CHAPTER-1 1.1 Introductions:

Heterocycl ic chemistry is a branch of organic chemistry. Heterocycl ic

st ructures are cycl ic organic compounds which have one or more than one

hetero atom is rep lace by carbon atom. Di f ferent hetero atoms, such as

Ni t rogen, oxygen, sul fur, s i l icone, phosphorus, selenium, and boron are

di f ferent element as a member of cycl ic organic compound wi th in a cycl ic

r ing structure. From al l known organic compounds, fi f t y percent o f them are

heterocycl ic compounds. Many of the natural products are heterocycl ic based

l ike v i tamins, amino acid, alkaloids, heme and chlorophyl l and ant ib iot ics.

Signi f icance of heterocycl ic compounds is parent moiet ies of commercial

dyes, pest ic ides and drugs industr ies. The greater parts of drugs products that

imi tate natural products wi th bio logical act iv i ty are heterocycl ic compounds.

Therefore, researchers are on a cont inuous search to design and produce

bet ter pharmaceut icals, pest ic ides and insect ic ides by fo l lowing natural

models.

Hetero subst i tuted r ings are those in which one or more carbon atoms in

a purely carbon-containing r ing (known as a carbocycl ic r ing) is replaced by

some other atom (referred to as a heteroatom). In pract ice, the most

commonly found heteroatom is ni t rogen, fo l lowed by oxygen and sul fur.

However, many other atoms can form the stable covalent bonds necessary for

r ing construct ion and can lead to structures of considerable importance in

contemporary heterocycl ic chemistry. Of note are P, As, Sb, Si , Se, Te and B.

In rare cases, even elements general l y considered to be metal l ic, such

as t in and lead, can be incorporated in r ing systems. In a 1983 report , the

Internat ional Union of Pure and Appl ied Chemistry (IUPAC) recognized 15

elements coming from Groups II to IV of the Periodic System capable of

forming cycl ic st ructures wi th carbon atoms.

The compound pyr id ine is an excel lent example of a s imple

heterocycle. Here, one carbon of benzene is replaced by ni t rogen, wi thout

interrupt ing the classic unsaturat ion and aromat ic ity o f benzene. Simi lar ly,

replacement of a carbon in cyclohexane by ni t rogen produces the saturated

heterocycle piper id ine. Between these extremes of saturat ion come several

st ructures wi th one or two double bonds. Rings may have more than one

heteroatom, which may be the sameor di f ferent . To broaden the f ie ld, other

r ings may be fused onto a parent heterocycle. This gives r ise to many new

r ing systems.

Heterocycl ic compounds are far f rom being just the resul t of some

synthet ic research effort . Nature abounds in heterocycl ic compounds many of

profound importance in bio logical processes. We f ind heterocycl ic r ings in

v i tamins, coenzymes, porphyr ins ( l ike hemoglobin), DNA, RNA, and so on.

The plant k ingdom contains thousands of n i t rogen heterocycl ic compounds,

most of which are weakly basic and cal led alkaloids (alkal i l ike). Complex

heterocycl ic compounds are elaborated by microorganisms and are useful as

ant ib iot ics in medicine. Marine animals and plants are also a source of

complex heterocycl ic compounds and are receiv ing much at tent ion in current

research efforts. We should even consider that the huge f ie ld of carbohydrate

chemistry depends on heterocycl ic f rameworks; al l disaccharides and

polysaccharides have r ings usual l y o f f ive (cal led furanose) or s ix (cal led

pyranose) members that contain an oxygen atom. Similar oxygen-containing

r ing structures also are important in monosaccharides, where they can be in

equi l ibr ium wi th r ing-opened structures, as observed in the case of D-

glucose.

A low concentrat ion of n i t rogen and sul fur heterocycles also can be

found in var ious pet roleums. Coal was for years the major source of pyr id ine-

based heterocycles, obtained by pyrolysis in the absence of oxygen

(destruct ive dist i l la t ion). An intr iguing new detect ion of heterocycles in

nature has occurred in the f ie ld o f chemistry of the solar system. Nicot in ic

acid and i ts two isomers were isolated along wi th 12 methylated and other

der ivat ives.

Heterocycl ic compounds can be synthesized in many ways. Al though

some of th is work is performed to study fundamental propert ies or establ ish

new synthet ic routes, much more is concerned wi th the pract ical aspects o f

heterocycl ic chemistry. Thus, many synthet ic (as wel l as natural ) compounds

are of extreme value as medicinals, agrochemicals, p last ics precursors, dyes,

photographic chemicals, and so on, and new structures are constant l y being

sought in research in these areas. Medicinal chemistry especial l y is

associated int imately wi th heterocycl ic compounds, and most of al l known

chemicals used in medicine are based on heterocycl ic f rameworks. We shal l

observe many of the prominent b io logical ly act ive heterocycl ic compounds as

proceeds to develop the f ie ld of heterocycl ic chemistry.

Heterocycl ic chemistry somehow di f ferent f rom the much more fami l iar

al iphat ic and aromat ic chemistry studied in basic organic chemistry courses.

