CHAPTER-I

INTRODUCTION

Medical and pharmacological research provides a basis for the development

of new approaches to combat human disease. The research has the effect of

obviating established therapies in favour of newer modalities, which are safer and

more effective.

The efficacy of heterocyclic compounds exhibited various biological and

pharmacological activities. Number of heterocyclic form an important

pharmacophore in several medicines and natural products, possessing biological

properties also they have found to possesses heterocyclic moieties, such as

thiophene, furan, pyridine, pyrimidine imiadazole, quinoline etc. In particular,

literature is well documented with the biological and pharmacological efficacy of

pyrimidines and thiophene derivatives. In view of these facts, the work of

synthesis of heterocyclic analogs of pyrimidine and thiophene molecules, and

investigation of their biological and pharmacological activity was undertaken.

Pharmaceutical chemistry is a science that makes use of the general laws of

chemistry to study drugs, i.e., their preparation, chemical nature, composition,

structure, influence on an organism and studies of the physical and chemical

properties of drugs, the methods of quality control and the conditions of their

storage.

Pharmaceutical chemistry occupies the most important place among the

related science' viz., drug technology, toxicological chemistry and

pharmacognosy. At the same time, pharmaceutical chemistry, being a specialized

science, depends on other branches of chemistry, (inorganic, organic, analytical,

1

CHAPTER-I

physical, colloid chemistry etc.,) and also on medico biological (pharmacology,

physiology, biological chemistry) disciplines.

Heterocyclic synthesis has emerged as powerful technique for generating

new molecules useful for drug discovery'. Heterocyclic compounds provide

scaffolds on which pharmacophores can arrange to yield potent and selective

drugs^.

Heterocyclic compounds containing two nitrogen atoms in pyrimidine,

pyrazole imidazole and piperazine are represents a very important group of

organic compounds because many of them exhibit significant biological activity,

so these properties predetermine them inter alia for the preparation of wide

spectrum of medicinal drugs^.

Pyrimidine is a heterocyclic aromatic organic compound similar to benzene

and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six-

member ring. It is isomeric with two other forms of diazine. Pyrimidine has many

properties in common with pyridine, as the number of nitrogen atoms in the ring

increases the ring n- electrons become less energetic and electrophiliCiaromatic

substitution gets more difficult while nucleophilic aromatic substitution gets

easier. An example of the last reaction type is the displacement of the amino

group in 2-aminopyrimidine by chlorine and its reverse Reduction in resonance

stabilization of pyrimidines may lead to addition and ring cleavage reactions

rather than substitutions. One such manifestation is observed in the Dimroth

rearrangement. Compared to pyridine, N-alkylation and N-oxidation is more

difficult, and pyrimidines are also less basic: The pKa value for protonated

CHAPTER-I

pyrimidine is 1.23 compared to 5.30 for pyridine. Pyrimidine also found in

meteorites, although scientists still do not know its origin. It decomposes

photolytically into Uracil under UV light" ' .

Pyrimidines have been the subject of substantial attention by synthetic and

medicinal chemists due to the role of such class of heteroaromatic ring in many

biological systems. Pyrimidines, being an integral part of DNA and RNA, impart

to diverse pharmacological properties as effective bactericide and fungicides.

Certain pyrimidine derivatives are also known to exhibit antimalarial antifilarial,

antileishmanial and anti-HIV activities. Some of the 3,4-dihydropyrimidines

(DHPM) have emerged as integral backbones of several calcium channel

blockers, antihypertensive agents, adrenergic and neuropeptide antagonist Several

alkaloids containing 3,4-dihydropyrimidine have been isolated from marine

sources and among them are the batzelladine alkaloids are found to be potent

HIV-gp-120-CD4 inhibitors*"'^

Currently, fifteen out of twenty-five drugs approved by US-FDA (United

States Food and Drug Administration) for the treatment of viral diseases'^ are

purine and pyrimidine derivatives; Idoxuridine, Trifluridine, Acyclovir,

Ganiciclovir for herpes; Zidividine and Lamividine for HIV and Ribavarine for

RSV infection in children.

Tamara Fursy and Alexi^° have reported synthesis of novel pyrimidine-4-

yl derivatives. Synthesized compounds have been evaluated as anticancer agents

at National Cancer Institute's (USA) Drug Discovery program, against leukemia,

CHAPTER-I

non small cell lung cancer, colon, CNS cancer, melanoma, ovarian cancer, renal,

prostrate and breast cancer; proven as potential drug candidates.

Some of the structures of functionalized pyrimidines^' and examples of

drugs containing these nuclei are shown below.

o

O^J O^^^ O ^ N ' .-V"'

H HO-A O 5-Florouracil W

H 0 - \ /O

HO " ° Triflorothymine ARA C

During the last few years interest in these areas W^PC focused on synthesis

and evaluation of biological activity of various pyrimidines either fused or

bridged with other hetero partner.

The above discussions reveal the importance of pyrimidines and their

biodynamic property, which prompted us to design pyrimidine derivatives

simulating pharmacophores and substituents responsible for diverse

pharmacological activities.

Methods of synthesis of Pyrimidine derivatives

01. From C-C-C and N-C-N units condensation"

A very important general method for preparing pyrimidines is the

condensation between at^he carbon of the type YCH2Z, where Y & Z = COR,

COOR, CN, and compounds having^amidirie, urea^_guanidine, thiourea andjheir

derivatives „on condensation is carried out in the presence of sodium hydroxide or

sodium ethoxide.

CHAPTER-I

NH

Acetamidine

O^ ^CH,

O O

EAA

O

HN

OH

- ^ HN

2,6-Dimethylpyriniidin-4(3//)-one

M INH2

fl + Thiourea

NC

Malonitrile

NH, NH,

HS' N NH N NH2 H

4,6-Diaminopyrimidine-2-thiol

Y s

Thiourea

NC O. ^CH,

O O

Ethylcynoacetate

i,- HN

OH

i. HS N NH. HS' N NH.

6-Ainino-2-inercaptopyrimidin-4(3i^-one

Antithyroid activity was first found in pyrimidine series. The simplest

compound to show this activityVmethyl thiouracil/is prepared ^fliHte'simply by

condensation of ethyl acetoacetate with thiourea. Further work in this series

shows that better activity was obtained by incorporating of lipophilic side chain.

Example: propylthiouracil 23

^ C O O E t

o • HjN

NH,

H3C

OH

Propylthiouracil

Condensation of ethylcyanoacetate with guanidine in the presence of

sodium ethoxide affords the starting pyrimidine. Reaction with phosphorus

CHAPTER-I

oxychloride tjjeffserves to replace the hydroxyl group by chlorine. Treatment of

this intermediate with metachloroperbenzoic acid results in specific oxidation of

the nitrogen at the 1 ' position. Displacement of the halogen with piperidine

affords minoxidil. This drug, minoxidil is an extremely effective hypertensive

agent acting by means of vasodilatation.

N C — \ COOEt

» . II I _ Ti T ^ " N NH ^-^^ ^ ^ N \ i ^ ' ^ ^N

CI NH, O " CI

Minoxidil N

02. From condenseation of C-N and C-C-C-N units

One of the important pyrimidine synthesis involves the condensation

between a molecule containing the C-C-C-N unit and a molecule containing C-N

unit, e.g. A^-Phenylbenzene carboximidoyl chloride, isocyanatomethane with

(C-C-C-N) unit and e-gr" l-ethoxyprop-l-en-2-amine, 3-ethoxypent-2-en-2-

• 22

amme .

0

N

P h ' " ' ^ XI +

H5C2O

CH3

HEAT

P h ' - ^ N ' ^ CH3

6-Methyl-5-ethyl-2,3-diphenylpyriinidin-4(3fl)-one

03. From substituted chalcones

Substuited chalcones are treated with urea or thiourea to get substituted

thio/oxa-pyrimidines^^ respectively. These substituted pyrimidines/screened for

many biological activities.

CHAPTER-I

HjN

X

R

b + NH2

R

R " ^ N ^ X H

04. From malonic ester synthesis

Bis-homologation of benzaldehyde, (for example, reduction of aldehyde to

alcohol, alcohol to halide and then to malonic ester), affords the hydrocinnamic

acid. Formation with ethyl formate and base gives the hydroxymethylene

derivative, pyrimidine, by a scheme similar to that above. The hydroxyl group is

then converted to the amine by successive treatment with phosphorus oxychloride

and ammonia. Thoro ig^ius obtained the antimalarial agent, Trimethoprim^^L>4 6c>^^^t^^4

MeO

J—^ \—COOEt MeO

05. Condensation of phenylacetonitrile with ethyl propionate

2,4-Diaminopyrimidines inhibit the growth of microorganisms by

interfering with their utilization of folic acid led to an intensive search for anti-

infective agents in this class of heterocyclic compounds. This work led to the

development of at least two successful antimalarial agents. Condensation of

phenylacetonitrile with ethyl propionate in the presence of sodium ethoxide gives

CHAPTER-I

the cyanoketonertreatment with diazomethane affords the methyl enol ether jifeel

undergoes condensation with guanidine/afford^ pyrimethamine .

