studies on potential antimicrobial agents brief...

Studies on potential antimicrobial agents

Page 59

Brief introduction to quinoline:

Quinoline (1-azanaphthalene or benzo[b]pyridine) is a

stable base. Its derivatives represent the major class of

heterocycles and a number of preparations have been

known for a long time. The quinoline ring system occurs

in various natural products, especially in alkaloids. The

quinoline skeleton is used for many valuable synthetic

agrochemicals and to design many synthetic compounds

with diverse pharmacological activities.

The remarkable capabilities of quinoline alkaloids with biological activity have

received considerable attention from the chemical community, especially from

biochemists and synthetic organic chemists who are concerned with human and

animal health care problems. Quinine is a natural white crystalline alkaloid having

antipyretic, antimalarial, analgesic and anti-inflammatory activities and bitter taste.

It is a stereoisomer of quinidine. Quinine was the first effective drug for malaria

caused by Plasmodium falciparum, appearing in therapeutics in the 17th century.1

The best use of quinine is to treat malaria found by Charles Marie de La Condamine

in 1737. Quinine was extracted from the bark of South American Cinchona tree and

was isolated and named in 1817 by French researchers Pierre Joseph Pelletier and

Joseph Bienaime Caventou.

In 1959 Rao and Cullen2 disclosed the isolation of an initially un-named dark brown

metabolite of streptomycin floccules that exhibited striking activity against several

animal tumors.3,4 The same crystalline compound was isolated from

S. afrochromogens and S. echinatus. The active agent of all these streptomyces and

actinomyces species is streptonigirin.5 By applying variations on the same molecular

framework,6 two closely related antibiotics, streptonigrone7,8 and lavendamycin were

isolated. Looking to the literature scan, there are number of reports available that

covers the isolation, structure determination, synthesis and biological activity of

quinoline alkaloids from plant, microbial and animal sources,9-15 in which some of

the therapeutically active quinoline alkaloids are cryptolepine as an antimalarial,16-19

buchapine as an anti-HIV,20 semecarpifoline as an antiplatelet and aggregation,21

galipeine as an antimalarial and cytotoxic,22 and aaptamine as cardiac.23

N

OCH3

OHH

N

Quinine


Page 60

N

O

O

H3CO

H2NN

H2N

COOH

CH3

OCH3

OH

OCH3

N

O

O

H3CO

H2NNH

H2N CH3

OCH3

OCH3

OH

O

StreptonigrinStreptonigrone

Lavendamycin

Cryptolepine

Buchapine

NH

OCH3

CH2OCH3

OH3CO

Semecarpifoline

NOH

OCH3

CH3Galipeine

N

N

H3CO

H3CO H

Aaptamine

NH O

O

N

O

O

H2NN COOH

CH3HN

NH

N

CH3

+

Quinoline constitutes important key core units in a large number of

pharmaceuticals, agrochemicals and in material science.24 Considerable interest has

been created in the chemistry of quinoline due to their wide spectrum of therapeutic

activities like bactericidal,25 anti-HIV,26 antimalarial,27 antitumor,28 inhibitors of

gastric (H+/K+)-ATPase,29 dihydroorotate dehydrogenase,30 5-lipoxygenase,31

leukotriene D4 receptor32 and anthelmintic.33

Methods for the preparation of quinoline:

Skraup synthesis:

The Skraup synthesis is probably the most important synthetic route for quinoline

derivatives. Quinoline is produced when aniline, concentrated sulfuric acid, glycerol

and oxidizing agent are heated together. The reaction has been shown to proceed by

dehydration of glycerol to acrolein; to which aniline then adds in a conjugate

fashion. Acid-catalysed cyclization produces 1, 2-dihydroquinoline, finally

dehydrogenated by oxidizing agent to give quinoline. Skraup synthesis is the best for

the ring synthesis of quinoline unsubstituted on the hetero-ring.34


Page 61

H2C

HC

OH

OH

H2C OH

Con. H2SO4 CH

CHO

CH2

+

NH2

130 oC

NH

OHC

-H2O

NH

C6H5NO2

[O]N

+

NH2

Conrad-Limpach Knorr synthesis:

-Keto ester, such as ethyl acetoacetate can react with an aromatic amine in either

of two ways. The factors governing the manner in which condensation takes place

have been greatly clarified by Houser and Reynolds.35

NH2

CH3COCH2COOC2H5

Room temp.

