires creativity, a vast range of scientific knowledge and great persistence.

Medicinal chemistry comprises of both art and science, henceforth requires a

comprehensive mind to collect and synthesize mountains of data - chemical and

biological, instinct to select the right direction to pursue, intellect to plan and execute

the strategy that leads to the formation of desired compounds.

Medicinal Chemistry has its roots in several branches of chemistry and biology.

However it concerns with the science that strive to identify, create and modify

molecules for their therapeutic applications. Medicinal chemistry basically deals with the

understanding of mechanisms of actions of drugs. Although associated with several

challenges in upbringing a drug candidate from bench top to clinic, the art of medicinal

chemistry has enriched greatly from the developments in the areas of organic chemistry,

biology, biophysical and chemical methodology and computational tools resulting in

significant acceleration of drug discovery process.

Medicinal Chemistry recognized as a scientific discipline for the benefit of

humanity, operates by collaborating with chemists, biologist, pharmacists and

computational experts for the search of molecules, which will become future‘s new

medicines. Today, major pharmaceutical companies are focused on discovery of low

molecular weight drug-like molecules, which not only interact with the target but also

have specific pharmacokinetic and toxicological properties that make them a drug.

Major duties of medicinal chemists involve design and synthesis of biologically

active compounds and also to improvise the existing methods of synthesis for bioactive

molecules put forward by several pharmaceuticals. Before a medicinal chemist

synthesizes new molecules, he tries to study and establish structure activity and

structure property relationships amongst series of compounds. This has always been a


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challenge for a medicinal chemist to optimize biological activity in parallel with other

drug-like properties, such as molecular weight, solubility, toxicity, metabolic stability

and bioavailability. Also, emphasis is given on adsorption, distribution, metabolism and

excretion (ADME) like features along with drug-drug interaction so that the drug does

not fail in the last stage of development, which is observed more commonly in large set

of molecules.

Medicinal Chemistry mainly focuses on the broad based variations embracing

influences on number of possible permutations and combinations with regard to the

chemical structure on the biological activity. With respect to the above statements of

facts supported by several volumes of scientific evidences, it is very important for a

chemist to logically understand overall physiochemical properties of the molecule along

with ‗mechanism of drug action‘. The physiochemical properties associated with

molecule includes acid/base character, partition co-efficient, water solubility, lipid

solubility, stereochemistry, chirality etc. It is, however, pertinent to mention here that

most of the aforesaid properties exert significant influence upon various biological

activities; such studies are more familiarly referred as Structural Activity Relationship

(SAR). A creative medicinal chemist should ponder over presence of each functional

group in the molecule with an aim to arrive towards non-toxic and potent medicinal

agents.

A medicinal chemistry project initiates with the designing of a lead compound

with specific pharmaceutical property. Nowadays, the aim of medicinal chemistry is

shifted from activity to selectivity. The more selective a compound is for a particular

target, the more effective it is likely to be a lead molecule. Medicinal chemists are much

interested in development of molecules with fewer side effects. Much interest is taken

in identifying the effect of biologically active compound at molecular level. Medicinal

chemistry has introduced several new techniques over the last few years in order to

speed up the drug discovery process, such as combinatorial chemistry, microwave-

assisted organic synthesis and green synthesis methodologies.


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IUPAC specified commission defines medicinal chemistry as ―it concerns the

discovery, the development, the identification and the interpretation of the mode of

action of biologically active compounds at molecular level.‖ The discoveries of the

medicinal properties of compounds have always led to the development of newer

method for the synthesis of substances similar to that of available lead molecules.


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1.3 About drugs

The word ‗drug‘ is derived from the French word ‗drogue‘ which means a dry

herb. In general, a drug may be defined as ―all chemicals other than food that affect

living process.‖ If the affect helps the body, the drug is a medicine. However, if a drug

causes harmful effects on the body, the drug is a poison. According to WHO, a drug

may be defined as ―any substance or product which is used or intended to be used for

modifying or exploring physiological system or pathological status for the benefit of

recipient.‖

Below indicated are the ways in which a drug can be classified:

1. According to their pharmacological effect – for example, analgesic drugs

(pain killing effect); antipyretic drugs (lowering the body temperature);

antimicrobial drugs (bacteriostatic, bactericidal and fungicidal).

2. Effective towards a particular biochemical process – for example,

antihistamines act by inhibiting the action of inflammatory agent histamine in the

body.

3. According to their chemical structure – drugs of this kind share a common

structural skeletal – for example, penicillin and cephalosporins contains β-

lactum ring and kills bacteria by the same mechanism.

4. In accordance to their molecular target – for example, anticholinesterases are

compounds that inhibit an enzyme called acetyl cholinesterase.

A drug molecule is designed in a way that the functional groups enacted with the

primary skeletal or nucleus are positioned in a defined geometrical array such that, it

enables the molecule to get bind specifically to a targeted biological macromolecule,

known as a receptor. A particular position of a functional group in three-dimensional

framework of the drug molecule helps it to exhibit a desired biological response,

thereby minimizing the probability of toxicity. A drug like molecule to be successful in

encountering a disease must have several other additional properties along with


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biological and chemical properties viz. it must be able to remain stable during journey;

from its point of administration until it finally reaches the receptor site.

For a molecule to be drug-like, it must possess some basic properties such as, it

should be much small molecule so that it can be easily transported throughout the body,

hydrophilic and lipophilic enough to dissolve in the blood stream and cross the fat

barriers within the body respectively. Also there must be enough number of polar

functional group present in the molecule so that to enable it to bind to the receptor.

Lipinski‘s rule of five helps to conduct tests for identifying such properties in a molecule

which can help it promote towards becoming a drug-like molecule. It has been

estimated that the number of possible molecules with much less molecular weight and

possessing basic drug-like properties are very few. The proportion of these drug-like

molecules synthesized till date is much less, roughly the ratio of mass of one proton to

mass of the sun!

It has been proved beyond any reasonable doubt that the success rate of

discovery of novel molecules are exclusively dependent on the ability to identify and

characterize novel targeted drug molecules more familiar as New Chemical Entities

(NCE‘s). The newly identified entities must possess inherent property of controlling a

specific disease, besides being non-toxic. The Research and development process for

most of the drugs available today has required 12-24 years from initiating a project to

the their launch.

There are several methods available to initiate with a drug discovery project of

finding biologically active molecules. Hits can be obtained via virtual screening approach

or by studying the scientific or patent literature. More often, a drug designing and

discovery process start with a screening campaign of commercially available compound

libraries against the target of interest. We performed a literature survey of

commercially available combinatorial libraries presenting the biological properties of

several heterocyclic compounds followed by screening the compounds via Lipinski‘s

rule of five – first stage of QSAR for identifying the drug-likeness properties of the

designed molecules.