NH2

N C O N C V.W3 I 1, „n2

3-Oxo-2-phenylpentanenitrile ^^3 Pyrimethamine

06. Condensation of ethoxymethylene malononitrile with acetamidines

Coccidia are protozoans that can wreak havoc in a flock of poultry b the

infection known as coccidiosis. Agents that control this disease -coccidiostats -

are in view of the world's heavy dependence on poultry as a source of protein, of

great economic significance. One of the more important drugs for treatment of

this disease incorporates the primidine nucleus. Condensation of ethoxymethylene

malononitrile with acetamidine affords the substituted pyrimidine. This reaction

involves conjugate addition of the amidine nitrogen to the malononitrile followed

by loss of ethoxide, addition of remaining amidine nitrogen to one of the nitrile

will then lead to the pyrimidine. Reduction of the nitrile gives the corresponding

amino methyl compound* exhaustive methylation of the amine followed by

displacement of the activated quartemary nitrogen by bromide ion affords the key

28 intermediate#dj«placement of the halogen by a-picoline gives amprolium

N C ^ + HjN-^ >-OEt CH3 N C ^ ^ ^ ^ ^ N ^ ^ ^ ^ A ^ N

H NH, CI

Amprolium NHj

CHAPTER-1

07. From imino-ethers

Knoevenagel type of condensation ijiy0lv©s-tWpphene-2-carbaldehyde with

cynoacetic acid gives the corresponding unsaturated nitrile. This is then

methylated in the presence o^'strong acid to affords the imino-ether^(condensation

with N-methyl propolene 1,3- diamino proceeds probably by addition-elimination

of each amino group in turn with the iminoether. There is thus obtained pyrantal.

The analog, morantaP^ is obtained by the sequence using 3-methylthiophene-2-

carboxaldehyde.

NH

I X -CH,

ij CN

CH,

Morantal

08. From three-component condensation (TCC)

A novel and efficient protocol is developed for the synthesis of various

spiro-2-amino pyrimidinones 1 via the three-component condensation of alkyl

cyanoacetates, guanidinium carbonate and N-substituted 4-piperidinones in

ethanol at reflux. High yields, neutral conditions, and short reaction times are

advantages of this method^°.

o NH

CO3

N ' I

R

X ^ + CN

HjN- // NC

NH2 ^ 2 , N .

R= Bn, -CH2CH2Ph, X=COOMe, COOEt

O

N

^N NH2 H

CHAPTER-I

09. From Biginelli reaction

Multicomponent one-step fusion of a variety of pharmacologically pertinent

pyrimidine heterocycles has efficiently been achieved from their respective

aldehydes, P-dicarbonyl compounds, and urea/thiourea in the presence of a

catalytic amount of tetrachlorosilane in DMF/AN mixture at normal ambient

3 . 1 temperature . '

X

H2N NHj

O-^ . H SiCl4(10mol%) R

DMF/AN(1:2)

Ambient temp. 4hr

10. From four-component Biginelli-type reaction

4-Aryl-2-cyanoimino-3,4-dihydro-l//-pyrimidine derivatives 3 have been

prepared using multicomponent reaction by reacting a mixture of arene or

heteroarenecarbaldehyde, 1,3-dicarbonyl compounds, and cyanamide under acidic

conditions. The novelty of this approach derives from its use of cyanamide as a

building block in a four-component Biginelli-type reaction^^. Varying the reaction

conditions led to the formation of either jV-(2-imino-6-phenyl-l,3,5-oxadiazinan-

4-ylidene) cyanamide or 3,4-dihydropyrimidin-2(l//)-one. The type of

heterocycle skeleton synthesized depends on the nature of the acid catalyst as well

as the reaction conditions employed.

10

CHAPTER-I

H,N^^^ 0

I 0

-R^ HCl/ AcONa/EtOH

0 R'

H

3 R'

0

I 0

-R^

78 °C / 4hr

0 R'

H

3

11. From a,p-unsaturated imines

A series of polysubstituted pyrimidines 4 were synthesized from in situ

generated a,p-unsaturated imines and the corresponding amidine or guanidine

derivatives in a convenient one-pot procedure^^.

R

Ar " Ar

R . ^ R . . ^ ^

Ar, ^NH Ar, N R

12. From Aza-Michael addition

A novel and expeditious synthetic protocol for functionalized pyrimidines

using unprotected aldoses as biorenewable resources is reported. The synthesis

involves aza-Michael addition "* of aromatic amines to aldose-derived 1,3-oxazin-

2-ones (thiones) followed by dehydrative ring transformation to afford 4-

polyhydroxyalkylpyrimidin-2-ones (thiones) This is a one-pot Montmorillonite K-

10 clay-catalyzed amine-driven process proceeding under solvent-free microwave

irradiation conditions.

11

CHAPTER-I

OHC

(CHOH)„ •

HOH2C

D-xylose n=3 D-giucose n=4

(H0HC)2 ,CH,OH

Ar. ^N'

5

? Nilo Zanatta^^ et al., have _©cfT found new cruzain inhibitors,^nw 2-(A' '-

benzylidenehydrazino)-4-trifluoromethyl-pyrimidines.

H2N

HN

H -N

F3C

N I V O R R N

6

NH N^ ^Ar

Synthesis of fused pyrimidines

Synthesis of fused pyrimidines like furo[2,3-</]pyrimidines 7 and 8 from

keto alcohols treated with malononitrile in dimethylformamide in the presence of

diethylamine to l-amino-2-cyano-3,4-disubstituted furan. Ring closure by two

different methods gives amino and hydroxy furo[2,3-<3f]pyrimidines, biological

evaluation as AKtl kinase Inhibitors 36

NH2 R'

Furo[2,3-d]pyrimidines

^ N ^ ^ O

12

CHAPTER-I

The synthesis of several 2-aminothiophene-3-carboxylic acid derivatives 9

by two-minute microwave irradiation allowed their efficient transformation to

thieno[2,3-<^pyrimidin-4-ones^^ and the corresponding 4-chloro derivative is also

reported under microwave irradiation.

1) HCOOH-H2SO4 CI

HO S NCCH^CN ?^ MW-15m.n / ^ Y " ^ N

MW -2min ^ MW - 2xl0min '

Recent synthetic strategies in synthesis and biological activity of pyrimidines

Pyrimidines have been important lead molecules due to their diverse

pharmacological activity and have a long and distinguished history extending

from the days of their discovery as important constituents of nucleic acids to their

current use in the chemotherapy of AIDS. We have emphasized on some of the

novel synthetic strategies for the synthesis of biologically active pyrimidines

which also includes microwave synthesis and one pot synthetic techniq<ie&, with

an aim to help medicinal chemist to explore more biologically potent analogs.

Clifford Jones^* et al., have Jjedi developed a novel series of imidazole

pyrimidine amides 10 as cyclin-dependent kinase (CDK) inhibitors, afe-descnbcdr

Optimizations of inhibitory potency against multiple CDK's (1, 2 and 9) resulted

in imidazole pyrimidine amides with potent in vitro anti-proliferative effects

against a range of cancer cell lines.

13

CHAPTER-I

N N AZD5597 H

H3C 10 ^

Series of 4,6-bis-anilino-l//-pyrrolo[2,3-cr]pyrimidines 11 have been

synthesized and these molecules reported as IGF-IR (IGF-IR) receptor tyrosine

kinase inhibitors".

NH2 F

Osamu Irie'**' et al., have Jjectf* described active and brain-penetrant

cathepsin S selective inhibitors 12. The brain-penetrating cathepsin S inhibitors

demonstrate potential clinical utility for the treatment of multiple sclerosis and

neuropathic pain.

. C H ,

HjC^

Huang, Daniel'*' et al, have b^eJiaesigned a series of pyrimidinopyridones

and shown to be potent and selective inhibitors of the FMS tyrosine kinase.

14

CHAPTER-1

Micheal''' et al, discovered series of 4-amino-6-piperazin-l-yl-pyrimidine-

5-carbaldehyde oximes and developed as potent FLT3 tyrosine kinase inhibitors

14. Mahbub Alam"* et al., developed a series of novel 2-aminopyrimidines 15 as

inhibitors of c-Jun N-terminal kinases is described.

15

CHAPTER-I

Tricyclic pyrimidines

Ayoob Bazgir'*'* et al, reported one-pot and efficient method for the

synthesis of pyrazolo[4',3'5,6]pyrido[2,3-</] pyrimidine-dione derivatives 16 by

condensation reaction of barbituric acids, l//-pyrazol-5-amines and aldehydes

under solvent-free conditions jc reported: These products have been evaluated in-

vitro for their antibacterial activities.

Ph Ar

1 0 u

M ' ^ fS P^NH N

/ K^ N - ^ Y

= ^ H 16

H

X

Series of pyriniido[4,5-6]quinolines, triazolo[4',3':l,2]pyrimido[4,5-*]-

quinolines and tetrazolo[4',3':l,2]pyrimido[4,5-i]quinolin-5-one and [1,3]-

pyrazolo[3',2':l,2] pyrimido[4,5-Z>]quinolines and 2-pyrazolyl-pyrimido[4,5-6]-

quinolines'*^ 17 have been synthesized and some of the new compounds were

tested against various bacteria and fungi species. In addition, the analgesic and

anti-inflammatory activities are reported.

Ar O Ar O

17

The pyrimido[4,5-6]quinoline'*^ ring system is of interest because of its

structural similarity to the pyrimido[4,5-Z)]quinoxaline system of naturally

16

CHAPTER-I

occurring flavins. Synthesis of several pyrimido[4,5-6]quinolines 18, 19 have

been reported in the literature, with a view to develop new chemotherapeutic

agents.

Recently, Althuis"* et al., have synthesized and tested a number of

pyrimido[4,5-Z)] quinolines for their antiallergic property. Among the compounds

tested, 20 was found to possess high oral activity. Pyrimido[5,4-Z>]quinolines 21,

which are regarded as 10-dezaflavins have been synthesized and are found to be

inhibitors of riboflavin synthesis.

Rj = H CH3, R3 = Pentyl

/cC U.S. Patent describes the preparation of polyfluorinated mono and dioxo

tricyclic quinolines 22. These compounds are reported to display antifungal

activity against Trichophyton rubrum and Epidermophyton floccosum at 1.6 and

0.39 mg/ml.