Certain ly, many react ions used to close r ings and to modi fy r ing subst i tuents

are common to these f ie lds, and as they are encountered, however, some

react ions can be found only in heterocycl ic chemistry. An excel lent example

is the cycloaddi t ion of 1,3-dipolar compounds wi th unsaturated groups, as in

the example that fo l lows, which has no counterpart in purely carbon

chemistry.

Heterocycl ic compounds play a key role in bio logical processes of

l iv ing cel l . The most common hetero atoms are ni t rogen, sul fur and oxygen.

Ni t rogen containing heterocycl ic compounds natural ly or synthet ical l y is

involved in a bio logical process. Many of the synthet ical heterocycles used as

pharmaceut ical drugs such as ant imicrobial ant icancer, ant i fungal etc. DNA

and RNA based structure is n i t rogen containing heterocycles.

The heterocycl ic compounds general ly have a stable r ing structure

which doesn’t readi ly hydrolyzed. Heterocycles containing one hetero atom is

stable structure. Those wi th two heteroatoms are more react ive than others.

Those wi th t ree atoms are more and more react ive because of r ing strain.

Heterocycl ic compounds that contain more than one of the react ive groups

di f ferent ial l y protected s igni fy a good source of out l ine for a l ibrary

product ion in a f ie ld of research. Heterocycles behave binary nature l ike an

acid or base they also depends pH of the medium, forming charge ions. Some

amphoter ic heterocycles they also easi ly ox id ized and hydrogenated. Al l of

the above ment ioned propert ies heterocycles are able to obtain wide range or

react ion types.

The studies of heterocycl ic compounds are interest ing, theoret ical as

wel l as pract ical point of v iew. Heterocycl ic compounds occur widely in

nature. A huge numbers of heterocycl ic compounds are essent ial for l i fe.

There are a large number of synthet ic heterocycl ic compounds appl icat ions

and many are valuable intermediates in synthesis.

The ni t rogen heterocycles whether natural or synthet ic one owing to

their interest ing b io logical propert ies is very o f ten involved as key

components in bio logical processes. Many synthet ic n i t rogen heterocycles

have wide spread uses as ant iv i ral , ant ibacter ial , ant i fungal , ant i

inf lammatory, ant iox idants, ant icancer, analgesics, ant iconvulsants etc.

agents. In nature too, especial l y in p lant k ingdom the ni t rogen heterocycl ic

compound have made indel ib le mark as insect ic ides, pest ic ides, weed ki l lers

rodent ic ides, etc. Certain ni t rogen heterocycles are used as ant i AIDS agents

and has been found to be a potent inhibi tor of HIV reverse t ranscr ipt ion and

has been l icensed in several count r ies for the t reatment of AIDS pat ient and

also as v i rucides which inhibi ted HIV in human lymphocytes.

The mul t i faceted propert ies and capt ivat ing structures of N-

heterocycl ic compounds encourage chemists to keep on synthesiz ing new and

novel n i t rogen heterocycles wi th versat i le b io logical act iv i t ies. The subject

matter of the thesis deals wi th N-heterocycl ic compounds containing pyrroles,

pyr imidine and the fused der ivates of pyrrole and pyr imidine, the group of

compounds.

Pyrazole is the s igni f icant member of the azole fami ly in which the

di rect l ink ing of the two hetero atoms has a very marked effect upon i ts

basici ty. Pyrazole der ivat ives are rarely produced in nature, probably due to

the di f f icul ty in construct ing N-N bond by l iv ing organisms. In 1884 Knorr

d iscovered the ant ipyret ic act ion of a pyrazole derivat ive in human beings

which actual l y in i t iated major interest in the study of these heterocycles. A

large number o f pharmaceut ical and dyestuff containing th is r ing system have

been synthesized in laboratory. The th iophene and related heterocycles are

found in coal tar and crude petroleum. The most important natural ly

occurr ing der ivat ive such as B-complex v i tamin which is an essent ial growth

factor for animals and human beings.

Tr iazole, a heterocycl ic nucleus has at t racted a wide at tent ion of the

medicinal chemist in search for the new therapeut ic molecules. Now a day’s

research is concent rated towards the int roduct ion of new and safe therapeut ic

potent agents of b io logical importance. The ni t rogen containing heterocycles

are found in abundance in most of the medicinal compounds. The synthesis of

h igh ni t rogen conta ining heterocycl ic systems has been at t ract ing increasing

interest over the past decade. Tr iazoles are wel l known f ive membered

heterocycl ic compounds belong to one of the most widely used class of

ant i fungal drugs known as azoles. Several procedures for their synthesis have

been extensively studied.

Pyrazol ines are f ive member heterocycl ic compounds and show var ious

type of pharmacological act iv i t ies. In the f ie ld o f therapeut ic chemistry

pyrazol ine base moiet ies are important because of their versat i le b io logical

act ions. During the last few decades, b io logical act iv i t ies, synthesis and

t ransformat ions of f ive membered heterocycl ic compounds have received

considerable at tent ion and importance due to their remarkable and wide range

of appl icat ions. Due to their extraordinary unique propert ies and have been

often employed in drug synthesis.