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1.4 Introduction to heterocyclic chemistry and its service to mankind

The drugs used in human medicine cover the whole range of chemical entities

including organic and inorganic compounds, but majorities are heterocyclic scaffolds or

have a heterocyclic structural components viz. N,O,S etc.1-3 These cyclic systems

containing at least one other element than carbon atom are called heterocyclic

compounds. Heterocycles are considered ―versatile‖ due to their properties of

possessing specific chemical reactivity and therefore have always attracted the attention

of scientists working in both the area of natural products and synthetic organic

chemistry. Heterocyclic compounds have great applicability in pharmaceuticals as

anticancer agents, anti-tubercular agents, analgesics, hypnotics, anti-malarial,

antimicrobials and as pesticides and insecticides.4-10 Heterocyclic compounds are

enormous, their chemistry is complex yet interesting and various synthetic procedures

have been developed resulting in diverse ring formations. The heterocyclic compounds

are of immense importance biologically, hence have stimulated considerable research

work in recent years leading to medicinal utility.

The greatest advantage of heterocyclic compounds in drug industries lies in the

ability to manifest substituent around a core scaffold in defined three dimensional

representations. Among other hetero atoms, heterocyclic compounds possessing

nitrogen and oxygen have maintained the interest of researchers through historical

development of novel synthetic procedures for the synthesis of N and O containing

heterocyclic entities. Several heterocyclic compounds occurring in nature involved

biologically, includes nucleic acids (in DNA are found to possess nitrogen containing

purine and pyrimidine bases), Vitamins (Thiamine B1, Riboflavin B2, Nicotinamide B3),

essential amino acids (proline, histidine and tryptophan)11 and heme (haemoglobin). 12

Heterocyclic scaffolds have widespread therapeutic uses such as antibacterial,

antifungal, antimycobacterial, anti-HIV, anti-tubercular, analgesics, anti-malarial,

anticancer, antidepressant, anthelmintic and antitumor.13-19 Other than being

medicinally important, heterocyclic compounds are found to be potent fungicides,

herbicides, agrochemicals, anticorrosive agents, dyestuff, flavuoring agent and photo

stabilizers.20-27 Compounds not necessarily have to be heterocyclic in nature to exhibit


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pharmaceutical properties, but nature itself has selected heterocyclic compounds as the

bases of most of the biological systems and the introduction of heteroatom into a cyclic

compound impart new properties and responds much better to the many demands of

biological systems.

Heterocyclic compounds have been in service to mankind since the day hetero

atoms were identified. Even the first antibacterial drug prontosil developed in 1983,

was found to possess hetero atoms. Several other important drugs discovered viz.

penicillin (antibiotic, 1940), chloroquine (anti-malarial, 1945), trimethoprim

(antimicrobial, 1965) were possessing heterocyclic skeletal as their basic structure.

Majority of the drugs available in the market have either hetero atoms present as a

substituent (functional group) or the core structure of the drug is found to be a

heterocyclic skeletal.

1.4.1 Antiviral drugs

Antiviral drugs used specifically for treating viral infections have heterocyclic

scaffold as their basic structure. The antiviral drugs designed nowadays are used for

treating HIV, herpes viruses, hepatitis B responsible for causing liver cancer. Abacavir –

a nucleoside analog, reverse transcriptase inhibitor used to treat HIV and AIDS,28

Darunavir – a protease inhibitor used to treat HIV infection,29,30 Entecavir – an oral

drug is a nucleoside analog used for treating hepatitis B infection31,32 and Lopinavir – an


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antiretroviral drug of the protease inhibitor class used for treating HIV infection and

AIDS.33

1.4.2 Antimicrobial drugs – antifungal drugs

Antimicrobial drugs comprises of both the antibacterial as well as antifungal

drugs. Antifungal drugs are used for treating skin infections, ringworm and candidiasis.

Several different class of heterocyclic compounds are used as antifungal drugs viz.

bifonazole – an imidazole antifungal drug helps in blocking the transformation of 24-

methylenedihydrolanosterol to desmethylsterol in fungi together with the inhibition of

HMG-CoA.34,35 Another well-known drug fluconazole belongs to triazole class of


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antifungal drugs, is used in the treatment of superficial and systematic fungal

infections.36

1.4.3 Antimicrobial drugs – antibacterial drugs

Antibacterial drugs comprises of such agents that inhibits the growth of bacteria

or kills them. Antibacterial agents are generally divided into two classes: bactericidal

agents responsible for killing bacteria, and bacteriostatic agents that slowdown bacterial

growth. Metronidazole is a nitroimidazole antibiotic used particularly against anaerobic

bacteria and protozoa.37 It is a drug used for treating mild-to-moderate Clostridium

difficile infection.38,39 Ciprofloxacin – a second generation fluoroquinoline antibacterial is

found to be active against most strains of bacterial pathogens responsible of respiratory,

urinary tract, gastrointestinal and abdominal infections.40,41 Ciprofloxacin is found to

exhibit excellent antibacterial property against a broad spectrum of gram-positive and

gram-negative bacteria.40


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1.4.4 Antihypertensive drugs

Antihypertensive therapy helps to prevent the complications of high blood

pressure such as stroke and myocardial infraction.42 Several heterocyclic drugs

responsible for lowering human blood pressure by different means are available today.

The different antihypertensive drugs used for treating hypertension includes thiazide

diuretics, the ACE inhibitors, the calcium channel blockers, the beta blockers and the

angiotensin II receptor antagonists. Chlorothiazide,43-46 flumethiazide,47-50

hyrdochlorothiazide51,52 and trichloromethazide drugs belong to thiazide diuretics class

of antihypertensive drugs and are found to reduce the risk of death due to stroke, heart

attack and heart failure due to hypertension.53-55

1.4.5 Antipyretic drugs

Antipyretics are drugs used to treat fever. Antipyretics cause the hypothalamus

to override an interleukin-induced increase in temperature. Once treated with

antipyretic drug, the body then works to lower temperature, resulting in a reduction in

fever. The most common antipyretics used are ibuprofen56 and aspirin.57-59


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1.4.6 Non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs, usually abbreviated as NSAIDs are a

class of drugs that provide antipyretic and analgesic effect in higher doses along with

anti-inflammatory effects. The term ―nonsteroidal‖ distinguishes these drugs from

steroids, which among a broad range of other effects, have a similar anti-inflammatory

action. NSAIDs are usually used in treatment of acute conditions where pain and

inflation are present. Celecoxib is a sulfonamide nonsteroidal anti-inflammatory drug

and a selective COX-2 inhibitor used in the treatment of acute pain, painful

menstruation and menstrual symptoms.60 Droxican is a NSAID of the oxicam class.61

1.4.7 Analgesic drugs

An analgesic or pain killer is any member of the group of drugs used to achieve

analgesia – relief from pain. Analgesic drugs act in various ways on the peripheral and

the central nervous system. They differ from anesthetics, which reversibly eliminate

sensation. Analgesics also include nonsteroidal anti-inflammatory drugs (NSAIDs) and


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can also be used as antipyretic agents. Phenazone is an analgesic as well as antipyretic

drug with elimination half life of 12 hrs.62,63 The other pyrazolone derivatives64,65 include

aminophenazone66 and apazone as analgesic drugs. These drugs are also much potent

antipyretic as well as anti-inflammatory drugs.