17

CHAPTER-I

Biological significance of pyrimidine derivatives

Pyrimidines have a long and distinguished history extending from the days

of their discovery as important constituents of nucleic acids to their current use in

the chemotherapy of AIDS.

Alloxan is known for its diabetogenic action in a number of animals'* .

Uracil, thymine and cytosine are the three important constituents of nucleic acids.

o o NH

O

0=" "^N'^O

"NH

H

O H3C. A

H

NH,

-N

N ^O H

H

Alloxan Uracil Thymine Cytosine

The pyrimidine ring is found in vitamins like thiamine , riboflavin and folic

I 50 acid . Barbitone, the first barbiturate hypnotic sedative and anticonvulsant is a

pyrimidine derivative 49

o HOHjCHjCC-v^ \

\ -N^ a HjC

A^Nx^, , .^^CH3 HN- ^ r y

O ^ N ^ N - ^ ^ ^ - ^ C H ,

CH2OH

Thiamine Riboflavine

OH

-. J^ /NH /t:.

V'^^r /COOH

H5C6 JT

O ^ N - ^ O

Folic Acid S [ . ^^COOH H Phenobarbitone

18

CHAPTER-1

During the last two decades, several pyrimidine derivatives have been

developed as chemotherapeutic agents and found wide clinical applications.

Antineoplastics and anticancer agents

There are large number of pyrimidine-based antimetabolites structurally

related to the endogenous substrates that they antagonize. The structural

modification may be on the pyrimidine ring or on the pendant sugar groups. One

of the early metabolites prepared was 5-fluorouracil'^' (5-FU), a pyrimidine

derivative S-jChiouracil also exhibits some useful antineoplastic activities'^.

o H

« ^ o N / ^N. /O

NH ^^^<^'^ CI / \ A .NH N

X=0, R = F, Ri = H, 5 -Thiouracil ^ CI Uramustine Tegafur

X = O, R = SH, R, = H, 5 -Fluorouracil

The antineoplastic compounds'^ possessing the guanine nucleus, in

azathioprine, mercaptopurine, thioguanine and tegafur'"*" etc. were discovered

after formulation of the antimetabolite theory by Woods and Fildes in 1940.

These drugs prevent the utilization of normal cellular metabolites'^. There are

many more in recent times, like mopidamol, nimustine, raltitrexed, uramustine

and trimetrixate, 1-P-D-Arabinosylcytosine (Ara-C,) is also an example of a

pyrimidine antimetabolite in which the sugar is arabinose having a beta

configuration. It is mainly used as an anticancer agent and also exhibits

significant therapeutic effects in patients with herpes virus infections and herpes

19

CHAPTER-!

encephalitis. Gemcitabine, a pyrimidine antimetabolite, shows excellent

antitumour activity against marine solid tumours^*' .

ABPP induces high levels of interferons in mice when administered orally. It has

shown antitumour activity in some experimental animal models^''.

2-Ainino-5-broino-6-phenylpyriinidin-4(3^-one(ABPP)

Drugs for hyperthyroidism

2-Thiouracil and its alkyl analogue, thiobarbital are effective drugs against

hyperthyroidism. Propylthiouracil is used as a drug for hyperthyroidism with

minimum side effects^'.

O R = R, =R2 = H, X = S 2-Thiouracil

R^-V^NH R = R, = H R2 = C3H7 X = S Propylthiouracil

R N X R = R, =C2H5 R2 = 0 X = S Thiobarbitol

Antifolates, antibacterials and antiprotozoals

In 1948, Hitchings made an important observation that a large number of

2,4-diaminopyrimidines and some 2-amino-4-hydroxypyrimidines are antagonists

of folic acid^'. Since then, a large number of 2,4-diaminopyrimidines have been

synthesized as antifolates. It was eventually proved that these pyrimidines are

inhibitors of the enzyme

20

CHAPTER-I

dihydrofolate reductase (DHFR) ' . Notable amongst the 2,4-diaminopyrimidine

drugs are pyrimethamine a selective inhibitor of the DHFR of malarial plasmodia;

trimethoprim, an antibacterial drug which selectively inhibits bacterial DHFR and

most importantly, the very potent but non selective DHFR inhibitors,

methotrexate and aminopterin both used in cancer chemotherapy^"*. 3',5'-

Dichloromethotrexate which is less toxic and more readily metabolized than

methotrexate, has recently been introduced for anticancer therapy^^. Brodimoprim

is also found to be an effective antibacterial compound^^.

OCH,

H3C0 H3C0

Trimethoprim Brodimoprim

Sulfa drugs

Pyrimidine derivatives of sulfa drugs, namely sulfadiazine, sulfamerazine

and sulfadimidine are superior to many other sulfonamides and are used in some

acute urinary tract infections, cerebrospinal meningitis and for patients allergic to

pencillins^'. Sulfanamide-trimethoprim combinations are used extensively for

opportunistic infections in patients with AIDS^^. Sulfadoxine^^^ a short and

intermediate acting sulfonamide with a half-life of 7-9 days is used for malarial

prophylaxis. Sulfisomidine with a half-life of 7 hours is used as a combination

sulfa therapy in veterinary medicine™. Sulfadiazine, sulfamerzine and

21

CHAPTER-I

sulfadimidine possess good water solubility and therefore carry minimum risk of

kidney damage, which makes them safe even for patients with impaired renal

functions.

In 1959, sulfadimethoxine^' was introduced with a half-life of

approximately 40 hours. The related 4-sulfanamidopyrimidine, sulfamethoxine

having two methoxy groups in 5 and 6 positions, has by far the longest half-life of

about 150 hours. Methyldiazine has a half-life of 65 hours. Also,

sulfamethoxydiazine possesses good half-life. A new broad-spectrum

sulfonamide, sulfamethomidine ' relatively nontoxic and patients do not need

extra fluid intake or alkalization. Sulfacytine has been reported to be 3-10 times

more potent than sulfaisoxazole and sulfisodimidine^'.

OCH,

N' n o O

V H3C' " N ' "N' ' H

Sulfamethomidine NH.

CHo

k N ' - - T O O

Sulfacytine

NH,

Antiviral and anti-AIDS drugs

Recently, pyrimidine derivatives have generated widespread interest due to

their antiviral properties. 5-Iododeoxyuridine'^ is an antiviral agent of high

selectivity. IDU (5-iodo-2'-deoxyuridine) has been extensively utilized for viral

infections. 5-Trifluromethyl-2'-deoxyuridine (F3 TDR) has been found useful

against infections resistant to IDU therapy. Ara-A 9-yS-D-arabinofiiranosyl

22

CHAPTER-I

adenine, a relatively new antiviral drug, is effective against herpes infections of

eye, brain and skin. It is especially effective against IDU-resistant herpes virus^^.

Some purine nucleosides are equally noteworthy. Retrovir (AZT-16) is a

potent inhibitor of the in-vivo replication and cytopathic effects of HIV and has

been recently approved for use against AIDS and severe ARC'^. At present

Acyclovir is the only remedy for genital herpes. The oral formulation of

Acyclovir is effective against both first and second-degree recurrence-genital

herpes with minimal side effects '*. Ganciclovir''^ (DHPG-2) has shown good in-

vivo activity against HCVi and HCV2.

Several members of a series of acyclic nucleosides, which contain a fused

pyrimidine ring (mainly purine), are found to be effective antivirals. Famiciclovir

and valacyclovir are drugs used for several DNA viruses, including Hsv types 1

and 2, Varicella-zoster virus and Epstein-Barr virus^^. Penciclovir^' is useful for

topical treatment of recurrent herpes, Libialis. Cidofovir, an antimetabolite for

deoxycytosine triphosphate is used for treatment of cytomegalovirus (CMV) in

AIDS patients. Lamivudine 23 is an effective anti-AIDS drug when used in

combination with zidovudine. Zidovudine^^ is an analogue of thymidine in which

the azido group is substituted at the 3-position of the dideoxyribose moiety. It is

active against RNA tumour viruses (retroviruses) that are the causative agents of

AIDS and T-cell leukaemia. It is used in AIDS and AIDS-related complex (ARC)

to control opportunistic infections by raising absolute CD4* lymphocyte counts.

Also, zalcitabine is another useful alternative drug to zidovudine. It is given in

combination with zidovudine, when CD4+ cell counts fall below 300 cells/mm .

23

CHAPTER-1

Didanosine^^ is a purine dideoxynucleoside, which is an analogue of inosine.

Didanosine inhibits HIV RT and exerts a virustatic effect on the retroviruses.

Combined with zidovudine, antiretroviral activity of didanosine is increased.

Stavudine is a pyrimidine nucleoside analogue that has significant activity against

HIV-1 after intracellular conversion of the drug to a D4T-triphosphate. It is more

effective than zidovudin or didenosine for treatment in patients for delaying the

progression of HIV infection. It is recommended for patients with advanced HIV

infection.

Abacavir sulfate was approved in 1998 as a NRTI (Nucleoside Reverse

Transcriptase Inhibitor) to be used in combination with other drugs for the

treatment of HIV and AIDS. The major use of abacavir appears to be in

combination with other NRTIs.

NH,

=N

N ^O I R

R = Cidofovir

O Lamivudine

-OH

HO

O

O^N-J

N3 Zidovudine

CH, NH,

HO O ^ N - ^

O \

Zalcitabine

HN

HO O.

