15

Chapter 1

Introduction and Literature Review

16

1.1 FUNDAMENTALS OF FUTURE PROPOSITION FOR

THERAPEUTIC ENHANCEMENT OF QUINAZOLINE BASED

DRUG CANDIDATES

1.1.1 Introduction

Quinazoline and Schiff’s base are of wide interest because of their diverse

biological and clinical applications. This created interest in researchers

who have synthesized variety of Quinazoline derivatives and screened

them for their various biological activities. Current research work

successfully explores the biological properties of Quinazoline and Schiff’s

base for their future studies.

1.1.2 Therapeutic activities associated with quinazolin nucleus

1.1.2.1 Quinazoline ring as antimicrobial, analgesic and anti-

inflammatory activity

A main clinical problem is the resistance against antimicrobial agents.

Therefore, there are very limited treatment options available for clinician

especially in severly ill and less immune patient {1, 2}. Alagarsamy et al

2000 {3} synthesized 1- (2-phenyl quinazolin-3-yl-4(3H)-one)-3-

substituted thioureas; compound-1 and tested for antibacterial activity

by agar dilution method against Salmonella typhimurium ATCC 33068,

Pseudomonas aeruginosa ATCC 2853, Salmonella paratyphi B, Proteus

vulgaris ATCC 9484, Klebsiella pneumoniae ATCC 13883, Edwersiella

17

tarda and Bacillus subtilis ATCC 6051. These compounds are also

screened for their analgesic activity and anti-inflammatory activity.

N

N

NH

S

N

CH3

CH3

O

Compound 1

The result of this study indicates that compound-1 exhibited potent

analgesic and anti-inflammatory activities. Biological evaluvation was

resulted in a better anti-inflammatory and antibacterial activity of

compound -2.

N

N

O

NH

S

NCH3

CH3

Compound 2

Sarvanan et al. 2009 {4} synthesized a new series of

compounds containing 6, 8-Dibromo-2-phenyl-3-(3-carbethoxy-4, 5,6,7-

tetrahydrobenzothiophene-2-yl)-quinazolin-4(3H)-one and evaluated for

their anti-microbial activity against four gram positive bacteria

(Staphylococcus aureus ATCC 9144, Staphylococcus epidermidis ATCC

155, Micrococcus luteus ATCC 4698 and Bacillus cereus ATCC 11778),

three gram negative bacteria (Escherichia coli ATCC 25922, Pseudomonas

18

aeruginosa ATCC 2853, and Klebsiella pneumoniae ATCC 11298) and two

fungi (Aspergillus niger ATCC 9029 and Aspergillus fumigatus ATCC

46645). Out of the synthesized compounds, brominated derivatives

Compound- 3 exhibited more activity than unsubstituted one.

N

N CH3

O

Br

Br C9H6NS

Compound 3

El-Sharief et al. 2008 {5} synthesized and evaluated a series of N-

Aminoquinazolinones for their antibacterial activity against gram positive

strains (Staphylococcus aureus NCTC-7447, Bacillus cereus ATCC-14579)

and few gram negative bacteria (Serrratia marcesens IMRU-70, Proteus

mirabilis NCTC-289) by the filter paper disc method. 2-Methyl-3-

phenyl(1,2,4)triazolo[5,1-b]quinazolin-9-one; compound-4, 3,3-diacet-

ylamino-6,8-diiodo-2-methylquinazolin-4(3H)-one; compound-5, N1-

Phenyl-N3-(2-phenylamino-4-oxoquinazolin- 3-yl)thiourea; compound-6

were resulted in a enhanced antibacterial activity against tested bacterial

strains.

19

N

N

O

I

IN

N CH3

N

N

O

CH3I

I NCOCH3

COCH3

Compound 4 Compound 5

N

N

O

NH

NH S NH

Compound 6

Furthermore Kohli and its co-workers 2009 synthesized seven

phenylquinazolin acetamide dervatives for their in vitro antibacterial

evaluvation against Staphylococcus aureus and Escherichia coli ESS 2231

at a concentration (100μg/ml) {6}. This was resulted in a screening of one

of the most active synthesized compound, 2-(4-nitrophenoxy)-N-(4-oxo-2-

phenylquinazolin-3(4H)-yl) acetamide; compound-7.