1.4.8 Anticonvulsant drugs

Anticonvulsant drugs, more accurately called antiepileptic drugs are a diverse

group of pharmaceuticals used in the treatment of epileptic seizures – abnormal

activities in the brain. Many of the anticonvulsant entities seem to act as mood

stabilizers,67 are used in the treatment of bipolar disorder and neuropathic pain. The

goal of anticonvulsants is to suppress the rapid and excessive firing of the neurons that

start a seizure. Barbiturates are drugs that act as central nervous system (CNS)

depressants, and by virtue of this they produce a wide spectrum of effects, from mild

sedation to anesthesia. phenobarbital,68,69 barbexaclone70,71 and mephobarbital

(methylbarbitol)72 are barbiturate derivatives used as anticonvulsant drugs.

Benzodiazepines are a class of drugs with hypnotic, anxiolytic, anticonvulsive and

muscle relaxant properties.73 They include nimetazepam and lorazepam drugs.74

Paramethadione and trimethadione are anticonvulsant drugs in the oxazolidinedione


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class, used in the treatment of fetal trimethadione syndrome and epileptic conditions

respectively.

1.4.9 Anti-diabetic drugs

Anti-diabetic drugs treats diabetes mellitus by lowering glucose levels in the

blood. Except insulin, all are administered orally and are thus called oral hypoglycemic

or antihyperglycemic agents. There are several anti-diabetic drugs and their selection

depends on the nature of diabetes, age and situation of the person, as well as other

factors. For diabetes mellitus I: caused due to lack of insulin, hence insulin must be

injected to the patient suffering from diabetes I. Diabetes mellitus II is caused by

resistivity of insulin by cells. The treatment for diabetes II includes i) agents that

increase the amount of insulin secreted by pancreas, ii) agents that increase the

sensitivity of target organs to insulin and iii) agents that decrease the rate at which

glucose is absorbed from the gastrointestinal tract. Glimepiride is a medium-to-long


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acting sulfonylurea antidiabetic drug used to treat diabetes mellitus type II, The drugs

helps to increase the production of insulin by pancreas.75,76 Miglitol is an oral anti-

diabetic drug that acts by inhibiting the ability of the patient to break down complex

carbohydrate into glucose. Primarily it is used in diabetes mellitus II for establishing

greater glycemic control by preventing the digestion of carbohydrates into

monosaccharide which can be absorbed by the body.77 As miglitol prevents digestion of

carbohydrates, it lowers the degree of postprandial hyperglycemia. It must be taken at

the start of meals to have maximal effect.77 Pioglitazone is a drug of the class

thiazolidinedione (TZD) with hypoglycemic activity to treat diabetes. It is used to

improve glucose control in adults over the age of eighteen with diabetes II.78

1.4.10 Antiulcer agents

A peptic ulcer, also known as peptic ulcer disease (PUD), is the most common

ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely

painful. It is defined as mucosal erosions equal to or greater than 0.5 cm. As many as 70

to 90% of such ulcers are associated with helicobacter pylori, a helical-shaped bacterium

that lives in acidic environment of stomach. Nizatidine and ranitidine are histamine H2-


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receptor antagonist that inhibits stomach acid production, and commonly used in the

treatment of peptic ulcer disease and gastroesophagel reflux disease (GERD).79,80

Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer

disease and gastroesophageal reflux disease. Omeprazole is one of the most widely

prescribed drugs all over the world.81,82


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1.5 Introduction to QSAR study and description of QSAR models

applied in our study

Nearly 40 years ago, quantitative structure-activity relationship (QSAR)

paradigm was first introduced in all facets of chemistry.83 The stability of the technique

for so long time may be attributed to the postulate of the theory that activity of a

molecule was due to the presence of substituent (functional group - skeletal

arrangement in three dimensions) and several properties associated with it like

electronic attributes, hydrophobicity and steric properties.84 The QSAR methodology

helps in finding the mechanism of action of drugs at molecular level and many other

physiochemical phenomena like hydrophobicity.85,86 Hansch was the first to use QSAR

to explain the biological activity of series of structurally related molecules.87 Hansch first

used the descriptors and proposed a correlation between the molecule‘s electronic

environment and its hydrophobicity.85,86 The study by Hansch regarding the relation of

biological properties and molecular structures helped him to lead to great conclusions.

QSAR – in-silico studies is the name usually applied to methods where molecular

structure is correlated to some kind of in vitro or in vivo biological properties. QSAR has

been applied extensively to predict models for activity of bioactive molecules. QSAR

study includes predicting drug-likeness of molecules, toxicity prediction, drug

metabolism, pharmacokinetic properties. Several stages are involved in the QSAR study

viz. first stage of QSAR study includes study of Lipinski‘s rule of five for designed

molecules, second stage and third stage involves carcinogenicity and mutagenicity

respectively.

1.5.1 Descriptors applied in our study: First stage of QSAR – Lipinski’s

rule of five

The first stage of QSAR includes the study of Lipinski‘s rule of five which was

formulated by Christopher A. Lipinski‘s rule of five is a rule to evaluate drug-likeness88

or to determine presence of certain pharmacological properties in a molecule that

would make it a likely active drug in humans. According to Lipinski‘s rule of five, an

orally active drug has no more than one violations of the following criteria;89


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1. Molecular weight under 500gm/mol.

2. Not more than 5 hydrogen bond donors.

3. Not more than 10 hydrogen bond acceptors.

4. Value of partition coefficient (log P) must be less than 5.


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1.6 Studies on benzimidazole derivatives

1.6.1 Introduction to benzimidazole derivatives

Benzimidazole is a fused organic heterocyclic compound – bicyclic fused ring of

benzene and imidazole. It contains two nitrogen atoms in its core structure in the

imidazole nucleus. More emphasis is given on synthesis of newer medicinally important

entities after the discovery of presence of benzimidazole nucleus as 5,6-

dimethylbenzimidazole in the structure of vitamin-B12.90,91 Benzimidazoles are weakly

basic, somewhat less basic than imidazoles. Also they are found to be sufficient acidic

which makes them soluble in alkali, resulting in the formation of N-metallic

compounds. Moreover benzimidazole is an isoster of naturally occurring nucleotide and

therefore it is capable of interacting easily with the biopolymers of the living system.