HjN N

\

Abacavir

24

CHAPTER-I

Antibiotics

There are few examples of pyrimidine antibiotics. The simplest of all is

bacimethrin (5-hydroxymethyl-2-methoxypyrimidin-4-amine), which is active

against several staphylococcal infections^''. Gourgetin, a cytosine derivative is

active against mycobacteria as well as several Gram(+) and Gram(-) bacteria*'.

There are more derivatives of cytosine, namely amicetin and plicacetin which

exhibit activity against acid fast and Gram-(+) bacteria as well as on some other

organisms. Puromycin has a wide spectrum of antitrypanosomal activity.

Aminoglycoside antibiotics phleomycin, bleomycin and related families are wide-

spectrum antibiotics containing the pyrimidine ring. Another antibiotic

tubercidine is reported to exhibit antitumour properties. In addition, they have

antineoplastic activity. Bleomycin is already in clinical use against certain

tumours like Hodgkin's lymphoma and disseminated testicular cancer .

CH3

Y"2 _ ^ ^ .NH . ^ , ^ J ^ __^ .NH,

N CH3

Bacimethrin

O' > ^ n T NH^N' O NH2

H,N'' " N ' ^ O Gourgetin

HO OH 6

Amicetin

H3C

HO OH

Plicacetin

25

CHAPTER-I

Antifungals

Pyrimidines also exhibit antifungal properties. Flucytosine*^ is a fluorinated

pyrimidine used as nucleosidal antifungal agent for the treatment of serious

systemic infections caused by susceptible strains of Candida and cryptococcus*"*.

Hexitidine*^ is mainly used for the treatment of aphthous ulceration.

NH,

N

H

Flucytosine

Antitubercular drugs

Capreomycin produced by Streptomyces capreolus is a second-line

bacteriostatic antituberculin drug containing pyrimidine^ '*''. Viomycin is more

tuberculostatic than p-aminosalicyclic acid. It is effective in the treatment of

experimental tuberculosis.

O CHjR H O NH,

Capreomycin

NH V ^ CH,

N - ^ O O

26

CHAPTER-I

HOH2C j ^

N ^ ^CHjOH

PiN^ N OH H

Viomycin

CNS active agents

Sedative/hypnotic/antiepileptic agents

Agents of the anxiolytic, sedative and hypnotic group include a wide variety

of barbiturates used as sedative and hypnotics and are classified as drugs having

short, intermediate and long duration of action**'* . Allobarbital , aprobarbital ,

pentobarbital, phenobarbital and secobarbital are frequently used clinically as

hypnotic barbiturates^^. Hexobarbital, cyclobarbital and propallylonal are some of

the current drugs in the market used as sedative hypnotics^'. Barbiturates as

sedative hypnotics have a long and fascinating history. In fact Eli Lilly^^ patented

secobutabarbital in 1932, while baritone, the first of the barbiturates was

introduced in 1903.

R

O^ Ji^ / O

o Barbiturates

27

CHAPTER-I

Anxiolytic agents

Few of the pyrimidine derivatives were also used as anxiolytics. Most

important of these is Buspirone (azaspirodecanediones), indicated in the

management of anxiety disorders accompanied with or without depression. It

lacks sedative, anticonvulsant and muscle-relaxant effects and most importantly

abuse potential. Buspirone lacks affinity to benzodiazepine receptors, but binds

avidly to one subclass of serotonin receptors, the

5-HTiA subtype 93-94

CI

H3C. / ^

,A. X H ,

H3C' . N

N N N ' H

Ritanserin Mezilamine

Ritanserin, a 5HT2 antagonist with anxiolytic activity is a pyrimidine

derivative^^. A simple pyrimidine derivative, mezilamine is classified as an

antipsychotic agent . Risoperidone is an antipsychotic drug, which is a structural

hybrid of butyrophenone and can be used as anxiolytic, antidepressant and

antiparkinsonism drug 97

. N ^ ^CH

Risoperidone

28

CHAPTER-I

Pyrimidine anaesthetics

Thimylal is a short acting general anaesthetic drug, which is also a

pyrimidine analogue ' . Saxitoxin^^ is a naturally occurring pyrimidine

containing anaesthetic agent, but is too toxic to be of clinical use. Saxitoxin is

isolated from some marine dinoflagellates.

o ^ ^ ^ "2 , /^ ; H,N^ ^O

CH2 CH3 o

HN .A. N

\ = N H 2

Saxitoxin

Diuretics, uricosurics

Several xanthine derivatives containing fused pyrimidine ring systems like

caffeine"'^ and analogs of caffeine are, etamiphylline"", lomiphylline"'^,

etophylline'*' , theophylline'^" and theodrendaline'°'* are known to promote a weak

diuresis by stimulation of cardiac function and by a direct action on the nephron,

acting as adenosine receptor antagonists'"".

O R

I CH3

There are a few examples of diuretics which contain a pyrimidine ring.

Noteworthy are quinethazine , metolazone'"^ and triamterene'"^.

29

CHAPTER-I

HjNOjS

R = C2H5, R =H Quinethazine

R = CH3, R, = 2-CH3-C6H5- Metolazone

HjN N / . N ^ ^NH2

A H5C6 N f

NH2

Triamterene

Cardiac agents

Antihypertensives

Several pyrimidine ring-containing drugs have exhibited antihypertensive

activity. Prazosin , a quinozoline derivative, is a selective oi-adrenergic

antagonist"^^"^*. Its related analogues bunazosin'°^, terazosin"" and trimazosin'"

are potent anti hypertensive agents.

o

NH.

R = H3C

-COCH2CH2CH3

Bunazosin

-COOCH2COCH2(CH3)2

Trimazosin Tetrazosin

Another quinazoline derivative, ketanserin"^ having a similar effect is an

antagonist of both a 1-adrenergic and serotonin-S receptors. Its mechanism of

action however is still controversial. A triaminopyrimidine derivative, minoxidil,

whose mechanism of action and therapeutic action are similar to prazosin, has

been introduced in therapy for its side effects, in the treatment of alopecia, male

baldness"^. Besides these, some more pyrimidine derivatives given below were

found to be antihypertensives"'*'"^.

30

CHAPTER-I

N O Ketanserin H

.114 Alfiizocin , a prazocin analogue and an a 1-adrenoceptor antagonist as well

as urapidil"^ are used especially in urinary obstruction caused by benign prostate

hyperplasia.

HjC^

Alfuzocin

H , C '

N

Urapidil

CH3

NH

O

Vasodilators

A series of xanthine derivatives are used as peripheral and cerebral

vasodilators. Especially, pentifylline and pentoxyphilline are used in

cardiovascular disorders"^. Other derivatives like xantinol nicotinate"^, a

vasodilator with general properties like nicotinic acid used in cerebral and

peripheral vascular disorders and pimephylline and pyridophylline are

noteworthy.

31

CHAPTER-I

H,C^

I CH,

Pentifylline R = -H R = -CH3 R = -CH3 A ^ Pimephylline R = ''^^^NH

Pentoxyphilline R,= =0 R, =-CH, R,-CH, • ' ^ 3 3 3 Pyridophylline R = —\

A new dopamine receptor stimulant, pirebidil"^ is reported to have

produced significant improvement in ADL (Activity of Daily Living) in patients

suffering from Parkinson's syndrome.

r ^ N Pirebidil

Cardiotonics, bronchodilators

Several xanthine derivatives theophylline, aminophylline'^° and

proxyphylline'^° exhibit good bronchodilator activity.

OH o

° H H3C. , X _ N * "3 "3C.^/>V^N

I CH3 CH3

Aminophylline Proxyphylline

32

CHAPTER-I

Antihistaminic pyrimidines

Taziphylline is ten times more potent than either astemizole or terfenadine

in its affinity for Hi-histamine binding site and appears to be devoid of CNS

activity'"^'. Another pyrimidine containing antihistaminic drug, temelastine is

comparable to mepyramine'^^. Radiolabelled studies have indicated that it does

not penetrate the CNS appreciably. Icotidine, a structural analogue of temelastine

lacks CNS activity and is a dual antagonist of both H] and H2 receptors'^^.

OH

o H , C .

N N

•~N -N

I

Taziphylline

I CH3

N CH,

1 _ 2 _ Temelastine ^ - Br R - CH3

Icotidine R, = H Rj = OCH 3

Analgesics and NSAID drugs

Acetiamine' "*, bentiamine'^^ and fursultiamine'^^ are new lipid-soluble

forms of thiamine (vitamin Bl) having therapeutic use in beriberi, polyneuritis,

encephalopathy, pain, malnutrition and alcoholism and especially in the treatment

of long-standing insulin-dependent diabetes mellitus. Fursultamine has been

reported to inhibit the arachadonic acid cascade-line activation and reverse the

increase in CBF (Coronary Blood Flow).

33

CHAPTER-I

O

Acetiamine R

R CHO fT V ^

CH,

-CH,

NH, O

H 3 C ^

Bentiamine R -C6H5 C6H5

0 = ^ S ^

N^ ^CH,

Fursultamine

Ademetionine'^^ is primarily used in conjunction to glucosamine and

chondroitin therapy. Octotiamine'^°, a vitamin Bl derivative also exhibits anti­

inflammatory activity. Proquazone'^', a condensed pyrimidin-2-one derivative has

been reported to exhibit good NSAID.

° H3C CH3

N^ ^CH,

Octotiamine Proquazone

34

CHAPTER-I

Metabolic electrolytes

Orotic acid' ^, a simple pyrimidine derivative and its mineral forms are used

in metabolic therapy, especially for cardiovascular patients to prevent heart failure

in cardiomyopathy. Oroate is needed as a key intermediate in biosynthesis of

pyrimidine nucleotides, which are building blocks for DNA and RNA required for

the final protein synthesis.