Boiling pointof mixtutre

N CH3

COOC2H5

NH CH3

COOC2H5

N

OH

CH3

NH

COCH3

O NH

COCH3

OH

N

CH3

OH

Friedlander synthesis:

Friedlander36 obtained quinoline by the condensation of o-aminobenzaldehyde with

acetaldehyde in the presence of sodium hydroxide. The Friedlander ring closure

involves two distinct reactions: (1) Schiff base formation between the amino group of

aniline and the carbonyl group of acetaldehyde and (2) an internal Claisen type

condensation between the aryl aldehyde group and -hydrogen of the acetaldehyde.

Piperidine is used as a condensing agent.37


Page 62

CHO

NH2

CH3

HO N

CHOCH3

H N

NaOH

-H2O

Piperidine

-H2O+

Besthorn and Fischer on the basis of Friedlander’s synthesis of quinoline

demonstrated the mode of formation of flavaniline.38 When acetanilide is heated with

zinc chloride, the acetyl group migrates in part to ortho and para position. The

resulting o-acetyl aniline and p-acetyl aniline then undergo condensation by

Friedlander’s synthesis of quinoline to yield flavaniline.

NHCOCH3

ZnCl2COCH3

NH2

+ H3COC NH2

N

CH3

NH2

Doebner-Von Miller synthesis:

This is a modification of Skraup synthesis of quinolines and consists in heating

primary aromatic amine and aldehydes with sulfuric acid.39 In this synthesis

glycerol is replaced by two molecules of aldehydes40. The ,β-unsaturated aldehydes,

initially formed from two molecules of aldehydes by acid-catalysed aldol

condensation, reacts with aniline to give secondary amine. Its cyclization in presence

strong acid in dehydrogenation yields quinoline homologue. It is believed that the

oxidative step is brought about by the action of Schiff base produced in situ (from

aniline and aldehyde).

NH2

+H3C

CHONH CH3

N CH3

H+

NH CH3

OHC

H3CN

Ph

+PhNHCH2CH3

Combes synthesis:

Combes method resembles Conrad-Limpach-Knorr synthesis so closely that it must

be classed as a variant of this method. Aromatic amines are condensed with 1,3-

diketones and the resulting substances are then ring-closed to 2,4-disubstituted

quinolines.41


Page 63

NH2

+

R1

R2

O

ONH R2

O

R1 H+

-H2ON

R1

R2

R1, R2=Different substituents

Pfitzinger synthesis:

The reaction was carried out by Pfitzinger in 1886, by boiling isatin with sodium

hydroxide solution and the resulting keto-acid is condensed directly with ketone.

Isatin is hydrolysed to an o-amino keto acid which condenses with ketones or acids

that have a reactive methylene group.42

NH

O

O

H3CNaOH

H2O

H3C

NH2

O

COONa

+

R1O

R

-H2O

N

H3C

COOH

R1

R

R, R1= -Me, -Et

Some other methods for the synthesis of quinoline and its various derivatives have

been reported in literature.43-45 In the broad field of quinoline, 2-chloro-3-formyl

quinoline possesses a prominent position in the intermediate category as it can be

utilized for the synthesis of many heterocyclic compounds. There has been relentless

interest towards the use of Vilsmeier-Haack reagent in organic synthesis of several

nitrogen and oxygen heterocycles. It is proved to be a mild and efficient method for

the formylation46-48 of reactive aromatic, heteroaromatic and carbonyl compounds.