The first benzimidazole was prepared by Hoebrecker, who obtained 2,6-

dimethylbenzimidazole by reduction of 2-nitro-4-methylacetanilide.92

Several years later the same compounds was obtained by Ladenburg by refluxing

3,4-diaminotoluene with acetic acid.93


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1.6.2 Synthesis of benzimidazole derivatives

Benzimidazoles have been synthesized by number of methods using variety of

precursors, reagents and via different reactions. Beaulies et al have synthesized

benzimidazoles from 1,2-phenylenediamines and aldehydes under solvent phase

synthesis using Oxone® as a medium. The composition of oxidizing agent Oxone® is

2KHSO5.KHSO4

.K2SO4.94

Fokas D et al have reported the procedure for the synthesis of benzimidazole

derivatives from o-nitroanilines and aldehydes by one step reductive cyclization using

Na2S2O4.95

One pot synthesis procedure for the conversion of aromatic and heteroaromatic 2-

nitroamines into bicyclic benzimidazoles has been reported by Hanan et al.96 Formic

acid, Fe and ammonium chloride were employed to reduce the nitro group and affect

the imidazole cyclization.

The versatility of a new approach of reacting o-substituted anilines with

functionalized orthoesters yields benzimidazole derivatives in an efficient quantity was


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reported by bastug et al. The success of these derivatives led to the development of new

libraries of heterocycles containing multifunctional sites.97

Bahrami et al has reported a convenient method for the synthesis of 2-substituted

benzimidazoles with excellent yields in short reaction time.98

Kim et al have reported a one pot, three component syntheses of 2-haloanilines,

aldehydes and NaN3 using CuCl and TMEDA as catalyst in good yield.99

Diao et al have reported the synthesis of benzimidazoles under acidic conditions

with in situ additive cyclization. The synthesis of benzimidazole derivatives were attained

by utilizing CuI and l-proline as a catalyst for carrying out a coupling reaction between

aq. Ammonia and 2-iodoacetanilides.100


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Saha et al101 have reported a very simple, efficient and ligand free synthesis of

substituted benzimidazoles via intramolecular cyclization of o-bromoaryl derivatives

using Cu(II) oxide nanoparticles in DMSO as catalyst. The group was also able to

recover the heterogeneous catalyst and reuse the same.

An efficient method for the transformation of N-benzyl bisarylhydrazones to

functionalized 2-aryl-N-benzylbenzimidazoles involving a copper (II)-mediated cascade

C-H functionalization C-N bond formation under neutral conditions was reported by

Guru et al.102

Chlorotrimethylsilane in DMF was used as a promoter and water acceptor agent

for the synthesis of benzimidazole from aromatic ortho-diamines and aldehydes, followed

by air oxidation by Ryabukhin et al.103

A simple and efficient procedure for the synthesis of substituted benzimidazoles

through a one-pot condensation of o-phenylenediamines with aryl substituted aldehydes


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in the presence of H2O2 and HCl in acetonitrile at room temperature featuring short

reaction time, easy and quick isolation of the products, and excellent yields was

reported by Bahrami et al.104

Du and Wang have reported various 2-arylbenzimidazoles were synthesized

from phenylenediamines and aldehydes via one-step process using hypervalent iodine as

oxidant. This method features mild conditions, short reaction times, high yields, and a

simple procedure for the synthesis of derivatives.105

Cui et al106 have reported a mild and efficient one pot process for the synthesis of

2-substituted benzimidazole from 1,2-phenylenediamines and triacyloxyborane

intermediates generated in situ from carboxylic acids and borane-THF.

Another procedure for the synthesis of 1,2-disubstituted benzimidazole was

reported by Yu et al utilizing Cu as catalyst. The benzimidazoles were derived from

imidoyl chlorides.107


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She et al have reported an efficienet and general cascade reaction of o-

aminoanilines with terminal alkynes and p-tolylsulfonyl azide – a one pot synthesis

resulting in the formation of benzimidazoles in good yields. 108

A NaH-mediated reaction of carbonitriles and N-methyl-1,2-phenylenediamine

was undertaken for the formation of N-methylbenzimidazole by Sluiter et al.109

A straightforward, efficient, and sustainable method for intramolecular N-

arylation provides a library of benzimidazoles in high yields using Cu2O as the catalyst,

DMEDA as the ligand, and K2CO3 as the base was reported by Peng et al.110


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Wary and Stambuli have reported the synthesis of benzimidazoles derivatives

from common arylamino oximes in good to excellent yields depending upon the base

used in the reaction. Trimethylamine promoted the reaction as a base.111


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1.6.3 Therapeutic importance of benzimidazole derivatives

The immense pharmacological properties of benzimidazole make it most

prominent among all the nitrogen bearing heterocycles. Benzimidazole has evolved as an

important heterocyclic system due to its presence in several bioactive compounds like

antiparasitic, analgesics, anticancer, anthelmintic, antifungals, antihypertensives,

antiulcer, antiviral, antifungal, anticoagulants and anti-inflammatory agents.112-118 Many

drugs and lead compounds have resulted from the optimization of different substituents

around the benzimidazole nucleus viz. albendazole, mebendazole, thiabendazole,

omeprazole, lansoprazole, pantoprazole, enviradine etc. Benzimidazole nucleus is of

much importance as it is found as an important core in many of the bioactive

compounds.

Yadav et al119 have synthesized antihypertensive derivatives possessing

benzimidazole derivatives. These benzimidazole derivatives were found to act as potent

AT1 receptor antagonist.

Sabat et al have synthesized anti-inflammatory derivatives by substituting the

benzimidazole nucleus at position-1 resulting in the formation of 1-

(substituted)pyrimidin-2-yl)benzimidazoles.120


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Taniguchi et al have synthesized still simpler anti-inflammatory molecules

possessing benzimidazole nucleus as 2-aminobenzimidazole derivatives. The 2-

aminobenzimidazole derivative with C6H4-4-OCH3 substituent at R1 and c-hexyl at R2

was found to be more potent than the standard drug used.121

Iwahi et al122 have reported 2-(substituted pyridyl methylsulfinyl)benzimidazole

as an antibacterial agent. The derivative was found to be active against Campylobacter

pylori.