H 0 \ N /O

NH

COOH

Orotic acid

35

CHAPTER-I

Thiophene derivatives

Thiophene was discovered as a contaminaent in benzene'^^ It was

observed that isatin forms a blue dye if it is mixed with sulfuric acid and crude

benzene. The formation of the blue indophenin was long believed to be a reaction

with benzene. Victor Meyer was able to isolate the substance responsible for this

reaction from benzene. This new heterocyclic compound was thiophene' "*.

Thiophene and its derivatives occur in petroleum, sometimes in

concentrations up to 1-3%. The thiophenic content of oil and coal is removed via

the hydrodesulfurization (HDS) process. In HDS, the liquid or gaseous feed is

passed over a form of molybdenum disulfide catalyst under a pressure of H2.

Thiophenes undergo hydrogenolysis to form hydrocarbons and hydrogen sulfide.

Thus, thiophene itself is converted to butane and H2S. More prevalent and more

problematic in petroleum are benzothiophene and dibenzothiophene.

Reflecting their high stabilities, thiophenes arise from many reactions

involving sulfur sources and hydrocarbons, especially unsaturated ones, e.g.

acetylenes and elemental sulfur, which was the first synthesis of thiophene by

Victor Meyer in the year of its discovery. Thiophenes are classically prepared by

the reaction of 1,4-diketones, diesters, or dicarboxylates with sulfiding reagents

such as P4S10. Specialized thiophenes can be synthesized similarly using

Lawesson's reagent as the sulfiding agent, via the Gewald reaction, which

involves the condensation of two esters in the presence of elemental sulfur.

Another method is the Volhard-Erdmann cyclization.

36

CHAPTER-I

Thiophene is produced on a scale of 2M kg per year worldwide.

Production involves the vapor phase reaction of a sulfur source, typically carbon

disulfide, and butanol. These reagents are contacted with an oxide catalyst'^^ at

500-550 °C.

At room temperature, thiophene is a colorless liquid with a mild pleasant

odour reminiscent of benzene, with which thiophene shares some similarities. The

high reactivity of thiophene toward sulfonation is the basis for the separation of

thiophene from benzene, which are difficult to separate by distillation due to their

similar boiling points (4 °C difference at ambient pressure). Like benzene,

thiophene forms an azeotrope with water.

The molecule is flat; the bond angle at the sulphur is around 93 degrees,

the C-C-S angle is around 109 degrees and the other two carbons have a bond

angle around 114 degrees. The C-C bonds to the carbons adjacent to the sulphur

are about 1.34 A°, the C-S bond length is around l.VOA" and the other C-C bond

is about 1.41A° (figures from the Cambridge Structural Database).

H

u H

Thiophene is considered aromatic, although theoretical calculations suggest

that the degree of aromaticity is less than that of benzene. The "electron pairs" on

sulfur are significantly delocalized in the 7i-system. As a consequence of its

aromaticity, thiophene does not exhibit the properties seen for conventional

thioethers. For example the sulfur atom resists alkylation and oxidation.

37

CHAPTER-I

E E

Although the sulfur atom is relatively unreactive, the flanking carbon

centers, the 2 and 5-positions, are highly susceptible to attack by electrophiles.

Halogens give initially 2-halo derivatives followed by 2,5-dihalothiophenes;

perhalogenation is easily accomplished to give C4X4S (X = CI, Br, I)'^^.

Thiophene brominates 10^ times faster than does benzene. Chloromethylation and

chloroethylation occur readily at the 2,5-positions. Reduction of the chloromethyl

product gives 2-methylthiophene. Hydrolysis followed by dehydration of the

chloroethyl species gives 2-vinylthiophene'^'"'^^.

Thiophenes are important heterocyclic compounds that are widely used as

building blocks in many agrochemicals and pharmaceuticals'^^. The benzene ring

of a biologically active compound may often be replaced by a thiophene without

loss of activity ^^^. This is seen in examples such as the NSAID's lomoxicam, the

thiophene analog of piroxicam. Lomoxicam (chlortenoxicam) is a NSAID's of the

oxicam class with analgesic, anti-inflammatory and antipyretic properties. It is

available in oral and parentral formulations.

OH O ^ ^ ^

Lomoxicam

Thiophene may have alkyl side chains or may be condensed with one or

more benzene ring(s) to form benzo[Z>]thiophenes, dibenzo[6]thiophenes,

38^

CHAPTER-I

naphthothiophenes or benzonaphthothiophenes. Indeed, sulfur is the third most

abundant element in crude oils'"*', and the condensed thiophenes are the most

common form in which sulfur is present. Alkyl dibenzo[A]thiophenes have been

shown to be quite persistent in petroleum contaminated environments''* '''*'' and

they concentrate in the tissues of aquatic species''*^"''* . Nonetheless, C-1 and C-

2 dibenzo[Z»]thiophenes are susceptible to biodegradation''*^"''' . Bressler'^° et al.,

have reviewed the literature on the ring cleavage of sulfur heterocycles. The type,

source and structure of various sulfur heterocycles have been examined and have

found the ring cleavage.

Compounds containing thiophene moiety 1 and 2 also have been isolated

from plants'^', bitumens, crude oils and in pyrolysates of kerogens and

asphaltenes 152

2-Hexadecyl-5-methylthiophene

2-Methyl-5-tridecylthiophene

2-Butyl-5-tridecylthiophene

CH32

39

CHAPTER-I

Thiophene analogs are also found in as a bithienyl derivative, it has been

isolated from the roots of Tagetes erecta Linn., commonly known as Marigold,

native of Mexico and other warmer parts of the America. An infusion of this plant

is used against rheumatism, cold and bronchitis. An extract of the root is credited

with laxative in action'^^.

The vitamin biotin is essential growth factor for a number of micro­

organisms and for animals. It was first isolated from egg yolk and it is easily

obtained from milk concentrates.

HN NH

COOH

Tuberculosis is the leading infectious disease caused by Mycobacterium

tuberculosis}^'^'^^^. The situation is becoming alarming with the recent emergence

of multi-drug resistant (MDR) strains and its synergy with global human

immunodeficiency virus (HIV)'^^. The search for more effective agents against M

tuberculosis (MT) is ongoing in an attempt to enhance survival and reduce

morbidity, as proven by the high number of patents of new antitubercular agents

in the past decade.'^'

40

CHAPTER-1

A new series of thiophene containing triarylmethane derivatives'^* were

synthesized from the Friedel-Crafts alkylation of diarylcarbinols followed by

incorporation of amino alkyl chains. These were evaluated against

Mycobacterium tuberculosis H37RV and showed the activity in the range of 3.12-

12.5 Ig/ml in-vitro.

A large group of related benzo(b)thiophene derivatives'^^ have been

screened for antiviral activity in a simple cell culture system. Three viruses were

used; influenza A2, vaccinia and herpes simplex type 1.51% of the compounds

inhibited at least one virus by 75%, while 25 per cent were inhibitory by 90% per

cent. This high degree of antiviral activity is in agreement with the range of

biological properties possessed by benzo(b)thiophene derivatives as a whole.

Sets of tetrasubstituted thiophene esters'^° have been synthesized by reaction

of l-(a-carbomethoxy-P-aminothiocrotonoyl)-aryl/aroyl amines with 3-

(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The

compounds were synthesized by nucleophilic addition of aryl/aroyl isothiocyanate

and enamine. The synthesized targeted compounds were evaluated for their in-

vivo anti-inflammatory, analgesic and nitric oxide radical scavenging activity

employed. Among all the targeted compounds showed maximum anti­

inflammatory activity of 71% protection at lOmg/kg and 77% protection at

20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also

maximum in-vitro nitric oxide radical scavenging activity having IC50 value

31.59 ^g/ml.

41

CHAPTER-I

Ticlopidine'^' is a drug analog of thienopyridine, it is indicated in

cerebrovascular diseases such as transient ischemic attacks, reversible ischemic

neurological defects, stroke, coronary artery disease such as unstable angina,

coronary artery bypass-grafts and secondary prevention of myocardial infarction.

It acts by inhibition of ADP-induced aggregation, which is common pathway of

aggregation. Ticlopidine was synthesized by starting with thiophene-2-aldehyde.

Method of synthesis

01. Pall knorr synthesis'"

It is a most general method for the synthesis of substuited thiophenes from

1,4-diketone and phosphorous pentasulfide.

I I HEAT / ~ S 0 0 R

02. Gewald's synthesis'"

2-Amino-4-phenylpenta-l,3-diene-l,l,3-tricarbonitrile reacted with

elemental sulfur in the presence of triethylamine to give 2-amino-3-(b-amino-a-

cyanoacrylonitrilo-3-yl)-4-phenylthiophene.

42

CHAPTER-I

H,N CN

N C - ^ CN

NH4OAC HjN

H5C6

CN

CN -CH3

HjN CN

CN H,N CN

N C - ^ CN

* •

0

CH3

HjN

H5C6

CN

CN -CH3

dioxane (Z y>~~ EtjN S

-CH3

03. Ring closure methods**'*

This approach involves the use of methyl thioglycolate and its condensation

with dimethyl fumarate in the presence of a base. An acetylenic compound may

also be used to obtain a thiophene ring.

o s/''"^ > •

COOH

/ ^ ^ ^ C O O H 1

COOH

/ ^ ^ ^ C O O H

OCH3

H3COOC COOCH3

COOH

/ ^ ^ ^ C O O H

04.1,4-Dilithiobutadienes'*^ with CS2

This reaction pattern was novel. When the reaction mixture of CS2 with

monolithium compounds at low temperature was treated yields thiophene

compounds were obtained.