Pyr imidine is a heterocycl ic aromat ic organic compound simi lar to

benzene and pyr id ine, containing two ni t rogen atoms of the s ix-member r ing.

I t is isomeric wi th two other forms. A pyr imidine has many propert ies in

common wi th pyr id ine, as the number o f n i t rogen atoms in the r ing increases

the r ing electrons become less energet ic and electrophi l ic aromat ic

subst i tut ion gets more di f f icul t whi le nucleophi l ic aromat ic subst i tut ion gets

easier. Pyr imidines can also be prepared wi th in the laboratory by organic

synthesis.

Pyr imidines are a lso less basic: The pKa value for protonated

pyr imidine is 1.23 compared to 5.30 for pyr id ine. Pyr imidine synthesis

inhibi tors are used in act ive moderate to severe rheumatoid arthr i t is and

psor iat ic arthr i t is . Examples include Lef lunomide. such as ant ibacter ial ,

ant iv i ral , ant ihypertensive, and ant i tumor ef fects and they are ef fect ive as

calcium channel b locker. The der ivat ives of pyr imidine plays v i tal ro le in

many biological processes and are present in nucleic acid, several v i tamins,

co-enzymes, ur ic ac id and in other pur ines nucleic acid. Being an important

component of l iv ing matter which is basical ly a polymeric chain, consists of

al ternat ing residual of phosphoric acid and sugar. Pyr imidines and Purines

are bound at the sugar moiet ies and i t is also wel l known that the structural

var iety o f l i fe and the diverse funct ion of l i fe are related to these basis

sequences and also on the k ind of basis i .e. on i ts basic const i tuents:

pyr imidines and pur ines. In addi t ion, the synthet ic members, containing these

der ivat ives are also important as synthet ic drugs.

A heterocycl ic compound is one which possesses a cyc l ic st ructure in

which al l the atoms other than carbon are considered as hetero atoms in the

r ing. Ni t rogen, Oxygen, and Sulphur are the most common hetero atoms, but

many other elements , including even bromine can also serve.

Several heterocycl ic compounds play a s igni f icant ro le in maintain ing

l i fe such as, b lood const i tuent haemoglobin and purines as wel l as

pyr imidines, the const i tuents of nucleic acid (DNA and RNA) are also

heterocycl ic compounds. Several amino acids, carbohydrates, v i tamins,

alkaloids, etc. are also heterocycl ic compounds that are essent ial for l i fe.

Heterocycl ic compounds also f ind several other applicat ions in the

plast ic industry, copolymer, in dye industry, vulcanizat ion acceletors in the

rubber industry, in photography as sens i t izers and developers. The synthesis

of heterocycl ic compounds using t ransi t ion metals and they are used as

intermideates in the synthesis of var ious organic compounds.

Many heterocycl ic compounds are biosynthesized by plants and animals

are bio logical l y act ive. Over mi l l ions of years these organisms have been

under intense evoluat ionary pressure, and their metabol i tes may be used for

advantages; for example; as tox ins to ward off predators, or as colour ing

agents to at t ract mates and pol l inat ing insects.

The biological propert ies of heterocycles in general make them one of

the pr ime interests of the pharmaceut ical and biotechnology industr ies.

However, the large numbers of heterocycl ic compounds, obtainable only by

laboratory syntheses, have valuable propert ies as chemotherapeut ic agents,

drugs, etc.

� Medicinal Chemistry:

Medicinal chemistry especial ly is associated int imately wi th

heterocycl ic compounds, and most of al l known chemicals used in medicine

are based on heterocycl ic f rameworks. Object ive of Medicinal chemistry is to

enhance the bio logical ef fect o f a new compound and to remove unwanted

s ide effects and have a benef ic ial ef fect on a disease. In cont inuat ion of

research stretchy, the medicinal chemist must ascertain SAR of newly design

and synthesize molecules and determine their absorpt ion and dist r ibut ion

throughout the body, and evaluate their metabol ic transformat ions.

� Medicinal chemistry covers the following stages:

I . In the f i rst stage new act ive substances or drugs are ident i f ied and

prepared from natural sources, organic chemical react ions or

b iotechnological processes. They are known as lead molecules.

I I . The second stage is opt imizat ion of lead structure to improve potency,

select iv i ty and to reduce tox ic i ty.

I I I . Third stage is development stage, which involves pharmacokinet ic and

pharmaceut ical propert ies of act ive substance to render i t c l in ical l y

useful .

The development o f new synthet ic drug compounds wi th many

other discip l ines as fo l lows.

[Modern Medicinal Chemistry]

The drugs are converted into pharmacological l y active metabol i te by

biotransformat ion. These metabol i tes are highly active. This act iv i ty

contr ibutes to pharmacological ef fect ascr ibed to parent drugs. In some cases

inact ive parent drug gets converted to bio logical l y act ive metabol i te. Since

al l the metabol i tes are non-tox ic, many tox ic s ide effects l ike t issue necrosis,

carcinogeneci ty are observed. The format ion of water-soluble metabol i te

enhances el iminat ion and pharmacological ly inact ive, non-tox ic and polar

compound format ion. Most of the drugs undergo metabol ic t ransformat ion in

the body. The main s i te of metabol ism is l iver.