Furthermore, the above produced antibacterial lead was further modified by

Masaki et al resulting in the formation of a similar compound having antibacterial activity

similar to that of omeprazole.123


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Hu et al have developed a series of benzimidazole derivatives and found that the

derivative with ethereal linkage in benzimidazole was exhibiting antimicrobial activity

even better than penicillin.124-126

Garuti et al have reported some 2-substitued benzimidazole-N-carbamates as

potent antiviral compounds, amongst which derivative with isopropylcarboxamide

group at position-2 was found to exhibit excellent antiviral activity.127


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Fonseca et al have reported dihydroabietic acid derivatives of benzimidazole and

were found to inhibit both cella-zoster virus (VZV) and cytomegalovirus (CMV)

replication.128

Animisova et al have reported a series of 2-(heteroaryl)imidazo[1,2-

a]benzimidazoles possessing 1-methylbenzimidazol-2-yl and 5-bromo-2-thienyl at R2

with varied dialkylaminoalkyl substituents at R1. These two derivatives were found to

possess antioxidant activity.129

Neff et al have reported another series of anticancer derivatives possessing

benzimidazole nucleus. All the compounds were found to possess significant anticancer

activity.130


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Ishikawa et al have synthesized a potent and metabolically stable GK activator by

making modifications in the 2-(pyridine-2-yl)-1H-benzimidazole, the synthesized

compound demonstrated glucose lowering efficacy in a dose-dependent manner.131


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1.7 Studies on 1,3,4-oxadiazole derivatives

1.7.1 Introduction to 1,3,4-oxadiazole derivatives

1,3,4-oxadiazole is a five member heterocyclic compound containing an oxygen

atom and two nitrogen atoms. It resembles a little with the structure of furan. The two

methylene =CH of furan if replaced by –N=, it forms 1,3,4-oxadiazole. The other

known isomers of 1,3,4-oxadizoles include 1,2,3-oxadiazole, 1,2,4-oxadiazole and

1,2,5-oxadiazole. However 1,3,4-oxadiazole is widely used and more better studies by

researchers because of its many important chemical and biological properties.

1,3,4-oxadiazole bearing compounds have a broad biological activity spectrum,

which includes antibacterial, antifungal, analgesic, anti-inflammatory, antiviral,

anticancer, antihypertensive, anticonvulsant and anti-diabetic properties.132-142 A variety

of therapeutically active compounds viz. raltagravir – HIV integerase inhibitor,

furamizole – an antibacterial, nesapidil – anti-hypertensive agent and anticancer activity

are found to possess 1,3,4-oxadiazole as a core nucleus.


32


1.7.2 Synthesis of 1,3,4-oxadiazole derivatives

There are number of different methods reported for the synthesis of 1,3,4-

oxadiazoles. Patel and Patel have reported the synthesis of 5-aryl-2-amino-1,3,4-

oxadiazole compounds in good yield. The reaction was carried out in presence of CNBr

and methanol was used as a solvent for carrying out this reaction.143

Kerimov et al144 have also synthesized a novel series of 1,3,4-oxadiazole bearing

compounds by reacting cyanogen bromide with 2-(2-(4-substituted-phenyl)-1H-

benzo[d]imidazol-1-yl)acetohydrazide. The reaction medium used here was ethanol.

Katritzky et al have synthesized 5-aryl-2-amino-1,3,4-oxadiazole derivatives in

high yields by reacting arylhydrazides and di(benzotriazol-1-yl)methanimine as under.145


33


Electro-cyclization of semicarbazones to their corresponding 5-aryl-2-amino-

1,3,4-oxadizoles have been reported by Lotfi et al and Sharma et al.146, 147

Rivera et al have reported the synthesis of 1,3,4-oxadiazole in excellent yield by

using an effective oxidizing agent 1,3-dibromo-5,5-dimethylhydantion. The cyclization

reaction of acylthiosemicarbazide lead to the formation of 1,3,4-oxadiazole

derivatives.148

Dolman and co-workers have reported a new method of synthesis for the

formation of 5-aryl(alkyl)-2-amino-1,3,4-oxadiazoles from acylsemicarbazides, using

tosyl chloride.149


34


Amir and Kumar have reported a multi step synthesis procedure for the

production of 2,5-disubstituted-1,3,4-oxadiazole derivatives. The starting material used

for the synthesis of oxadiazole derivatives was anti-inflammatory drug ibuprofen.150

Sharma et al developed a simple method for the synthesis of 1,3,4-oxadiazoles

from diacylhydrazines using ZrCl4 as a catalyst. The yield obtained here is higher with

less reaction time and the catalyst used here is inexpensive.151


35


Pouliot and co-workers reported a procedure for the preparation of 1,3,4-

oxadiazoles using diethylaminodifluorosulfinium tetrafluoroborate (XtalFlour-E) as a

novel cyclodehydration agent.152

Li and Dickson have developed a convenient one-pot reaction for the synthesis

of 1.3.4-oxadiazole from carboxylic acids and hydrazides using HATU as coupling

agents and Burgess reagent as dehydrating agent.153

Guin et al have reported a procedure for the synthesis of both symmetrical and

unsymmetrical 2,5-disubstituted -1,3,4-oxadiazoles using Cu(OTf)2 as catalyst.154

Polshettiwar and Varma reported a novel one-pot solvent free synthesis of

1,3,4-oxadiazoles by condensation of benzohydrazide and triethylorthoalkanates under

microwave irradiation. The reaction was efficiently catalyzed by using Nafion ®NR50

and phosphorous pentasulfide in alumina (P4S10 / Al2O3).155


36



37


1.7.3 Therapeutic importance of 1,3,4-oxadiazole derivatives

The need for new, safer and more efficient antimicrobial agents has been fulfilled

upto a great extent with the development of 1,3,4-oxadiazole possessing antimicrobial

drugs. Researchers around the globe have reported several 1,3,4-oxadiazole derivatives

possessing different biological properties, which includes antibacterial, antifungal, anti-

malarial, antiviral, anticancer, anti-inflammatory and antitubercular activity.156-162 A

variety of drugs possessing 1,3,4-oxadiazole ring have been reported viz. raltegravir –

an antiretroviral drug used to treat HIV infection,163 furamizol is used as a nitrofuran

anti-bacterial,164 nesapidil as an antihypertensive, antimicrobial and anticancer agent.

Oliveira et al have reported antistaphylococcal activity of 1,3,4-oxadiazolines

against the strain S.aureus. All the derivatives were showing better activity than the

standard chloramphenicol by 2-8 folds.165

Sahin et al have synthesized a new series of derivatives of 5-(1-/2-

napthyloxymethyl)-1,3,4-oxadiazol-2-(3H)-thione and 5-(1-/2-napthyloxymethyl)-

1,3,4-oxadiazol-2-amino. These derivatives, when evaluated for antimicrobial

properties were found to possess excellent microbial activity against S. aureus, P.

aeruginosa, C. albicans etc.166


38


2,5-disubstitued 1,3,4-oxadiazole compounds synthesized by Fuloria and co-

workers; when evaluated against a broad spectrum of bacterial and fungal strains were

found to exhibit excellent antimicrobial properties.167

Kashaw et al have synthesized a new series of oxadiazole derivatives possessing

quinazoline nucleus exhibiting excellent anticonvulsant property.168

A few more derivatives possessing 1,3,4-oxadiazole nucleus and exhibiting

anticonvulsant activity were synthesized by Rajak and co-workers. Most of the

derivatives showed positive results in a three model test MES, scPTZ and scSTY.169


39


Burbuliene and co-workers have investigated for the anti-inflammatory activity

of synthesized derivatives having 1,3,4-oxadiazole core. The results obtained for the

designed compounds were found to be more potent than ibuprofen.170

Gilani and co-workers have synthesized compound possessing 1,3,4-oxadiazole

ring bearing 2,4-dichlorophenyl group at position-2 on the oxadiazole ring. The

maximal analgesic activity showed by the synthesized compounds was almost equivalent

to that of ibuprofen.171


40


Savariz et al have synthesized and evaluated the in vitro antitumor activity of

novel 1,3,4-oxadiazole based mannich bases.172

Ouyang and co-workers173 as well as Tuma and co-workers174 have synthesized

and evaluated various 1,3,4-oxadiazole derivatives as to their ability to inhibit tubulin

polymerization and block the mitotic division of tumor cells173.