The utility of this reagent also explores a powerful route for the synthesis of

substituted 2-chloro-3-formyl quinoline. Meth-Cohn et al49 have shown that

treatment of acetanilide with Vilsmeier-Haack reagent using POCl3 allows the

preparation of 2-chloro-3-formyl quinoline (1).

NH O

CH3

+DMF

POCl3

N Cl

CHO

(1)


4

MECHANISM:

NH

CH3

O

POCl3

N

CH3

Cl O

H

N

CH3

CH3

N

C

Cl

HC N

CH3

CH3

H

NH3C

H3C

CCl

H

N

CN

CH3

CH3

CClH N

H3CCH3

HC

H

N Cl

H N(CH3)2

NCH3

CH3

HH

-NH(CH3)2N Cl

CH NCH3

CH3

N

CHO

Cl

H2O

-HCl

Yang D et al50 have synthesized a rapid and efficient method for the preparation of

various poly-substituted 11H-indeno[1,2-b]quinolines (4) via the Friedlander

condensation of 2-aminoarylaldehyde (2) with a carbonyl compound (3) containing a

reactive α-methylene group in the presence of sodium ethoxide (10 mol %).

R1

R2

R3

R4

CHO

NH2

+

R7

R5

R6

O

CH3CH2ONa

CH3CH2OH

Reflux N

R7R1

R2

R3

R4

R5

R6

R1, R2, R3, R4, R5, R6, R7= Different substituents

(3) (4)(2)

Subhas Bose and Kishore Kumar51 have developed an efficient method for the

condensation of 2-aminoaryl ketones (5) with -methylene ketones (6) in the

presence of catalytic amount of reusable catalyst CeCl3· 7H2O (25 mol %) at ambient

temperature to afford the corresponding poly-substituted quinolines (7) in high

yields under mild conditions.


Page 65

NH2

R

O

+ R2

O

R1

CeCl3. 7H2O

CH3CN

N

R

R1

R2(5) (6) (7)

R, R1, R2= Different substituents

Room temp.

Kidwai M et al52 have developed a convenient eco-friendly procedure for the

quantitative synthesis of novel quinoline derivatives (10) by a simple one pot

reaction of substituted aniline (8) with β-ketoesters (9) at 60˚C in ethanol using

recyclable indium chloride as catalyst. The reaction proceeds smoothly under

solvent free conditions with quantitative yield.

NH2

R + OC2H5

OO

InCl3, Ethanol

60oC

N

CH3

OH

R

R= Different substituents

(8) (9) (10)

Ramakrishnan V T et al53 have synthesized methyl 2-methyl-4-aryl-5-oxo-1H,4H-

5,6,7,8-tetrahydro-quinoline-3-carboxylates (14) by the condensation of cyclic 1,3-

diones (13) with aromatic aldehydes (11) and β-aminocrotonate (12) using thermal

and ultrasound irradiation methods.

CHO

R1

R2

+

NH2H3C

COOCH3

+

O

O

(A) Thermal, 5 hrs Ethanol(B) Ultrasound, 20 mins.

Ethanol, 65-70oC NH

O

CH3

COOCH3

R1

R2

R1= -H, -OH, -NO2

(11) (12) (13) (14)

R2= -H,-Cl, -NO2

Martinez R et al54 have synthesized polysubstituted quinolines (17) by the direct

reaction between the corresponding 2-aminobenzylic alcohol derivative (15) and

either a ketone or alcohol (16) in the presence of a base, without any transition-

metal catalyst.


Page 66

NH2

OH

R

+

R2

O(H)

R1

t-BuOK, Ph2CO

1,4-dioxan, 90oC

N

R

R1

R2(15) (17)

R, R1, R2= Different substituents

(16)

Pawar P A et al55 have synthesized 2-chloro-3-formyl-4-methyl quinoline (19) from

acetophenone oxime (18) under the Vilsmeier cyclization condition.