� Pharmacophore

The physiological act iv i ty of drugs has been found to depend upon the

presence of part icular funct ional groups or st ructural uni ts. Such a part of the

drug, which causes the actual physiological ef fect , is known as

pharmacophore.

When a pharmacophore is int roduced into bio logical inact ive

compound, th is makes the compound biological l y act ive many t imes. Thus, i t

is possible to make the compounds biological l y act ive but less tox ic by

introducing var ious pharmacophores. Some examples of pharmacophores are

alkyl , hydroxy, alkoxy, aldehyde or ketone, acidic, n i t ro, n i t r i le, ef fect of

unsaturat ion, ef fect of isomerism, halogens and unsaturated l ip ids.

The fo l lowing gives a short account of physiological ef fect exerted by a

given compound due to the presence of a certain funct ional group.

� Effect of alkyl group

Whenever an alkyl group subst i tutes act ive hydrogen of drug, fo l lowing

observat ions are to be noted:

(a) In some compound the bio logical act iv i ty is decreased on alkylat ion i .e.

the bio logical act iv i ty of the alkylated-compound is decreased to that

of the non -alkylated. e.g. NH3> CH3NH2 > (C2H5)N (convuls ive

propert ies)

(b) In some compounds, the tox ic i ty is increased on alkylat ion.

e.g. NH3 < CH3NH2 < (C2H5) N; R – OH < R – O – R (tox ic i ty)

(c) In some compounds, the alkylat ion of a carboxyl, hydroxyl and amino

group cause the fu l l appearance of certain marked propert ies, e.g.

ant ipyr ine is a strong ant ipyret ic whi le i ts analogue having one methyl

group is inert .

NNH

CH3

O

PhN

N

CH3

O

Ph

CH3

Phenyl-methyl-pyrazolone Ant ipyr ine

( Inert ) (Act ive)

The s ize of alkyl group also shows marked effect on the

pharmacological act iv i ty, e.g. the ethyl group has more marked inf luence as

compared to that o f methyl group. Dulcine having an ethyl group is about 200

t imes as sweet as i ts methyl analogue, which is tasteless.

OC2H5

NH NH2

O

OCH3

NH NH2

O

(Sweet) (Tets less)

Dulcine

� Effect of hydroxyl group

Weakening the phys iological act iv i ty has been found to the number of

hydroxyl groups int roduced into the al iphat ic compound, e.g. n-propanal is

more act ive than glycerol .

Somet imes the presence of a hydroxyl group makes the compound to

lose i ts part icular physiological act iv i ty. For example, hydroxycaf feine has

none of the physiological act iv i ty present in caffeine.

The issomeric alcohols having the same number of carbon atoms show a

drop of act iv i ty f rom the pr imary to secondary to tert iary. For example, the

co-ef f ic ient of 1-propanol against Staphylococcus aures is 0.082 as compared

to that of 0.054 for 2-propanol .

The physiological act iv i ty is general ly decreased by ether i f icat ion,

ester i f icat ion and the condi t ions unfavorable to ester hydro lysis. It has been

proved beyond doubt that the hydroxyl group i tsel f , in such compounds, does

not have physiological act ion of i ts own but i t s imply anchors the molecule

on a react ive posi t ion of cel l chemical .

In some aromat ic compound, the introduct ion of a hydroxyl group

increases the physiological act iv i ty of the compound. This is completely

reverse to that in the al iphat ic compounds. For example, phenol is more tox ic

and a strong ant isept ic than benzene; sal icyl icacid is not only a stronger

ant i fungal agent but is also an.ant i -rheumat ic agent, a property missing in the

inert parent compound, the benzoic acid. Introduct ion of more hydroxyl

groups in aromat ic nucleus increases the tox ic i ty. For example, resorcinol

and pyrogal lo l are more tox ic than phenol .

� Effect of aldehyde and ketone groups

Aldehydes are more react ive than ketones and thus also exhibi t a more

intense biological act iv i ty. Formaldehyde, the s implest aldehyde, has a strong

ant isept ic property and a hardening effect on the tissues, a property for which

tax idermist uses i t . The higher members have the combined property o f the

aldehydic and alkyl groups. The introduct ion of hydroxyl groups in the

molecule decreases the physiological act iv i ty of compound, which may even

cause the compound to be medicinal ly inert , v iz . glucose. However, on the

whole the physiological ef fect produced by aldehydes cannot be general ized.

In general , the pharmacological propert ies of ketones have been found

to be s imi lar to that of the corresponding secondary alcohols, i .e. , ketones, in

general , possess narcot ic act ion. In al iphat ic ketones, due to presence of alkyl

groups, the hypnot ic act ion is fai r l y wel l marked but the mixed ketone,

acetophenone is a strong hypnot ic (used under the name hypnone). a, b -

unsaturated ketones are found to possess diuret ic act iv i ty.

� Effect of acidic groups

The introduct ion of an acidic group such as –SO3H or –COOH in

molecule ei ther decreases or completely destroys the physiological act iv i ty of

the parent compound. For example, phenol is poisonous but benzene

sulphonic acid is harmless. From this i t may appear that th is is because of the

disappearance of OH group. However, the introduct ion of acid ic groups

wi thout al ter ing the act ive or anchoring group also makes compound less

tox ic, e.g. n i t robenzene is poisonous but n i t ro benzoic acids are harmless,

ani l ine is toxic but m-amino benzoic ac id is harmless.