1.CS2

2. H

Recent Synthetic strategies in synthesis and biological activity of thiophenes

A series of 3,4,5-trisubstituted'^* derivatives have been synthesized and

investigation for HIV-1 reverse transcriptase inhibitor. An X-ray structure with

43

CHAPTER-I

HIV-IRT secured the binding mood and allowed the key interaction with enzyme

to be identified.

A novel 5,4-dialkyl substituted thiophene'^^ was discovered in silico

screening of the 3D polymerase crystal structure that demonstrated single digit

micromolar HCV inhibition activity in the replicon assay.

CONH,

4,5-Dihydroxypyrimidine carboxamidines'^*, which evolved from a related

series of HCV NS5b inhibitors, have been optimized to provide selective HIV

integrase stand transfer inhibitor. Similarly thiophene containing fused and

substituted pyrimidine derivative 2-methyl-3-substituted-5-(thiophen-2-

yl)thieno[2,3-^pyrimidin-4(3//)-ones was synthesized and these molecules have

been proved to be a good antitubercular agents'^^.

1 R = -NH2,=N=CHR

O 4-CI-C6H4

4-HO-C6H4

44

CHAPTER-I

The synthesis of thiophenes and fused derivatives as importance of such

compounds is based on their use as anti-inflammatory, anti-protozoal and

antitumor agents, for serine protease inhibition and alternate substrate inhibitors

of cholesterol esterase. In addition to this some fused thiophene with pyrimidine

and tetrahydrobenzen analogs have been reported as antidepressants, sedative and

analgesics activities'^°.

Y CONHPh

V-N

CJS-'"-Keeping in view of biological importance of pyrimidines and thiophene

derivatives and inspired by the scope of research in this field, we have carried out

the research work on the synthesis of pyrimidines and thiophene derivatives to

explore their biological profile.

In the present investigation, the starting materials were synthesized by the

condensation of ethylcynoacetate, thiourea with different substituted

arylaldehydes in the presence of potassium carbonate using dry alcohol as solvent

by conventional and microwave method "''^.

Syntheses of paracetamol and eugenol analogs were prepared by reacting

with ethylchloroacetate and hydrazine hydrate.

45

CHAPTER-I

HjN

O NC

OEt

NHj +

Scheme-I

Dry alcohol

,CHO K2CO3

O

H 6-Substituted-5-cyano-,3,4-

dihydrothiouracils

OCH,

OH Eugenol

1 CICH2COOC2H5

Acetone K2CO3

HjN-NH, H2O

C2H5OH

OCH,

H •. h—Q N-NH2

O 2-[2-Methoxy-4-(prop-2-en-l-yl)

phenoxyjacetohydrazide

CH3

N—(\ /)—OH

1 MW, 160 W, 4min

CICH2COOC2H5 Acetone

CH3

w N—(\ A—0 NHNI H ^ ^ J ^ 2 MW, 160 W, 4niin H \-J V_^

A'-(4-hydroxyphenyl)acetainide H2N-NH2

C2H5OH H2O 0

N-[4-(2-hydrazinyl-2-oxoethoxy)

phenyl] acetamide

CH3

H 5 C 2 0 0 C . , ^ ^ CH3

1 MW 4Min H2NHNOC. J \ , ^ ^ NH

^ 5 ^ ^ C H 0 - r NHj 2 H2N-NH2 ^ " ^ V ^ N ^ O

alcohol IT

4-Anisyl-6-methyl-2-oxo-l,23»4-tetrahydropyriinidine-5-carbohydrazide

COOH

J O H C - ^

CH3C00Na o ~ N

(CH3co)20* y \ _ p ~ ^

2-Phenyl-4-(thiophen-2-ylinethylidene)-l,3-oxazol-5(4ff)-one

46

CHAPTER-I

Employing sophisticated techniques such as IR, ' H N M R and Mass

spectroscopy, the structures of all the newly synthesized compounds were

elucidated. The reaction mechanism was also predicted for reactions and in

exploration of their biological investigation. We have screened for their

antibacterial, antifungal, antitubercular and cytotoxicity properties.

47

CHAPTER-I

ORGANIZATION OF THE WORK

The thesis consists of nine chapters and each chapter contains proper

classification of the work and discussion.

CHAPTER! Introduction

CHAPTER-II Synthesis of substituted pyrimidinopyrazoJes and pyriiTiidinotriazoles.

CHAPTER-III Synthesis of novel piperazine and morpholine linked pyrimidine derivatives.

CHAPTER-IV Synthesis of 6-(substituted)-5-cyano-2-(substituted)-3-N-methyl-3,4-dihydro pyrimidin-4-ones.

CHAPTER-V Synthesis of 4-(substituted)-6-methyl-5-[3-(substituted)prop-2-enoyl]-1,2,3,4-tetrahydropyriniidin-2-ones and 5-(5-(substituted)-4,5-dihydro-l//-pyrazol-3-yl)-4-anisyl-6-methyl-l,2,3,4-tetrahydropyrimidin-2-ones.

CHAPTER-VI Synthesis of 3-(substituted)-2-phenyl-5-(thiophen-2'-ylmethylidene)-3,5-dihydro-

4//-imidazol-4-ones.

CHAPTER-VII Synthesis of 6-(thiophen-2'-yl)- 5-cyano~2-(substituted)-3-N-methyl-3,4-dihydro pyrimidin-4-ones.

CHAPTER-VIII Pharmacological and biological activities.

48

CHAPTER-I

REFERANCES

01. P.H. Hermakens, H.C. Ottenheijm and D.C. Rees, Tetrahedron., 1997, 53, 5643.

02. E. Gordon, R.W. Barrett and W.J. Dower, J. Med. Chem., 1994, 37, 1485.

03. M. Koos, Chem. Papers, 1994, 48, 108.

04. L.Thomas Gilchrist, Heterocyclic Chemistry (3rd Edition).

05. Organic Syntheses, Coll. 1963. 4,182.

06. Organic Syntheses, Coll. 1963,4, 336.

07. M. Nuevo, S.N Milam, S.A. Sandford and J. E. Elsila, Astrobiology., 2009, 9, 683.

08. R.R. Williams and J. K. Cline, J. Am. Chem. Soc, 1936, 58, 1504.

09. C. Reidlinger, and R. Dworczak, Dyes and Pigments., 1994, 24, 185.

10. G.E. Hardtman and H.Otto, Chem. Abstr., 77, 52313, (1972).

11. D.J. Brown, 77? Pyrimidines, Suppl II, edtd by Taylor, The Chem. of Heterocyclic Compounds. 1985.

12. D.J. Brown, The Pyrimidines, Edtd by A.R. Katrizky and C.W. Rees, Comprehensive Heterocyclic Chemistry, 1984, III, 57.

13. C. Kashima, Katoh and Omote, J. Org. Chem., 1981, 56, 4393.

14. M. Okabe, R.C. Sun and G.B. Zenchoff, J. Org Chem.,199\, 56, 4393.

15. M. A. Pasha and M.Ramchandraswamy, Ind. J. Chem., 2005, 44B, 823.

16. C. O. Kappe, Eur J. Med Chem., 2000, 35, 1043.

17. C. O. Kappe and O.V. Shishkin, Tetrahedron., 2000, 56, 1859.

18. A. D. Patil and N. V. Kumar, J. Org Chem., 1995, 60, 1182.

19. A Text Book of Burger's Med. Chem. and Drug Disc, (5* edition ) edited by Manfred Wolf, A Willy Inter Science Publication.

49

CHAPTER-I

20. Tamara Furzi and Alexei, Synthesis of Novel heterocyclic System from a-(2-R-S- halogenopyrimidin -4-yl) -2 azahetarylacetonitrile. New potential Anti cancer Agent (www.chi.ac.uk).

21. Thomas L Lemke, A Text Book of Review of Organic Functional Groups, Lippincott's., 2003, 89.

22. I.L. Finar, Text Book of Org Chem., ELBS Publications.1989, 2.

23. R. H. Thorp and E. Walton, J. Chem. Soc, 1948, 559.

24. W. C. Anthony and J. J. Ursprung, U. S Patent, 1969, 3,461,461.

25. Amit .R. Trivedi, Dipti .K. Dodiya, Naresh .R. Ravat and Viresh .H. Shah, Arkivoc, 2008, xi, 131; M.A. Azam, B.R.P. Kumar, S.Shalini and B.Suresh, Ind J. Pharm. Scl, 2006, 70(5), 670.

26. P. Stenbuck and H. M. Hood, U. S. Patent, 1962, 3, 049, 544.

27. P. B. Russell and G. H. Hitchings, J. Amer. Chem. Soc, 1951, 73, 3763.

28. L. H. Sarett, J, Amer. Chem. Soc, 1960, 82, 2994.

29. R. Chaux and C. Dufraise, U. S. Patent, 1931, 1, 869.

30. Sorour Ramezanpour, Mehri Seyed Hashtroudi, Hamid Reza Bijanzadeh and Saeed Balalaie, Tetrahedron Letters, 2008, 49, 3980

31. Chennan Ramalingan and Young-Woo Kwak, Tetrahedron, 2008, 64, 5023.

32. R. Hulme, O.D.P. Zamora, E.J. Mota, M.A. Pasten, R. Contreras-Rojas, R. Miranda, 1. Valencia-Hernandez, J. Correa-Basurto, J. Trujillo-Ferrara and F. Delgado, Tetrahedron, 2008, 64, 3372.

33. Alexander S. Kiselyov Tetrahedron Lett., 2005, 46, 1663.

34. Lai Dhar S. Yadav, Chhama Awasthi, Vijai K. Rai and Ankita Rai, Tetrahedron

Lett., 2008, 49, 2377.