CH3

NOH

DMF+ POCl3

N

CH3

CHO

Cl

(18) (19)

Li-Min W et al56 have proved that ytterbium perfluorooctanoate [Yb(PFO)3], is an

efficient catalyst for Doebner reaction of pyruvic acid (20), aldehydes (22) and

amines (21) under mild conditions in water to afford quinoline-4-carboxylic acid

derivatives (23) with three component one-pot method in good yield. The process is

operationally simple and environmentally benign and the catalyst has readily been

recycled several times with consistent activity.

OH

O

O

+

NH2

R

+

CHO

R1

Yb(PFO)3H2O, Reflux

N

COOH

(20) (21) (22) (23)

R, R1= Different substituents

R

R1

Gemma S et al57 have synthesized series of N1-arylidene-N2-quinolyl (24) and tested

for their antimalarial activity. These compounds showed remarkable anti-plasmodial

activity in vitro especially against chloroquine resistant strains. Savini L et al58 have

synthesized series of 4-quinolylhydrazones (25) from 4-quinolylhydrazine and aryl or

heteroaryl-carboxaldehyde. These compounds were tested against Mycobacterium

tuberculosis H37Rv and showed interesting antitubercular properties. All the

synthesized diazepino quinoline derivatives showed antibacterial and antifungal


Page 67

activities. Novel 6,8-difluoro-1-alkyl-5-amino-1,4-dihydro-4-oxo-7-{4-substituted

piperazin-1-yl}-quinoline-3-carboxylic acids (26), with the substituents at 4th

position of piperazine being [2(pyridine-4-carbonyl)hydrazono]propyl and

2[(pyrazine-2carbonyl)amino]ethyl, were synthesized and evaluated in vivo against

Mycobacterium tuberculosis H37Rv in Swiss albino mice by Shindikar A V et al.59

N

HN N CH Ar

R

(24)

R= Different substituents

N

HN N CH Ar

R1

R

(25)

R, R1=Different substituents

N

COOH

ONH2

F

N

FN

H3C

CH3

H3C

NHN

O

N

(26)Ar = Different aromatic substituents

Zarghi A et al60 have synthesized a group of 4-carboxyl quinoline (27) derivatives

possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-2

phenyl ring as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure activity

relationships were determined by varying the substituents on the C-7 and C-8

quinoline ring. Nandhakumar R et al61 have showed the study of Vilsmeier–Haack

reagent on 4-hydroxy-quinaldines which resulted in a new versatile intermediate

4-chloro-3-formyl-2-(2-hydroxy-ethene-1-yl)quinolines, which on further treatment

with hydrazine hydrate yielded the desired diazepino quinoline derivatives (28).

Ismaili L et al62 have synthesized new hexahydropyrimido[5,4-c]quinoline-2,5-diones

and 2-thioxohexahydropyrimido[5,4-c]quinoline-5-ones (29) by Biginelli reaction

using appropriate aldehydes, urea derivatives and ethyl acetoacetate. Their

antioxidant properties were evaluated and results showed that compounds

containing thiourea moiety have better activity.

N

COOH

R1

RSO2CH3

R= -H,-CH3,-C6H5 R1= -H

R & R1= -C6H5 & Cyclohexyl

(27)

N

NH

N

Cl

R

R1

R2

R3

R, R1, R2, R3=Different substituents

(28)

R= R1= -CH3

NH

NHN

O

X

R1

CH3R

(29)

X= -O, -S; R= -H, -Cl, -F

R1=-CH3, -C2H5


Page 68

Desai et al63 have synthesized N-(4-((2-chloroquinolin-3-yl)methylene)-5-oxo-2-

phenyl-4,5-dihydro-1H-imidazol-1-yl)-(aryl)amides (30) and studied their

antimicrobial activity. Same group64 has synthesized 1-[2-(2-chloro(3-quinolyl))-5-(4-

nitrophenyl)(1,3,4-oxadiazolin-3-yl)]-3-(aryl)prop-2-en-1-ones (31). Some of these

compounds were found to be good antimicrobial agents.