However, the physiological propert ies of the compounds, which have

disappeared due to the introduct ion of acid ic groups, can be restored by

ester i f icat ion. For example, tyrosine, a phenol ic amino acid, is harmless

whi le i ts ethyl ester is poisonous. Simi lar ly p-amino benzoic acid has no

anesthet ic property but i ts esters are used as local anesthet ics.

The acylat ion of basic compounds by means of organic acids reduces

the basici ty and physiological act ion of the compounds.

The benzoylat ion has been found benef ic ial to the increase

physiological act iv i ty of the var ious compounds.

� Effect of halogens

The introduct ion of negat ive halogens, i .e. , when the halogen is present

in non-conjugated posi t ions, has been found to increase the useful as wel l as

the toxic propert ies but at d i f ferent rates. However, the halogenat ion

increases the tox ic i ty only to a l imi ted extent but increases the useful

propert ies appreciab ly Hence halogenat ion is used for increasing act iv i ty and

widening the margin of safety in the given ser ies.

On the other hand, the introduct ion of posi t ive halogens as in acid

hal ide, a-halogen carbonyl compounds decreases the tox ic i ty of the

compounds. Compounds having avai lab le halogens, such as chloramines are

strongly ant isept ic, depending upon the percentage of hypohalous acid

l iberated on hydrolysis.

Among halogens Cl , Br and I, hypnot ic propert ies general ly decrease

wi th increase in atomic weight but the ant isept ic propert ies increase. It is to

be noted that f luor ine compounds are comparat ively much less

physiological l y act ive than the corresponding other halogens. The less

act iv i ty of f luor inated compounds may be due to their stabi l i ty.

� Effect of nitro and nitri te group

The introduct ion of n i t ro aromat ic compounds increases their tox ic i ty.

For example, n i t ro benzene, n i t ro naphthol and ni t ro th iophene have been

found to be more tox ic than the parent hydrocarbons. However, i f a more

ox idisable group such as –CH3 or –CHO group is int roduced, then the

tox ic i ty decreases. For example, p-ni t rotoluene is less po isonous then the

ni t ro benzene and also ni t ro aldehydes are somewhat l i t t le poisonous.

Ni t r i te group, which is isomeric wi th ni t ro group, d i f fers in their

act ion. For example, al iphat ic n i t r i tes have di lat ing ef fect on blood vessels

whereas ni t ro compounds o have no act ion.

� Effect of amino group

In general , the amino group is tox ic. Successive alkylat ion of the amino

group decreases tox ic i ty. In general , the acylat ion of amino group decreases

physiological act iv i ty, e.g. , ani l ine is tox ic whi le acetani l ide is used as

afebr i fuge.

Sulphonat ion and carboxylat ion decrease the physiological ef fect of the

amino compounds, e.g. , ani l ine is poisonous whi le p-amino benzoic acid

(PABA) is actual ly a v i tamin of B group. Second amino group increases the

tox ic i ty of the compound. For example, al l the three phenylenediamines are

more poisonous than ani l ine. It is to be remembered that aromat ic amines and

hydrazines are used as ant ipyret ics and analgesics.

1. Effect of nitri te (-CN) group:

The parent compound of n i t r i le group is HCN, which is wel l -known

strong poison. The introduct ion of n i t r i le group may give r ise to two ser ies of

compounds, the ni t r i les RCN and isoni t r i les RNC. Both are poisonous.

2. Effect of unsaturation

In general , the unsaturated compounds found to be more tox ic than

their corresponding saturated compounds. For example, 1 - propanol has mi ld

narcot ic property but is non-poisonous whi le al lyl a lcohol has strong. It is to

be noted that the tox ic i ty of a compound increases wi th unsaturat ion.

� Effect of i somerism

(a) Structural isomerism

Structural isomers of ten show marked di f ferences in their

physiological . This can be seen in ortho, meta and para der ivat ives in the

aromat ic ser ies For example, o-hydroxy benzoic acid is phys iological l y act ive

whi le both p- and m- isomers are inact ive. Simi lar ly, i t can be explained that

ordinary Cocaine is a local anesthet ic whi le a-cocaine does not have th is

property p-Amino benzene sulphonic acid is an act ive drug whereas i ts two

other isomers are inact ive.

(b) Stereoisomerism

Both geometr ical and opt ical isomers show di f ferent phys ioloaical -

act iv i ty, e.g. maleic acid is poisonous whi le fumaric acid is harmless. (–) -

Adrenal ine is about 12 t imes as act ive as the (+) - form. Simi lar ly, (–) -

n icot ine is twice as act ive as (+) - form.

� Quantitative Structure - Activi ty Relat ionships (QSAR)

Why QSAR is necessary?