N

N

O

NH

O

O

N+

O-

O

Compound 7

20

Moreover further advancement in anti-microbial resistance

was brought by Nanda et al. 2007 {7} by synthesizing ten 3-

(arylideneamino)-2-phenylquinazoline-4(3H)-ones derivatives. These

compounds were investigated for their antimicrobial activity against both

Gram-positive (Staphylococcus aureus 6571 and Bacillus subtilis) and

Gram-negative bacteria (Escherichia coli K12 and Shigella dysenteriae 6)

using a turbidometric assay method. These results suggest that

Quinazoline derivatives 3-Amino-2-phenyl-2-Chloro-N-(4-oxo-2-

phenylquinazolin-3- quinazolin-4(3H)-one; compound-8 showed

enhanced antibacterial activity than parent compound.

N

N

O

N

Compound 8

For further antibacterial activity evaluvation Quinazolinone fused Propyl

dervatives were synthesized by Eissa et al 2008 {8}. Screening results

showed that 2-chloro-N-(4-oxo-2-propylquinazolin-3(4H) - yl) acetamide

compound-9 and 6-propyl-2H-[1, 2, 4] triazino [2, 3-c] quinazolin-3-(4H)-

one compound-10 were highly active against E. coli and B.sublet.

N

N

O

NH

CH3

OCl

21

2-chloro-N-(4-oxo-2-propylquinazolin-3(4H)- yl) acetamide (compound 9)

N

NCH3

NH

N O

6-propyl-2H-[1,2,4]triazino[2,3-c]quinazolin-3-(4H)-one (compound 10)

The reports on the novel synthesis for amino substituted quinazolin

derivatives were initially explored by Mathew et al. 2008 {9}. These

derivatives of 2-(-N-substituted amino) methyl-3-(4-chlorophenyl)-

quinazolin-4(3H)-ones were synthesized and tested for antiinflammatory

and antimicrobial activity by carrageenan-induced rat paw oedema model

and cup-plate method. This evaluvation was resulted in the evolution of a

potent anti-bacterial and anti-inflammatory agent i.e. 3-(4-chlorophenyl)-

2-[(3-hydroxy phenyl amino) - methyl]-3h-quinazolin-4-one; compound-

11.

N

N

Cl

NH

O

OH

3-(4-chlorophenyl)-2-[(3-hydroxy phenyl amino)- methyl]-3h-quinazolin-

4-one (Compound 11)

22

Further contribution towards antibiotics was given by Rohini et al. 2009

{10}. They synthesized a series of 6-arylbenzimidazo [1, 2 c] quinazolines

from 2-(o-aminophenyl) benzimidazole by studing on three Gram-positive

(S. aureus, B. subtilis, S. pyogenes), three Gram-negative (S. typhimurium,

E. coli, K. pneumonia) bacteria and three fungal strains (A. niger, C.

albicans, T. viridae). Screening results showed that 2-

Benzo[4,5]imidazo[1,2-c]quinazolin-6-yl-4-nitrophenol compound-12, 6-

(1-Isoquinolyl)benzo[4,5] imidazo[1,2-c]quinazoline compound-13, 6-(3-

Pyridyl)benzo[4,5] imidazo[1,2-c]quinazoline compound-14 were the most

potent inhibitor against tested bacteria.

N

N

NOH

NO 2

2-Benzo[4,5]imidazo[1,2-c]quinazolin-6-yl-4-nitrophenol (compound 12)

N

N

N

N

6-(1-Isoquinolyl)benzo[4,5] imidazo[1,2-c]quinazoline (compound 13)

23

N

N

N

N

6-(3-Pyridyl)benzo[4,5] imidazo[1,2-c]quinazoline (compound 14)

Nineteen substituted quinazolinyl/imidazolyl-salicylic acids and their

peptide derivatives were synthesized. All derivatives were assayed for

antimicrobial and anthelmintic activities against eight pathogenic

microbes and three earthworm species. Among the tested compounds,

compound-15 and their hydrolyzed analogs exhibited higher

antimicrobial and anthelmintic activity {11}.