Wang and co-workers have synthesized a series of raltegravir derivatives by

modifying the 5-hydroxyl group of the pyrimidine ring and were evaluated for their


41


anti-HIV activity. This modification in raltegravir derivatives significantly increased their

anti-HIV activity to a great extent.175

Bankar et al176 have synthesized a compound exhibiting vasroelaxant effect in rat

aortic rings by blocking L-type calcium channels. The compound 4-(3-acetyl-5-

(pyridine-3-yl)-2,3-dihydro-1,3,4-oxadiazole -2-yl)phenylacetate synthesized by Banker

and his co-workers exhibited excellent anti-hypertensive activity.


42


1.8 Studies on chalcone derivatives

1.8.1 Introduction to chalcones

Chalcones are the compounds with a conjugated π system represented as -C=C-

C=O, where aromatic or aliphatic substituent are introduced at terminal position of this

system. Chalcones are characterized by their position on a R-CO-CH=CH-R‘ system,

in which two aromatic rings/aliphatic chains (R and R‘) are linked by an aliphatic three

carbon chain system. The alternative names given to chalcone include phenyl styryl

ketone, benzalacetophenone, β-phenylacrylophenone, α-phenyl-β-benzoylethylene.

Chalcones or 1,3-diaryl-2-propen-1-ones, belong to flavanoid family and chemically

they consist of open-chain flavanoids in which two aromatic rings are joined by a three

α, β-unsaturated carbonyl system. Chalcones are in general, colored compounds

because of the presence of the auxochrome.

The chemistry of chalcones has generated great interest among the researchers

around the world. Along with the chemistry of chalcones, the biological and industrial

applications of chalcones have generated intensive scientific studies throughout the

world. Chalcones can be synthesized in laboratory by Claisen-Schmidt condensation of

various substituted acetophenones with aldehydes.

The first condensation was reported by Kostanecki,177,178 who gave the linkage,

the name ―Chalcones‖. The important feature of chalcones is that they serve as starting

materials for the formation of various heterocyclic compounds viz. pyrimidines,


43


pyrazolines, flavones, flavanols, flavones etc.179 Chalcones are also found to exhibit

excellent biological activities.180 The above facts and the potent biological properties

possessed by chalcones make them desired synthetic targets for medicinal purpose.


44


1.8.2 Synthesis of Chalcones

A variety of methods are available for the synthesis of chalcones,181,182 and most

convenient is the one that involves the Claisen-Schmidt condensation reaction utilizing

substituted acetophenones with varied aldehydes in presence of an aqueous alkaline

solution. Cannizaro reaction also takes place and formation of chalcones occurs with

appropriate amount of yield.183 Several methods adopted by researchers are reported as

under.

Russell and Todd reported a simple procedure for the synthesis of chalcones

from ketones by condensation with aldehydes in presence of dry hydrochloric acid gas.

The dry HCl gas has been used as a condensing agent in a suitable solvent like dry ethyl

acetate at O°C.184

Kruoda and Matsukama have reported a procedure for the synthesis of chalcones

by condensing acetophenones obtained from anisole and other polymethoxy benzene

with various mehoxy aldehydes in presence of anhydrous AlCl3.185

Bhat et al186 have synthesized a series of chalcones and their corresponding

pyrazole derivatives using KOH/EtOH and hydrazine hydrate respectively. The

resulting chalcones were found to possess E-geometry.


45


Climent et al187 have reported a novel method for the synthesis of chalcones

using Zeolites as a catalyst. Zeolite based catalyst were used for the Claisen-Schmidt

condensation of acetophenones and benzaldehydes.

Pore and co-workers have invented a novel efficient synthesis process for the

preparation of chalcones at room temperature, utilizing potassium phosphate (K3PO4) as

a catalyst.188

Narender and Reddy have reported a simple and highly efficient method for the

synthesis of chalcones by using borontrifluoride-etherate. The products were obtained

in excellent yields and purity.189

Smith and Paulson have developed and reported a method for the synthesis of

chalcones by reacting hydroxy and methoxy aldehydes with ketones.190


46


Paradis and Lyle191 have adopted an acid catalyzed condensation for the synthesis

of chalcones. The acid catalyzed condensation was carried out by using methanolic

hydrogen chloride solution. The products were obtained in excellent yields.

An improved synthesis method was carried out by Mazza and Guarna in 1980.

Phosphorous oxychloride was used for the synthesis of 1,3-diphenyl-2-buten-1-ones (β-

methylchalcones).192 Another novel method for the synthesis of chalcones was adopted

by Trivedi and co-workers.193


47


Calloway and green have reported a process where β-unsaturated ketone

formation occurred as a side reaction in friedel-crafts acylation. The reaction was carried

out in presence of metallic halides (catalyst).194

Iranpoor and Kazemi have reported a procedure describing the aldol

condensations of aldehydes and ketones.195 The duo has conducted the reaction under

solvent free conditions in presence of anhydrous RuCl3 (aldol condensation catalyst). It

was also kept in mind while performing the reaction that the self condensation of

reactants should not occur. The yield for most of the derivatives was obtained in high

amount.195


48


Jadhav and Kulkarni have reported a procedure for the synthesis of chalcones by

condensing substituted aldehydes and various acetophenones in presence of aqueous

solution of borax.196


49


1.8.3 Therapeutic importance of chalcones

The chalcones are found to be of great pharmaceutical interest due to their wide

applicability as antimicrobial, antitumor, anti-malarial, antibacterial, antifungal,

antituberculars and antiviral agents.197-206 Chikhalia and co-workers have synthesized

novel quinolyl chalcones possessing antibacterial properties.207

A series of chalcone derivatives were synthesized by Baviskar et al and were

studied for their antimicrobial properties.208

Dawane and his co-workers209 have synthesized new 1,3-diaryl-2-propene-1-

ones (chalcones) and were evaluated for their antibacterial and antifungal activities. The

activity obtained in the study exhibited excellent results. PEG-400 was used as a

recyclable solvent in this procedure.