1. Predict ion of b io logical act iv i ty.

2. Understand mechanism of act ion.

3. Classi f icat ion of compounds.

4. Opt imizat ion of b io logical act iv i ty.

5. Lead search.

6. Reduct ion of use of animal .

7. Minimize random synthesis.

8. Economize new drug development.

� A small molecule drug design process

The underlying process of creat ing or d iscovering the new chemical

ent i t ies (NCE's), which develop into drugs is h ighly innovat ive and is

precisely drug design and broadly referred as drug discovery process. It

involves two dist inct inter l inked step of ident i f icat ion and opt imizat ion of the

lead structure. Among di f ferent approaches to drug design, the one based on I

the ident i f icat ion. of substructures (pharmacophores) and their annealat ion or

incorporat ion on to carr ier systems, or bui ld ing of act ive molecules into

conformat ional l y r igid structures, fo l lowed by opt imizat ion of the act iv i ty by

structure-act iv i ty analysis has not only resul ted in the discovery of new drugs

and lead structures but also added to the knowledge about the contours o f

receptors and the s i tes important for interact ion-wi th the drugs.

� Drug binding

Extensive drug binding in the body occurs in the blood. Blood contains

6.5% of protein o f which 50% is albumin. It is mainly involved in drug

binding. I ts molecular weight is 69000 and i t has net negat ive charge at b lood

PH 7.4. I t can interact wi th anions and cat ions also. The drug-protein binding

may be due to ion- ion interact ions, hydrogen bonding, hydrophobic and

Vander Waal 's forces. This protein drug binding is usual ly reversib le

react ion.

The drug binding resembles sal t format ion. This protein binding acts as

a t ransport system for the drug. which whi le bound is b indered in i ts access

to the s i te of metabol ic act ion and excret ion.

� Pro-drug

A bio logical l y act ive drug, which by la ternt i tat ion is converted into an

inact ive carr ier form, is cal led a pro-drug. Pro-drug on react ing enzyme or

nonenzyme compound, releases the act ive compound (drug). Latent iat ion of

drug produces: Prolongat ion of act ion, shortening of act ion, drug

local izat ion, t ransport regulat ion, adjuncts so pharmaceut ical formulat ion,

lessening of tox ic i ty and s ide effects.

� Chemotherapy

The t reatment of infect ious disease by using a chemical agent is cal led

chemotherapy. The substance so employed is referred to as chemotherapeut ic

agent. These agents are designed in such a way that they k i l l or destroy the

disease-producing organisms wi thout any harmful ef fect on the cel ls in which

organisms are preset .

Paul Ehrl ich (1845-1915) cal led ‘Father of Chemistry’ . He gave

or iginal ideas about the modules of act ion of drugs. Accord ing to him, there

are some cel lu lar const i tuents in mammal ian cel ls , which were ear l ier cal led

receptors by Langely (1878).

� Chemotherapeutic drugs

According to Ehrl ich chemotherapeut ic agents are chemical substances

wi th high parasi totropism and low or no organotropism. In other words, they

are select ively toxic , being harmful to as much as possible to the invading

organism but innocuous to the host .

Chemotherapeut ic agents are drugs used in the t reatment of infect ious

diseases. These diseases are caused by certain species of metazoa, protozoa,

fungi , bacter ia, r icket ts ia and vi rus. Drugs act ive on these pathogenic agents

div ided into the fo l lowing type according to their therapeut ic act iv i ty.

Anthelmint ic Agents, Ant imalar ial Agents, Ant iprotozoal Agents, Ant i fungal

Agents, Ant ibacter ial Agents, Ant isept ic Agents, Ant i tuberculosis and

Ant i lepral Agent, Ant ib iot ics, Ant ineoplast ic Agents, Ant iv i ral Agents.

� Pharmacodynamic agents

The drugs, which depress or st imulate var ious funct ions of body rel ie f

f rom symptoms of d iscomfort , are known as pharmacodynamic agents.

Al though these agents have a character is t ic ef fect on the animal , they have no

speci f ic remedies for part icular d iseases. Examples of pharmacodynamic

agents are analgesics, sedat ives, anaesthet ics, antih istamines, etc.

Some di f ferences may be pointed out between chemotherapeut ic agents

and pharmacodynamic agents; among them are the fo l lowing:

1. Chemotherapeut ic agents f ind use in the t reatment and cure of

infect ious disease; pharmacodynamic agents are used for rel ief and

correct ion of abnormal funct ions.

2. Chemotherapeut ic agents usual ly exert an i r reversib le act ion, by

at taching strongly, somet imes through a covalent bond, to special

moiet ies of macromolecules of invading organism; pharmacodynamic

agents should preferably produce reversib le resul ts, by forming weak

bonds wi th pharmacological receptors.

3. In chemotherapeut ic agents the al l - or-nothing effect has been

unobject ionable, whereas pharmacodynamic agents are expected to give

a graded response, according to the doses administered.

4. Potent ial chemotherapeut ic agents are of ten easil y screened, because in

many cases i t is very s imple to isolate the invading organism and study

i t separately; pharmacodynamic agents have been found to be more

di f f icul t to test , because i t is not possible to yet to isolate receptor

molecules.