24

N

N CH3

OH

NHO

X OCH3

N

NCH3

NH

CH3 O

O

X

Compound 14

Patel and its co-workers 2007 experimented the synthesized

drug (2-[2-(2, 6 dichlorophenyl) amino] phenyl methyl-3-[4-(2-substituted

phenyl-4-oxothiazolidinyl) aryl]-6-bromo quinazolin-4 (3H) one derivatives)

on bacterial and fungal strains {12}. This furnished an outcome that

compounds containing 4-OCH3; compound-15 and 3, 4, 5-(OCH3)3;

compound-16 was found to be most active compounds.

25

N

N

ON

S

O

N HC l

C l

B r

H 3 CO

(Compound15)

N

NH

Br

ON

S

O

NHCl

Cl

OCH 3

ClH 3CO OCH 3

(Compound 16)

A series of 4-[2-methyl-4-oxo-4H-quinazolin-3-yl] benzoic

acid were synthesized and screened for anti-inflammatory, antibacterial

and antifungal activity. This investigation suggests that compound-18

was most potent {13}.

26

N

N NH

O

Compound 17

Amulgmation of mannich base and quinazoline nucleus

lead to the development of a potent anti-bacterial agent; 3-[(4-hydroxy-3-

iodo-5-methoxybenzylidene) amino]-2-methyltetrahydropyrimidin-4(1H)-

one - 1,3-dichlorobenzene (1:1), compound -18 and compound-19

against E. coli, S. aureus, X. citri and E. carotovora. {14}.

Cl

Cl

N

NH

CH3

N

O

I

OHOCH3

Cl

Cl

N

NH

CH3

N

OO

I

OHOCH3

Compound 18 Compound 19

Structure associated synthetic and anti-inflammatory evaluation of a

series of nine 5-(4chlorophenyl)-9-iodo-3-substituted-1, 2, 4 triazole {4,

3-c} quinazoline and 2-(4-chlorophenyl)-6-iodo-4-substituted quinazolin

was experimented by M.S Mohmed et al. 2005 {15}. Throughout this

screening compound-20, compound-21 and 22 showed high anti-

inflammatory activity.

27

N

N

Cl

I

NN

Compound 20

N

N

Cl

I

NNN

Compound 21

N

N

Cl

I

NO

Compound 22

Investigation on 2-(4-chlorophenyl)-6-iodoquinazoline frame work was

done by Mosaad et al. 2004 {16}. This study was further explored by

identifying some of the most pathogenic strain resistant biological

molecule such as Quinazolin-4-yloxy-2-thiobarbituric acid compound-23,

Quinazolin-3-yloxy-2- thiobarbituric acid compound-24, Quinazolin-4-yl-

2-thiobarbituric acid compound-25.

28

N

N

Cl

I

O

NH

NH

O

O S

N

N

Cl

IO

O

NHNH

OO

S

Compound 23 Compound 24

N

N

Cl

I

NH NH

O O

S

Compound 25

NH

N

Cl

I

NHN

O

O

Compound 26

29

NH

N

Cl

I

NHN

O

O

Compound 27

Again amulgemation of indole and pyrrolidine (1-{[2-(4-chlorophenyl)-

6-iodo-3, 4-dihydroquinazolin-4 yl] amino} pyrrolidine-2, 5-dione

compound-26 and 2-{[2-(4-chlorophenyl)-6-iodo-3,4-dihydroquinazolin-4-

yl]amino}-1H-isoindole-1,3(2H)-dione; Compound-27 resulted in superior

antibacterial activity.

A new series of eighteen anthranilic acid derivatives were prepared and

investigated for their antibacterial activities against Staphylococcus

aureus and Bacillus subtilis. Out of which Compounds 28, showed the

highest activity {17}.