35. Nilo Zanatta, Simone S. Amaral, Josiane M. dos Santos and Debora L. de Mello, Bioorg. & Med. Chem., 2008, 16, 10236.

36. Se Young Kim, Dong Jin Kim, Beom Seok Yang, and Kyung Ho Yoo. Bull. Korean Chem. Soc. 2007, 28, 7.

50

CHAPTER-I

37. Stephanie Hesse, Enrico Perspicace and Gilbert Kirsch Tetrahedron Lett. 2007,48,5261.

38. Clifford D. Jones, David M. Andrews, Andrew J. Barker, Kevin Blades, Kate F. Byth, M. Raymond V. Finlay and Catherine Geh, Bioorg. & Med. Chem. Lett. 2008, 18,6486.

39. Stanley D. Chamberlain, Joseph W. Wilson and Felix Deanda, Bioorg & Med Chem. Lett., 2009, 19, 469.

40. Osamu Irie, Fumiaki Yokokawa, Takeru Ehara, Atsuko Iwasaki and Yuki Iwaki, Bioorg & Med Chem Lett. 2008, 18, 4642.

41. A. Hui Huang, Daniel, Hutta, Huaping Hu and L. Renee, Des Jarlais, Bioorg & Med Chem. Lett., 2008, 18, 2355.

42. Micheal D. Gaul, Guozhang Xu, Jennifer Kirkpatrick, Heidi Ott and Christian A. Baumann, Bioorg & Med. Chem. Lett., 2007, 17 4861.

43. Mahbub Alam, Rebekah E. Beevers, Tom Ceska, Richard J. Davenport, Karen M. Dickson, Bioorg & Med. Chem. Lett., 2007, 17, 3463.

44. Ayoob Bazgir, Maryam Mohammadi Khanaposhtani, AH Abolhasani Soorki, Bioorg Med Chem Lett., 2008, Sep 18,18842404.

45. A.R. El-Gazzar, M.M. El-Enany and M.N. Mahmoud, Bioorg Med Chem., 2008, 16(6), 3261.

46. A.C. Ranade, R.S. Malia and H.R Deshpande, Experientia., 1979, 35, 574.

47. T.H. Althuis, S.B. Khadin, L.J. Czuba, P.P. Moore and H.J Hess, J. Med. Chem., 1980, 23, 262.

48. T. Tilakraj and S.Y. Ambekar, J. Lndian Chem. Soc., 1985, 62, 251.

49. J. A. Eussell, Annu. Rev. Biochem., 1945, 14, 309.

50. R. A. Cox, Quart. Rev., 1968, 22, 499,

51. R. A. Cox, Quart. Rev., 1968, 22, 934; P. Gallery and P. Gannett, Cancer and cancer chemotherapy. In Foye 's Principles of Medicinal Chemistry (eds Williams, D. A and Lemke, T. L.), Lippincott Williams and Wilkins, Philadelphia, 2002, 934.

52. Al Safarjalani, O. N., Zhou, X. J., Ras, R. H., Shi, J., Schinazi, R F., Naguib, F. N. and El Kouni, M. H., Cancer Chemother. Pharmacol., 2005, 55,541.

51

CHAPTER-1

53. W.A. Remers and J.N. Delgado, Antineoplastic agents. In Wilson and Gisvold'sTextbook of Organic Medicinal and Pharmaceutical Chemistry, Lippincott Williams andWilkins, Philadelphia, 1998, 366.

54. G.B. Elion, Fed Proc, 1967, 26, 898.

55. J. H Burchenal, M. L. Murphy and M. P. Sykes, Blood, 1953, 8, 965.

56. B.D. Clarkson, Cancer, 1970, 5, 227.

57. S.A. Giller, R.A. Zhuk and M.I.U. Lidak, Dokl. Akad NaukSSR, 1967, 176,332.

58. J.L. Ambrus, and L. Stadler, J. Med. Chem., 1996, 27, 21; M. Weller, B. Muller, R. Koch, M. Bamberg, and P. Krauseneck, J. Clin. Oncol., 2003, 21, 3276; T. M. Horton, Clin. Cancer Res., 2005, 11, 1884; B. J. Kennedy, J. L. Torkelson, and E. Torlakovic, Cancer., 1999, 85, 2265; J. R. Bertino, Biochem. Pharmacol, 1979, 28, 1983; H. T. Chris, The Oncologist, 1996, 1, 68,

59. L. W. Hertel, G. B. Border, J. S. Kroin, S. M. Rinzel, G.A. Poore, G. C. Todd and G. B. Grindey, Cancer Res., 1990, 50, 4417.

60. Harikishan Singh, V.K. Kapoor, Med and Pharm. Chem., 2001, 497.

61. C. C. Cheng, and B. Roth, In Progress in Medicinal Chemistry (G. P. Eds Ellis, and G. B. West,) Butterworths, London, 1971, 8, 61.

62. G. H. Hitchings, G. B. Elion, H. Wanderers, and E. A. Falco, J. Biol. Chem., 1948, 174, 765.

63. S. Futterman, J. Biol. Chem., 1957, 228, 1031.

64. W. C. Werkheiser, J. Biol. Chem., 1961, 236, 888.

65. C. C. Cheng, and B. Roth, In Progress in Medicinal Chemistry (G. P. Eds Ellis, and G. B. West,) Butterworths, London, 1982, 19, 267.

66. J. A. Montgomery, T. P. Johnston and Y. F. Shealy, In Burgers Medicinal Chemistry, Part II (ed. M. E. Wolf), Wiley-Interscience, New York, 1979, 595.

67. I. Kompis, and A. Wick, Helv. Chim. Acta, 1977, 60, 3025.

68. Shinogi, US Patent, 1959. 2888, 455,

52

CHAPTER-I

69. L. MacDonald, and P. Kazanijan, Formulary., 1996, 31, 470.

70. N. J. White, A . Engl. J. Med., 1996, 335, 800.

71. 1. Von Zabem, R. Nolte, H. Przyklenk, and W. Vogt, Int. Arch.Allergy Appl Immunol., 1985, 76, 205.

72. J. Huges, L. C. Roberts and A. J. Coppridge, J. Urol, 1975, 114, 912.

73. M. S. L. Kwee, and L. M. L. Stolk, Pharm. Weekbl. (Sci.)., 1984, 6, 101.

74. H. Mitsuya, Proc. Natl. Acad. Sci. USA., 1985, 82, 7096.

75. M. M. Mansuri, and J. C. Martin, Annu. Rep. Med. Chem., 1987, 22, 147.

76. V. Sullivan, C. L. Talarico, S. C. Stanat, M. Davis, D. M. Coen, and K. K. Biron, Nature, 1992, 358, 162.

77. M. A. Johnson, G. A. Verpooten, M. J. Daniel, R. Plumb, J. Moss, D. Van Caesbroeck, and M. E. De Broe, Br. J. Clin. Pharmacol, 1998, 46, 21.

78. R. Van Leeuwen, J. Infect. Dis., 1995, 171,1161.

79. H. Mitsuya, (ed.), Anti-HIV Nucleosides: Past, Present and Future, Chapman and Hall, New York, 1997.

80. S. L. Gorbach, J. G. Barlett and N. R. Blacklow, Infectious Diseases, Saunders and Company, Philadelphia, 1998, 330; 1154.

81. J. J. Reddick, S. Saha, J. Lee, J. S. Melnick, J. Perkins and T. P. Begley, Bioorg. Med. Chem. Lett., 2001, 11, 2245.

82. P. Singh, R. Kumar, and B. K. Sharma, J. Enzyme Inhib. Med.Chem., 2003, 18,395.

83. L. P. G. Wakelin, and M. J. Waring, DNA intercalating agents. In Comprehensive Medicinal Chemistry, Drug Compendium (ed. P. G. Sammers), Pergamon Press, 1990, 2, 731.

84. A. Polak, and H. J. Scholer, Chemotherapy., 1975, 21,113.

85. P. A. Hunter, K. G. Darby and N. J. Russel, Fifty years of antimicrobials Past perspectives and ftiture trends. In Symposia of thesociety for General Microbiology (ed. M. Collins), Cambridge University Press, Cambridge, 1995.

53

CHAPTER-I

86. B. Chadwick, M. Addy and D. M. Walker, Br. Dent. J., 1991, 71, 83.

87. F. Hunziker, Helv. Chim. Acta., 1967, 50, 1588.

88. S. Nomoto, J. Antibiot., 1977, 30, 955.

89. E. F. Gale, E. Cundliffe, P. E. Reynolds, M. H. Richmond and M. J. Waring, The Molecular Basis of Antibiotic Action, Wileyand Sons, 1981, 2, 500.

90. T. C. Daniels, and E. C. Jorgensen, Central nervous system depressants In Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry (ed. R. F. Doerge), J. B. Lippincott,Philadelphia, 1982, 33.

91. S. Furukawa, J. Vet. Med Sci., 2000, 62, 23.

92. D. S. Threlkeld, Facts and Comparisons., 1998, 269.

93. J. Vida, and J. Yevich, Sedative hypnotics. In Burger's MedicinalChemistry and Drug Discover (ed. D. J. Abrahim), John Wiley, New Jersy, 2003, 6, 6th edn, 203.