Some therapeut ic agents may have one or both of the fo l lowing

effects:

(a) static , when they inhibi t further growth or mul t ip l icat ion of

invading organism or cel l ; (b) cidal, when they k i l l or destroy i t . For

instance, we have both bacter iostat ic and bacter ic idal agents. Stat ic or c idal

ef fects depend on several factors, such as concentrat ion of drug, pH,

temperature, durat ion of act ion metabol ic phase of the invader, presence of

interfer ing substance. Thus drug wj th stat ic ef fects may exert c idal ef fects i f

the doses are increased.

The ideal chemotherapeut ic agent is considered to be one wi th select ive

tox ic i ty to the paras i te and innocui ty to the host . As no such agent ex ists and

very l ikely never wi l l be developed or found, the relat ive ef f ic iency and

safety of chemotherapeut ic agents has been indicated by the so-cal led

chemotherapeut ic index, which may be expressed by the relat ionship

Chemotherapeut ic index = Maximal to lerated dose by the host /minimal

curat ive dose

The greater th is index, the bet ter the chemotherapeut ic agent because of i ts

greater safety to the pat ient .

� Antibacterial Chemotherapy

Bacter ia are commonly responsible for many diseases, which were

considered unt i l recent ly to be resistant to chemotherapy.

� Bacteria

These are a group of microorganisms, which are unicel lu lar and

surrounded by r igid , complex, protein cel l wal l . These may be free l iv ing,

saprophyt ic or paras i t ic; some are pathogenic to man, animals and plants.

Bacter ia are classi f ied into two types, i .e. gram-posi t ive and gram-

negat ive according to method developed by Christ ian Gram, which is as

fo l lows:

In th is method, the f ixed bacter ial smear is f i rs t t reated wi th a solut ion

of crystal v io let and then wi th iodine solut ion, which reacts wi th the dye and

the cel l const i tuents. The smear is then washed wi th alcohol (decolour iz ing

agent) and safranine or some other counter stain is added.

The bacter ia that retain the colour of crystal v iolet and appear deep

vio let ( in colour) are cal led Gram-pos i t ive bacter ia, whereas those, which

lose the v io let colour and get counters tained by safranine and appear red in

colour, are cal led Gram-negat ive bacter ia. The fo l lowing are some of the

disease causing bacter ia classi f ied in th is manner:

Gram-posit ive bacteria Gram-negative bacteria

Diphtheria baci l lus Col i and Typhoid baci l lus

Leprosy baci l lus Gonococcus

Pneumococcus Meningococcus

Staphylococcus Plague baci l lus

S treptococcus Spirochaetes

Tubercle baci l lus Vibrios (V. Cholerae)

� Antibacterial agents

The history o f ant ibacter ial has been dynamic, character ized by the

constant emergence of new chal lenges fo l lowed by invest igat ion, d iscovery

and the product ion of new drag. A complete review of the var ious agents

employed as ant ibacter ial would be beyond the scope of th is work and hence

is not at tempted. A br ief summary of the important c lasses of ant ibacter ial

compounds are given below.

� Synthetic antibacterial agents

The synthet ic ant ibacter ial agents are comprised of two major c lasses

of compounds; those effect ive systemat ical ly and those used topical ly.

[A] Topical antibacterial agents

Ant ibacter ial agents that are employed topical ly are commonly termed

ant isept ics, d is infectants or preservat ives depending on how they are

employed. Since there is a considerable degree of over lap in usage among

these three groups, the more convenient method of classi fying them,

according to stnictural types.

The ant isept ics and dis infectants compounds are of ten improperly

ut i l ized and overrated in thei r e f fect iveness by both lay and medical

personnel , they are invaluable when properly employed3. The

hexachlorophene t ragedy has shown that extensive toxicological studies are

just as important for topical agents as-for systemat ic, and o lder agents should

be employed wi th due care. Topical synthet ic ant ibacter ials are classi f ied as

fo l lows:

Halogens and Halophors, Phenols, Alcohols, Aldehydes,

Quaternary Ammonium compounds, Dyes9, Ureas, Amidines,

Heavy Metal Compounds, Miscel laneous.

[B] Systematical ly antibacterial agents

The systemat ical ly act ive ant ibacter ial has been div ided into three

groups, two of which, the sul fonamides and the ant imycobacter ial agents. The

remaining compounds pr incipal ly agents for the t reatment of ur inary t ract

infect ions.

Except for the sul fonamides and ant imycobacter ial drugs, only a few

systemical l y act ive synthet ic ant ibacter ials are commercial ly important today.

The mul t i tudes of h ighly ef fect ive relat ively nontox ic ant ib iot ics avai lable

for the t reatment of bacter ial infect ions have provided st i f f compet i t ion for

the medicinal chemist at tempt ing to synthesize new ant ibacter ial agents.

Systemic synthet ic ant ibacter ials are classi f ied as fo l lows:

1. Ant imycobacter ia l agents

2. β -Lactam ant ib iot ics

3. Tr imethoprim, Cotr imoxazole

4. Methanamine

5. Ni t rofurans

6. Quinolones

7. Sul fonamides

According to the effect produced, ant ibacter ial drugs can be

bacter iostat ic ( inhibi t growth of bacter ia) or bacter ic idal (k i l l the bacter ia).