N

N

Cl

IO

O

NHNH

OO

S

Compound 28

30

Inco-operation of thiadiazol ring in quinazoline chloro

associated benzoyl framewok helps in development of another series of

antibacterial agents Compound-29; reported by the Pattan et al 2009

{18}. Furthermore N1-3-(5-substituted-1, 3, 4-thiadiazol-2- yl)–(2-amino

methyl) quinazolin (3H)-one compound released its thirty derivatives and

gained wide applications in medicinal chemistry.

N

N

N

S

N

NH

ONO2

N

N

N

N

Compound 29

Two new series of 6-iodo-2, 4-dithio-4(3H) Quinazoline and 6-iodo-2-

thio-4-oxo-quinazoline were prepared and screened for their

antimicrobial activity. 2-[(1H-benzimidazol-4-ylsulfanyl) methyl]-3-(4-

chlorophenyl)-6-iodoquinazolin-4(3H)-one compound-30 showed marked

antimicrobial activity against a panel of Gram-positive and Gram-

negative bacteria and pathogenic fungi {19, 20}.

N

N

O

I

Cl

S N

NH

31

Compound 30

Sahu et al. 2008 {21} synthesised a series of novel Schiff bases of 2-

methylquinazoline/6-bromo-2-methylquinazoline- 4(3H)-ones and

screened for antimicrobial, analgesic, anti-inflammatory and

antihelmintic activities. Compound-31, which contain morpholinomethyl

moiety at 1 position, was found to be the most active compound as

analgesic, anti-inflammatory and antimicrobial agent.

N

NH

CH3

O

N

N

O

NH

Br

NO

Compound 31

1.1.2.2 Quinazolin-4-One Derivatives as Potential Antitubercular

Agents

Worldwide prevalence of Tuberculosis (TB) requires an effective molecule

to inhibit the multiplication of Mycobacterium tuberculosis among various

spieces {22, 23}. According to recent data of World Health Organization

(WHO), 5000 people die every day from this infection {24}. It was

estimated that if proper control measures are not established up to 2020,

approximately 1000 million people will suffer from this disease {25-27}.

32

Wide observations among drug resistant patients broadened the class of

anti-tubercular agent every day. Thus to avoid the time consumed while

seeking the novel molecule, the existing molecules can be worked out to

improve their effectiveness.

Additionally antitubercular activity of synthesized quinazolin-3(4H)-ones

acetamide derivatives was confirmed by Raghvendera et al 2007 {28}.

During this study 6,8-dibromo-3-{[3-(5-methyl-2H-imidazol-4-yl) prop-1-

en-2-yl] amino}-2-phenylquinazolin-4(3H)-one; Compound-32 showed

excellent activity due to presence of imidazole ring.

N

N

NH

CH2OBr

Br

N N

CH3

Compound 32

Omar Al-Deeb et al. 2009 {29} observed that incorporation of alkylthio

moiety in quinozoline nucleus was responsible for improved

antitubercular activity of 2-alkylthio-6-iodo-3-substituted-quinazolin-4-

one derivatives against Mycobacterium tuberculosis strain HRv, using the

radiometric BACTEC 460-TB methodology. However toxicity test based

screening was assessed by serial dilution on VERO cell line. The results

indicate that 2-{[2-(4-bromophenyl)-2-oxoethyl]sulfanyl}-6-iodo-3-[(1E)-

prop-1-en-1-yl] quinazolin-4(3H)-one; compound-33, 6-iodo-3-[(1E)-

prop-1-en-1-yl]-2-[(1E)-prop-1-en-1-ylsulfanyl]quinazolin-4(3H)-one;

33

Compound-34 and 6-iodo-3-phenyl-2-[(1E)-prop-1-en-1-

ylsulfanyl]quinazolin-4(3H)-one; compound-35 showed 96%, 97% and

94% growth inhibition, at a concentration of 6.25 µg/ml. The Inhibitory

Concentration for these 3 compounds, was found to be 8.522 µg/ml, 50

2.589 µg/ml and 23.167 µg/ml.

N

N

O

SO

Br

ICH3

N

N

O

S

ICH3

CH3

Compound 33 Compound 34

N

N

O

S

I

CH3

Compound 35

Waisser et al. 2000 {30} observed that the alkyl group bound to an

electron deficient carbon atom in Quinazoline can be used as

pharmacophore for the development of antitubercular drug.