50


Vyas et al have synthesized chalcones namely (2E)-3-(3,5,-dibromo-4-

methoxyphenyl)1-arylprop-2-en-1-one and were found to exhibit excellent anti-

tubercular property. These derivatives were also found to possess antimicrobial

properties.210

Another series of chalcones synthesized using methanolic KOH solution by Yar

et al were also found to report excellent antimycobacterial activity.211

Jadhav and Ramaa have prepared a series of fluorinated chalcones using Claisen-

Schmidt condensation reaction process. The compounds synthesized were screened for

their anti-inflammatory activity.212


51


Cheng et al have introduced Claisen-Schmidt condensation method for the

synthesis of novel chalcones, 2,5-dialkoxychalcones. The resultant chalcone derivatives

were screened for their cytotoxicity, anti-inflammatory and anti-oxidant activity.213

Modzelewska et al214 have synthesized novel chalcones and bis-chalcones

containing boronic acid moieties and were evaluated for their antitumor activity against

the human breast cancer MDA-MB-231 and MCF-7 cell lines. The chalcones as well as

bis-chalcones were found to exhibit potent inhibition results against most of the cell

lines.


52


Xia and co-workers215 have synthesized a novel series of 2-amino chalcones. The

synthesized derivatives were exhibiting potent antitumor activity.

Zhao et al have synthesized trihydroxychalcones and were evaluated for their

antiplatelet activity.216


53


1.9 Spectral studies

1.9.1 Infrared spectroscopy

Infrared spectroscopy is one of the most common techniques for the

determination of functional groups in organic and inorganic compounds. IR study helps

to determine different functional groups present in the chemical compounds. Different

functional groups absorb characteristic frequencies of IR radiation at different

wavelength and are found to respond accordingly in the spectra obtained. IR

spectrometers can be used to determine samples of any types such as solid, liquid and

gas. IR spectrometry is thus an important technique for structure elucidation and

identification of compounds.

IR spectrometry more precisely gives information about the transitions between

vibration and rotational energy levels in a molecule. Absorption of radiation in IR region

results in the excitation (bond deformations) resulting in either stretching or bending.

These stretching and bending vibrations occurs at certain quantized frequencies. When

infrared light of that frequency is incident on the molecule, energy is absorbed by the

functional group and the amplitude of that vibration increases confirming its presence.

Thus an infrared spectrum is obtained when the frequency of molecular vibration

matches to the frequency of the infrared radiation absorbed.

The normal range of IR spectrum (also called middle infrared region), used by

organic chemists for structural determination of organic compounds extends from 4000

cm-1 to 667 cm-1. The position of absorption spectra is usually expressed in the terms of

wave number (cm-1) of the absorbed light. The compounds entitled here were scanned

in ATR module of Bruker-alpha-t IR spectrophotometer.

1.9.2 1H NMR spectroscopy

The phenomena of nuclear magnetic resonance was first reported independently

in 1946 by two group of physicists namely, 1) Block, Hansen and Packard at Stanford

university detected a signal from the protons of water, and 2) Prucell, Torrey and

Pound at Harvard university observed a signal from the protons of paraffin wax.


54


Nuclear Magnetic Resonance spectroscopy is one of the latest methods of

investigating the organic compounds. The shift observed as nuclear magnetic resonance

signal for a particular proton is on the basis of the electronic environment around it. The

1H NMR spectral data were conducted on Bruker Avance II 400 spectrometer (400

MHz) with TMS as an internal reference. DMSO-d6 was used as a suitable solvent.

1.9.3 Mass spectroscopy

Francis Aston, A physicist was the first to put the concept of mass spectroscopy

into practice in 1919. In 1922 he was awarded Nobel Prize. The technique was used to

determine mass of elements (isotopes) and now this technique has turned into one of the

most powerful tools in analytical chemistry.

Mass spectroscopy is used to determine the mass of known and unknown

compounds. The technique uses the interaction of electric and / or magnetic fields with

matter to determine mass of the matter under study. A very minute quantity of

compound is needed for mass spectrometric determination. Mass spectroscopy is based

upon the motion of charged particle, called an ion, in an electric and magnetic field. The

mass to charge ratio (m/z) of the ion affects this motion.


55


1.10 Introduction to microbes and antimicrobial agents

1.10.1 Microbes

Despite of useful functional activities of microorganisms for humans in

manufacture of dairy and food products, processing of certain medicines and

therapeutics and in other numerous ways, these microscopic organisms are more

familiar as causal agents of human beings. All the people around the globe have

experienced diseases caused by microbes.

It is much necessary to control the population of microbes in order to prevent

the transmission and generation of diseases, infections and contamination caused by

them. This is possible only by developing potent antimicrobial agents which can either

cease the growth of microbes or kill them.

In 1928, a German scientist C.E. Chrenberg first used the term ―bacterium‖ to

denote small microscopic organisms. These microorganisms are capable of producing

diseases in the host and are known as pathogens. There are mainly two types of bacteria:

gram-positive bacteria and gram-negative bacteria. For the evaluation of antibacterial

properties of the compounds synthesized in present study, gram-positive bacterial

strains used were S. aureus and E. faecalis while gram-negative bacterial strains were E.

coli and P.aeruginosa.

Fungi are non-photosynthetic eukaryotes growing either as colonies of single cell

or as multicellular aggregates. A small number of fungi are responsible for producing

diseases in humans as well as animals. The fungal strains used for determining the anti-

fungal properties of synthesized derivatives include C. albicans and A. niger.

1.10.2 Antimicrobial agents

A significant increase in microbial disease is observed in past few decades.

Microbial diseases are caused by bacteria, fungi, viruses etc. Henceforth a huge amount

of contribution is seen in this class of drugs in this century. Scientists are focusing greatly

on developing more potent, effective and medicinally important antibacterial and

antifungal agents. Antimicrobial agents kill bacteria or inhibit their growth, therefore

are called bactericidal or bacteriostatic. Similarly fungicidal agents are also found to


56


exist. In several instances it is necessary to combine different antimicrobial agents for

broadening the bioactivity spectrum and to minimize the development of microbial

resistance. Combination therapy has proved its value as latest therapy for antimicrobials

as sometimes bacteriostatic agents on novel combinations gives bactericidal activity.

Both sulfamethoxazole and trimethoprine are bacteriostatic, but combination of these

drugs is now widely used as bactericidal. This is termed as synergism.

1.10.3 Evaluation technique implemented for antimicrobial screening of

compounds

The conditions to be taken into consideration for the screening of antimicrobial

activity are

There should be intimate contact between the test organisms and

synthesized compounds to be evaluated.

The minimum conditions required for the growth of microorganisms

should be established and maintained.

Sterile environment should be maintained.