Commonly used bacter iostat ic and bacter ic idal drugs are given below.

Bactericidal Drugs Bacteriostatic Drugs

Penici l l in Sul fbnamides

Aminoglycosides Ni t rofurans

Polymyxin, Col is t in Erythromycin

Cephalosporins Tetracycl ines

Isoniaz id Chloramphenicol

Cotr imoxazole Lincomycin

The work presented in th is thesis is yet another humble ef fort in the

f ie ld of medicinal chemistry though very minute even to be regarded as a

smal l s tepoin of fer ing a pract ical solut ion to the innumerable problems,

nevertheless, a devoted effort to s incerely contr ibute to a heal th ier and

happier human l i fe. The-work deals wi th some of the commonest ai lments v iz .

helminthiasis, tuberculosis, other bacter ial and fungal infect ions though not

considered fatal by and large. But even today these i rr i tate physicians at

t imes, when coupled wi th other chronic condi t ions and also due to the

resistance offered by infect ing organisms to var ious forms of therapy.

1.2 Need of the study:

Nowadays, the ent i re pharmaceut ical industry is faced wi th the

chal lenge of increasing product iv i ty and innovat ion. The major hurdles are

the increasing costs of research and development and a s imul taneous

stagnat ing number of new chemical ent i t ies (NCEs). The cause of th is

innovat ion def ic i t is def in i t ively not the bio logy. Decoding of the human

genome has led to a weal th of drug targets. With more than 30,000 human

genes, the assumpt ion is that at least 1,000 are s igni f icant ly involved in the

emergence and course of d isease. Furthermore, because each of these genes is

l inked to the funct ion of between f ive and ten proteins, the conclusion is that

there might be 5,000–10,000 targets for new drugs . Medicinal chemistry as

a scient i f ic d iscip l ine has introduced several new techniques over the last few

years in order to speed up the drug discovery process, such as combinator ial

chemistry, Despi te th is steady increase in research and development, the

number of molecule reaching the market has decrease.

1.3 Problem statement:

In order to start a new drug discovery project and to f ind bio logical l y

act ive compounds, d i f ferent opt ions are avai lable. Hi ts can be obtained via a

vi r tual screening approach or can be copied from scient i f ic or patent

l i terature. Very of ten, drug discovery projects start wi th a high-throughput

screening campaign of commercial l y avai lable compound l ibrar ies against the

target of interest . I t became clear in recent years that combinator ial l ibrar ies

are not d iverse enough. As the main interest of the laboratory of medicinal

chemistry lays in the synthesis and biological evaluat ion of aromat ic

heterocycles, we performed a l i terature survey of commercial l y avai lable

combinator ial l ibrar ies.

1 .4 Research Objectives:-

In the pharmaceut ical f ie ld, there has a lways been and wi l l cont inue to

be a need for new and novel chemical ent i t ies wi th diverse bio logical

act iv i t ies. During the course of our research work, looking to the

appl icat ion of heterocycl ic compounds.

1. To design, synthesize & character ize new chemical ent i t ies (NCEs) having

good biological act iv i ty on var ious strains of bacter ia as wel l as fungi .

2. To synthesize organic heterocycl ic molecules in rout ine organic synthesis.

3. Optimizat ion of react ion condi t ion to achieve high yield and select iv i ty of

products.

4. To understand biological and chemical aspects o f ident i f icat ion,

modi f icat ion of new chemical ent i t ies to make them sui table for

pharmaceut ical use.

5. To understand structure-act iv i ty relat ionships (SAR) of synthesized

der ivat ives.

Taking into considerat ion the appl icabi l i ty o f heterocycl ic compounds, the

placement of var iety o f subst i tuent in th is nuclei have been designed in

order to evaluate the synthesized products for their bet ter pharmacological

prof i le.

1 .5 Importance and scope :

Today a large number of d ieses are cured or at least control led by drug

therapy. To f ight against bacter ial and fungal infect ions has been largely won

and s igni f icant progress has been made in t reat ing disturbed mental ,

cardiovascular, gast rointest inal condi t ion. To boast i t , can be claimed that

certain form of causes can be cured by chemotherapy but even today these

i rr i tate physician al l t imes when coupled wi th other chronic condi t ions and

also due to the resis tance of fered by act ing to various form of therapy.

The great expansion in medicinal research in past has contr ibuted much

to the unparal le led progress in medicine dur ing that per iod. Improved and

basical ly more meaningful b io logical tests, procedures and methods of

d iagnosis have provided bet ter guidance in drug discovery by point ing out

suggest ive observat ions which could be used in the design of new

prophylact ic and therapeut ic agents. The growth of molecular b io logy wi th i ts

chemical ins ight in to experimental b io logy has contr ibuted more s igni f icant

pharmacological theor ies.

Heterocycl ic compounds have to potent ial for having good act iv i ty

against bacter ia, ant i tumor, ant i inf lammat ion, antisept ic, d iuret ics,

analgesics etc. Among a wide var iety of heterocycl ic that have been explored

for developing pharmaceut ical l y important molecule l ike chalcones and

f lavanoids have played an important ro le in medical chemistry.