94. Eli Lilly, US Patent, 1 856 792,1932.

95. D. P. Taylor, L. E. Allen, J. A. Becker, M. Crane, D. K. Hyslop and L.A. Riblet, Drug Rev. Res., 1984, 4, 95.

96. D. L. Temple, J. P. Yevich Jr. and J. S. Now, J. Clin. Psychiatry., 1982, 43,4.

97. S. S. Peroutka, Biol. Psychiatry., 1985, 20, 971.

98. F. C. Coalpaert, T. F. Meert, C. J. E. Niemegens and P.A Janssen, J., Psychopharmacology., 1985, 86, 45.

99. G. Fur, M. C. Le Burgerin, C. Malgoures, and A. Uzan, Neuropharmacology., 1979, 18, 591.

100. H. R. Howard, and T. F. Seeger, Annu. Rep. Med Chem., 1993, 28, 39.

101. Abott, US Patent, 2 153 729,1939.

102. Abott, US Patent, 2 153 729,1934.

54

CHAPTER-I

103. M. J. Arnaud, Products of metabolism of caffein. In Caffein, Perspectives from Recent Research (ed. P. B. Dews), Springer-Verlag, New York, 1984, 3.

104. J. Klosa, Arch. Pharm. Ber. Dtsch. Pharm. Ges, 1955, 288, 301.

105. Chemische Werke Albert, DOS, 1973, 2 330 741.

106. Gane's Chem. Works, US Patent, 2 715 125,1955.

107. DE Degussa, 1 119 868, 1959.

108. Wallace and Tieman, US Patent, 3 360 518,1967.

109. R. G. W. Spickett and G. M. Timmis, J. Chem. Soc, 1954, 2887.

110. Pfizer, US Patent, 3 511 836,1970.

111. M. M. Koshy and D. Mickey, Circulation, 1977, 55, 533.

112. H. Hara, M. Ichikawa, H. Oku, M. Shimazawa and M Araie, Cardiovasc. DrugRev.,2mS,22>,A'i.

113. E. Honkanen, A. Pipuri, P. Kairisalo, P. Nore, H Karppaness and I. Paakari, J. Med. Chem., 1983, 26, 143.

114. P. A. Meredith, P. J. Scott, A. W. Kelman, D. M. Hughes and J. L. Reid, Am. J. 77?er., 1995, 2, 541.

115. W. Ganzevoort, A. Rep, G. J. Bonsel, J. I. de Vries, and H. Wolf, Hypertension, 2004, 22, 1235.

116. W. M. Wong, Ann. Pharmacother., 1994, 28, 290.

117. A. Jargon, Lancet, 1991, 337, 1457.

118. H. D. Langtry, Drugs., 1989, 38, 900.

119. J. E. F. Reynolds, (ed.), Martindale, The Extra Pharmacopoeia,Council of The Royal Pharmaceutical Society of Great Britain,London, 1996, 31st edn, 926.

55

CHAPTER-I

120. J. A. Wulfing, US Patent, 2 924 598, 1960.

121. J. Debarge, FE-M, 828, 1960.

122. J. Engel, A. K. Granerus, and A. Svanborg, Eur. J. Clin. Pharmacol, 1975, 8, 223.

123. J. E. F. Reynolds, (ed.), Martindale, The Extra Pharmacopoeia,Counci\ of The Royal Pharmaceutical Society of Great Britain,London, 1996, 31st edn, 1651.

124. Gane's ChemWorks, US Patent, 1955. 2715 125.

125. E. A. Brown, R. Griffith, C. A. Harvey, and D. D. A. Owen, Brit. J. Pharmacol., 1986, 87, 569.

126. C. R. Ganellin, Engl. Reg. Allergy Proc, 1986, 7, 126.

127. B. Gauthier, Ann. Pharm. Fr., 1963, 21, 655.

128. Takeda, US Patent, 1962, 3016380.

129. Schlenk, Enzymologia, 1965, 29, 283.

130. Fujisawa, US Patent, 3 098 856, 1963.

131. S. P. Clissold and R. Beresford, Drugs, 1984, 33, 478.

132. M. E. Jones, Annu. Rev. Biochem., 1980, 49, 233.

133. Victor Meyer, Berichte der Deutschen chemischen Gesellschaft., 1883, 16, 1465.

134. Ward C. Sumpter, Chemical Reviews. 1944, 34(3), 393.

135. Jonathan Swanston, "Thiophene" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2006.

136. Henry Y. Lew and C. R. Noller Org Synth., 1963, 4, 545.

137. W. S. Emerson and T. M. Patrick Jr., Org Synth., 1963, 4, 980.

138. K. B. Wiberg and H. F. McShane , Org Synth., 1955, 3, 1.

56

CHAPTER-I

139. Daniel Lednicer, The Organic Chemistry of Drug Synthesis, New York: Wiley Interscience., 1999, 6, 187.

140. J.G. Speight, The Chemistry and Technology of Petroleum. Marcel Dekker Inc., New York, 1980.

141. P.D. Boehm, D.L. Fiest and A. Elskus, Proceedings of the International Symposium Centre Oceanologique de Bretagne. Brest, 1981, 159.

142. D. Hostettler and K.A. Kvenvolden, Alaska. Org. Geochem., 1994, 21, 927.

143. Z.Wang, M. Fingas and G. Sergy, Environ. Sci. Technol.,. 1994, 28, 1733.

144. J.L. Laseter, G.C. Lawler, E.B. Overton, J.R. Patel, J.P. Holmes, M.I. Shields and M. Maberry, Proceedings of the International Symposium Centre Oceanologique de Bretagne. Brest., 1981, 633.

145. M. Ogata and K. Fujisawa, Water Res., 1985, 19, 107.

146. R.M. Atlas, P.D. Boehm and J.A. Calder, Estuarine, Coastal Shelf Sci., 1981, 12, 589.

147. P.M. Fedorak and D.W.S. Westlake, Can. J. Microbiol., 1982, 29, 291; P.M. Fedorak and D.W.S. V^QsWakQ, Air Soil Pollut., 1984, 21, 225.

148. S. Safti'c, P.M. Fedorak and J.T. Andersson, Environ. Sci. Technol. 1993, 27, 2577.

149. K.G. Kropp, J.T. Andersson and P.M. Fedorak, Environ. Sci. Technol., 1997,31, 1547.

150. C. David. Bressler, A. Jason. Norman and M. Phillip. Fedorak, Biodegradation., 1998, 8, 297.

151. L.P. Christensen and J. Lam, Photochemistry., 1990, 29, 2753.

152. S. Sinninghe Damst'e, W.I.C. Rijpstra, J.W. De Leeuw and P.A. Schenck, Cosmochim. Acta., 1989, 53, 1323.

153. Neeru vasudeva and Pankaj Gupta., Ind, J. Hetero chem.., 2007, 16, 303.

154. M.C. Raviglione, Tuberculosis., 2003, 83, 4; M. A. Espinal, Tuberculosis., 2003, 83,44.

155. D.B. Young, K. Duncan, Ann. Rev. Microbiol, 1995, 49, 641.

57

CHAPTER-I

156. B.C. De Jong, D.M. Israelski, and E.L. Corbett, Annu. Rev. Med, 2004, 55, 283.

157. G. Panda, Shagufta, J.K. Mishra, V. Chaturvedi, and A.K. Srivastava, Bioorg.Med. Chem., 2004, 12, 5269.

158. Maloy Kumar Parai, Gautam Panda, Vinita Chaturvedi, Y. K. Manjub and Sudhir Sinhab Bioorg. Med. Chem. Lett., 2008, 18. 289.

159. E. Janice, Boyd and R. G. Sommerville., Archi. Virology., 1974, 45, 3.

160. Khurshid I. Molvi, Mustakim Mansuri, Vasudevan Sudarsanam, Madhubhai M. Patel, and Syed Muzaffar, Journal of Enzyme Inhibition and Medicinal Chem., 2008, 23, 829.

161. S. Robert, A.J. Miller and S.C. Pagan, Pharmacotherapy., 1991, 11(4), 317.

162. D.E. Wolf and K. Polkers, org, Reac, 6,410,1951.

163. M. Rafat, Mohareb, and Karama El-Sharkawy, Acta Pharm., 2008, 58, 429.

164. D. Binder and P. Stanetty., Synthesis, 1977, 200.

165. Congyang Wang, Jinglong Chen, Qiuling Song, Zhiping Li and Zhenfeng., Arkivoc, 2003, (ii), 155.

166. Thorsten A. Kirschberg, Mini Balakrishnan, Wei Huang and Rebecca Hluhanich, Bioorg Med Chem. Lett., 2008. 18, 1131.

167. Shirley Louise-May, Wengang Yang, Xingtie Nie, Dongmei Liu and S. Milind, Bioorg Med Chem. Lett., 2007, 17, 3905.

168. Alessia Petrocchi, Uwe Koch, Victor G. Matassa and Barbara Pacini, Bioorg Med. Chem. Lett., 2007, 17, 350.

169. R.V. Chambhare and A.S. Bobade., Ind. J, Het Chem., 2002, 12, 67.

170. Wagnat W Wardakhan, Omar M. E. Abdel-Salam and Gamal A. Elmegeed, Acta Pharm., 2008, 5S, 1.

171. H.S. Basavaraja, G.M. Sreenivasa, and E. Jayachandran, Ind. J. Hetr. Chem., 2005, 15,69.

58

CHAPTER-I

172. B. Ramesh, D.R. Bharathi, and H.S. Basavaraja, Asian. J. Chem., 2008, 20, 2591; L.V.G. Naragund and G.R.N. Reddy, Ind. J. Chem., 1996, 25, 499.

173. K. Ishwar Bhat and Mumtaz. M Russian, Asian. J. Chem., 2009, 21, 3371.

174. Richa mishra, Brijesh kunvar Mishra and N.S. Hari Narayana Moorthy, Trends in Applied Sciences Research., 2008, 3, 203.

175. A.I. Vogel, Text book of Practical organic chemistry, ELBS, 4* edition, 1978, 884.

59