The different method adopted by researchers to evaluate the antimicrobial

activity includes turbidometric method, agar streak dilution method, serial dilution

method, agar diffusion method, broth dilution method etc. The method used for the

evaluation of antimicrobial activities in present study was broth dilution method. This

method yielded a quantitative result for the amount of antimicrobial agents that is

required to inhibit the growth of specific microorganisms. DMSO was used as a diluent

to get the desired concentration of drugs for evaluating their antibacterial and antifungal

potency. The values of antimicrobial properties of the synthesized derivatives were

recorded in form of Minimum Inhibitory Concentration (MIC). The standard drug used

for antibacterial and antifungal tests included ciprofloxacin and fluconazole. The highest

dilution showing at least 99% inhibition is considered as MIC.


57


1.11 Objectives of the study

Since the existence of mankind it has become an important and integral part to

find a suitable remedy for the diseases prevailing in the society. Henceforth the general

objective is to synthesize new effective bio-molecules which can be established as lead

compounds in future. The present approach undertaken by most of the chemists

includes combination of biologically active moieties into one molecule as a major

technique to discover a new drug. Literature survey revealed that molecules with

benzimidazole and 1,3,4-oxadiazole nucleus are key building blocks used to develop

compounds with medicinal interests. Along with the designing and development of

molecules with above mentioned heterocyclic rings, inclusion of electronegative

fluorine atom and its various substituent (-CF3 and -OCHF2) on the benzimidazole and

1,3,4-oxadiazole rings has also been studied. The vast applications of chalcones

compelled us to synthesize several chalcone derivatives. Thus the objectives of present

study include:

1. To design newer heterocyclic derivatives by evaluating the molecules

using Lipinski‘s rule of five – first stage of QSAR.

2. To synthesize novel derivatives possessing different heterocyclic rings

(benzimidazole and 1,3,4-oxadiazole) by undertaking various types of

chemical reactions.

3. To characterize the synthesized derivatives by various spectral-analytical

techniques like 1H NMR, IR, Mass and elemental analysis.

4. To screen the synthesized derivatives for their antimicrobial properties

against a broad spectrum of bacterial and fungal strains.

5. To undertake SAR study, in order to prove the presence of a particular

functional group as a responsible factor for the exhibition of higher

biological activity as antibacterial or antifungal agents.


58


1.12 Significance of the study

The study will produce novel heterocyclic derivatives exhibiting excellent to

good antibacterial and antifungal properties. The compounds with excellent

antimicrobial activity can be further optimized to gain some better leads. The SAR study

will help to conclude the correlation between the nature of substitution (i.e. electron-

withdrawing or electron-donating functional groups) and the biological activity results

related to it. Overall the entitled study will help in generating promising antimicrobial

heterocyclic motifs.


59


1.13 Work plan

1.13.1 Chapter-2 Studies on fluorine based 1,3,4-oxadiazoles

(Under review with Journal of Chemical Sciences – Springer JCSC-D-13-00442)

General nomenclature for compounds 5a-j

2-(5-aryl-1,3,4-oxadiazol-2-ylthio)-N-(3-(trifluoromethyl)phenyl)acetamide

General nomenclature for compounds 5k-t

N-(4-chloro-3-fluorophenyl)-2-(5-aryl-1,3,4-oxadiazol-2-ylthio)acetamide

General structure for compounds 5a-t

This chapter will deal with the synthesis of derivatives possessing fluorine based

1,3,4-oxadiazole. To prove the importance of fluorine atom here, it is kept in mind that

during the synthesis of each entity of this chapter, fluorine atom must be included along

with the oxadiazole nucleus. Two different series are synthesized comprising of 10

derivatives each possessing 1,3,4-oxadiazole ring along with –CF3 and –F substituted

phenyl nucleus. The formation of derivatives will be confirmed by spectral data.

Spectral analysis via IR and 19F NMR will be undertaken in order to confirm the

formation of derivatives. Also these data will be helpful in proving the presence of

fluorine in each compound. SAR study in this chapter will play a vital role in proving the

importance of fluorine in enhancing the biological activity of the compounds.


60


1.13.2 Chapter-3 Studies on 1,3,4-oxadiazole based chalcones

(Under minor revision with Medicinal Chemistry Research MCRE-3678)

General nomenclature for compounds V1-14

(Z)-N-(4-(3-(4-aryl)acryloyl)phenyl)-2-(5-(3-nitrophenyl)-1,3,4-oxadiazol-2-

ylthio)acetamide

General structure for compounds V1-14

The biological importance of chalcones and heterocyclic compounds depicted

from literature studies and other series of work carried out influenced to synthesize a

novel series of 14 derivatives possessing 1,3,4-oxadiazole scaffold bearing -NO2 group.

The formation of the derivatives will be confirmed by spectral data and their biological

study will be undertaken. SAR study will be carried out in order to prove the

importance of electron-donating functional group in enhancing the biological potency of

synthesized derivatives.


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1.13.3 Chapter-4 Studies on benzimidazole derivatives

Section 1 (IIIa-j): under review with Arabian Journal of Chemistry ARABJC-13-00802

Section 2 (III1-13): accepted for publication with Medicinal Chemistry Research - doi:

10.1007/s00044-013-0732-z)

General nomenclature for compounds III1-13

2-(5-methoxy-1H-benzo[d]imidazol-2-ylthio)-N-arylacetamide

General nomenclature for compounds IIIa-j

2-(5-(difluoromethoxy)-1H-benzo[d]imidazol-2-ylthio)-N-arylacetamide

General structure for compounds III1-13 and IIIa-j

In this chapter, two series will be synthesized indicating the formation of

different acetamide derivatives bearing methoxy and fluoromethoxy substituted

benzimidazole derivatives. Thirteen derivatives possessing methoxy substituted

benzimidazole and ten derivatives with fluoromethoxy substitution will be synthesized,

characterized and tested for their antimicrobial properties. SAR study if carried out here

will help to confirm the importance of electron-withdrawing substitutions present in the

derivatives as responsible agents for the excellent exhibition of antimicrobial

properties.19F NMR will be included exclusively for the confirmation of formation of

benzimidazole derivatives with fluoromethoxy substituent.


62


1.13.4 Chapter-5 Studies on benzimidazole clubbed-chalcones

(Published with Medicinal Chemistry Research (2013) Vol. 22; Issue 8; 3688-3697)

General nomenclature for compounds III1-16

(E)-2-(1H-benzo[d]imidazol-2-ylthio)-N-(aryl)phenylacetamide

General structure for compounds III1-16

This chapter will deal with the synthesis of chalcones possessing benzimidazole

derivatives. Total sixteen derivatives will be synthesized in this series and characterized

by using different spectral data. The formed entities will be tested against gram-positive

bacteria, gram-negative bacteria and fungi. The SAR study conducted here can help to

conclude that among the derivatives bearing either electron-donating or electron-

withdrawing functional group will be helpful in enhancing the biological activity.


63


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