Mosaad et al. 2007 {31} synthesized a series of 2-(4-

chlorophenyl)-6-iodo-3, 4-dihydroquinazolin-4-one derivatives and

screened for antitubercular activity. {[2-(4-chlorophenyl)-6-iodo-3, 4

34

dihydroquinazolin-4-yl] sulfanyl} acetonitrile; compound-36 was most

active compound.

NH

N

I

Cl

S

CN

Compund 36

Kubicová et al. 2003 {32} synthesized two series of 2, 2-

dimethyl-3-phenyl-1, 2-dihydroquinazoline-4(3H)-thiones and 2- methyl-

3-phenylquinazoline-4(3H)-thiones and investigated for their

antimycobacterial, photosynthesis-inhibiting activity. 6-Chloro-3-(4-

isopropylphenyl)-2-methylquinazoline-4(3H)-thione (compound 35)

exhibited higher activity than the isoniazid standard against

Mycobacterium avium and M. kansasii.

N

N

ClS

CH3

isoC3H7

Compound 37

Pattan et al. 2006 {33} synthesized a new series of N-3[4-(4-chlorophenyl

thiazole-2-yl)-2 amino methyl] quinazolin-4(3H-one) derivatives and

screened for their antitubercular activity using H37RV strain. N-({3-[4-(4-

35

chlorophenyl)-1,3-thiazol-2-yl]-4-oxo-3,4-dihydroquinazolin-2 yl}methyl)

pyrazine-2-carboxamide compound-38, Compound-39 and compound-40

showed maximum antitubercular activity.

N

N NH

O N

S

Cl

O

N

N

N

N NH

O N

S

Cl

NH

O

N

Compound 38 Compound 39

N

N N H

O N

S

C l

O

OH

O H

Compound 40

1.1.2.3 Quinazolinones as antioxidant

Amino functionality regulated antioxidant activity of 6-iodo-2-propyl-

4(3H)-quinazolinone derivatives was proved by Al-Omar et al. 2006 {34}.

36

By keeping in view of this they synthesize a series of 6-iodo-2-propyl-

4(3H)-quinazolinone derivatives as well as its fused heterocyclic and

screened for their antioxidant activity. 98% inhibition of aldehyde

oxidase was achieved by 1-(6-iodo-4-oxo-2-propylquinazolin-3(4H)-yl)

urea; compound 41 and 3-amino-6-iodo-2-propylquinazolin-4(3H)-one;

compound 42. It was analyzed that Ki values ranging from 50-400 mM

was reliant on percentage of aldehyde oxidase inhibition.

N

N

O

INH

O

NH2

C3H7

N

N

O

INH2

C3H7

Compound 41 Compound 42

1.1.2.4 Quinazoline as anticancer

Cancer, a metastatic disorder proliferates from centuries which are not

eliminated yet from root level. Previous therapies were failed to show

their results. Hence chemotherapy is one of the ways to fight against

cancer. Therefore, the need for accelerated development of new, more

effective as well as less toxic chemotherapeutic agents has appeared.

Cipak et al. 2007 {35} synthesized a new series of 2-phenoxymethyl-3H-

quinazolin-4-one (PMQ} derivatives. Out of which 2-(phenoxymethyl)

quinazolin-4(3H)-on PMQ Compound-43 was chosen that inhibit the

growth of HeLa cells. Although optimal concenteration of PMQ (1.0 μM

and 5.0 μM was required to induce features typically associated with

37

apoptosis. Analysis of HL-60 cells treated with 5.0 μM of PMQ provided

clear evidence that PMQ-treated cells were dying by apoptosis as sub-G0

cell fraction, apoptotic DNA fragmentation and active forms of caspase-9

and caspase-3 were detected.

NH

N

O

O

Compound 43

Chandrika et al. 2009 {36} synthesized a series of Quinazoline derivatives

and screened for anticancer activity. Based to the IC50 values, it is

concluded that compound-44 showed highest activity against THP-1 and

HL-60 among all the compounds.

NH

N

NH( )n CH3

CH3

Compound 44

1.1.2.5 Antimalarial Activities

Malaria is one of the most epidemic and endemic diseases in developing

countries. Owing to the prevalence of malaria, several novel drugs were

38

developed. However, till now no drug was proved to be more effective

against this disease. Therefore, there is an eminent need for new and

safe antimalarial drugs to combat this disease in areas of malaria

endemicity.

Guan et al 2005 {37} synthesized some derivatives wherein

the amino groups at positions 1 and 3 were substituted to render the

new carbamate, carboxamide, succinimide or alkyamine derivatives. The

antimalarial efficacy of all new derivatives was first assessed in vitro

against four clones of P. falciparum, D-6, RCS, W-2, and TM91C235,

followed by the Thompson test against P. berghei in mice. Based on the

preliminary test result, compound-45 was further tested in aotus

monkeys against P. falciparum and P. vivax, the latter of which is highly

resistant to antifolates.

N

N N CF3

NH

O

OCH3

NH

OCH3

Compound 45

Several 6-substituted 2, 4-diaminoquinazolines and 2, 4-diamino-5, 6, 7,

8-tetrahydroquinazolines derivatives are synthesized and evaluated by

Ommeh et al. 2004 {38}. Compound-46 are potent inhibitors of the

39

growth of the highly pyrimethamine-resistant strain V1S, with IC50 > 50

nM.

N

NNH2

NH2

OCH3

Compound 46

1.1.2.6 Antiviral and cytotoxic activities

Khalil et al 2003 {39} synthesized a new series of 2-substituted mercapto-

3-benzyl-6-iodo-4(3H)-quinazolinone. Compound 2-[(3,6-dioxo-pyridazin-

4-yl)thio]-3-benzyl-4-oxo-6- iodo-3H-quinazoline; compound-47 proved to

be the most active members, as compared to the known drug. They

showed MG-MID, GI50 values of 12.8 μM.

NH

NH

O

O

SN

N

OI C6H5

Compound 47

1.1.2.7 C.N.S Activity

Padia et al. 1998 {40} synthesized a novel series of

CCK-B receptor antagonists by combining key pharmacophores.

40

Introduction of -NH- as a linker dramatically enhanced binding affinity

and selectivity for CCK-B receptors.

Further investigation was carried out by Zappala et al. 2003

{41}. They designed and screened a set of novel 1-aryl-6, 7-

methylenedioxy-3H-quinazolin-4-(thione} (compound 48) as

anticonvulsant agents in DBA/2 mice.

NH

N

S

O

O

Compound 48

A series of eighteen novel 3-[5-substituted phenyl-1, 3,

4-thiadiazole-2-yl] substituted quinazoline-4(3H)-ones derivatives was

synthesized and evaluated for anticonvulsant, sedative-hypnotic and

CNS depression activities by Jatav et al. 2008 {42}. Two seizures induced

models were adopted for this study is Maximal electroshock induced

seizures (MES) and subcutaneous pentylenetetrazole (scPTZ).

Experimental observations indicate that 3-(2, 5-dihydro-1, 3, 4-

thiadiazol-2-yl)-2-(2-phenylethyl) quinazolin-4(3H)-one; compound-49

was better sedative-hypnotic and CNS depressant.

41

N

N

N

S

NO

Compound 49

Georgey et al. 2008 {43} synthesized number of 3-substituted-2-

(substituted-phenoxymethyl) quinazolin-4 (3 H) one derivatives.

Evaluvation of structurally linked anticonvulsant properties were found

to be remarkable in chloro substituted quinazoline compounds such as

Compound-50.

N

NO

ClCl

NH ( )n

O

O Cl

Compound 51

1.1.2.8 Other activity

Quinazolin ring have many other activity like antidiabetic {44}, anti-HIV

{45}, antihypertensive activity {46} and Bronchodilatory activity {47}.

Diversified actions brodenes the research scope for the Quinazolin

compounds since more attention is still required in its amulgmation for

the future developed pathogenic strains.

42

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44

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