(30)

R = Different aryl substituents

N Cl

N

N

ONH

R

O

N Cl

O

NN

C CHO CH

NO2(31)

R = Different substituents

R

Domingueza J N et al65 have synthesized quinolinyl chalcones (32) and evaluated for

their inhibition of the Plasmodium falciparum cystein protease falcipain and their

activity against cultured P. Falciparum parasites. Prasad R et al66 have reported 2-

oxo-pyrano[2,3-b]quinoline derivatives (33), and these were subjected to ammonia

treatment to yield the corresponding 2-oxo-pyrido[2,3-b]quinoline derivatives (34).

These compounds were tested for antimalarial, diuretic and antimicrobial activities.

N

H3CO

H3CO Cl

O

R N O O N NH O

(32) (33) (34)R= Different substituents

R R

Introductory features of pyrimidine:

Pyrimidine is the most important member of all the diazines as this ring system

occurs widely in living organism. Pinner67 was the man who first gave the name

pyrimidine to the unsubstituted parent ring. The chemistry68,69 of pyrimidine has

been widely studied in detail. Derivatives of barbituric acid (35), i.e. oxygenated

pyrimidines are perhaps the most widely used in medicine. For example veronal (36)

is used as hypnotics while sodium pentothal (37) is used as an anaesthetic.


Page 69

NH

NH

O

O O

Et

Et

NH

N

O

O S

Et

Me

Et

Na+.NH

NH

O

OO

(35) (36) (37)

Several important sulpha drugs are pyrimidine derivatives and namely they are

sulphadiazine (38a), sulphamerazine (38b) and sulphamethiazine (38c). The

antibiotic bacimethrin (39), is a comparatively, simple pyrimidine which has been

synthesized.70

SO2NHH2N

N

N

R1

R2a) R1= R2= -H

b) R1= -CH3 and R2= -H

c) R1= R2= -CH3

(38a-c)

N

NMeO

NH2

CH2OH

(39)

Three pyrimidines are of considerable biological importance because of their relation

to the nucleic acid, these are uracil (40a), thymine (40b) and cytosine (41). These

are known to be concerned principally with the biosynthesis of complex

carbohydrates and lipids. The purine ring system obtained from the fusion of

pyrimidine and imidazole nuclei is very important because certain of its derivatives,

as example adenine (42), are building block of RNA and DNA. Many substituted

pyrimidines and compounds in which pyrimidine ring is a part of a more complex

ring system are very widely distributed. Vitamin B1, B2 and B10 are pyrimidines.

Certain pyrimidine ribosides and deoxyribosides called nucleosides occur as

phosphoric esters. Some coenzymes are nucleotides that play a key role in metabolic

processes. Hence, at present research is focused on the chemistry of pyrimidines.

NH

NH

O

O

R

a) R= -H

b) R= -CH3

(40a, b)NH

N

O

NH2

(41)

N

NN

NH

NH2

(42)


Page 70

In medicinal chemistry,71 pyrimidine derivatives have been very well known for their

therapeutic applications. The presence of a pyrimidine base in thymine, cytosine

and uracil, which is an essential building block of nucleic acids, DNA and RNA is

one possible reason for its activity. Compounds having pyrimidine nucleus possess

broad range of biological activities, like 5-fluorouracil as anticancer; idoxuridine and

trifluridine as antiviral; zidovudine and stavudine as anti-HIV; trimethoprim,

sulphamethiazine and sulphadiazine as antibacterial; sulphadoxin as antimalerial

and antibacterial; minoxidil and prazosin as antihypertensive; barbiturates e.g.

phenobarbitone as sedative, hypnotics and anticonvulsant; propylthiouracil as

antithyroid; thionsylamine as H1-antihistamine; and toxoflavin and fervennuline as

antibiotics.

HN

N OOH

F

Fluorouracil

N

NH

O

O

O

HO

I

Idoxuridine

HN

NO

OF

F

F

O

OHHO

Trifluridine

N

NH

O

OOHO

NNN- +

Zidovudine

N

NH

O

OOHO

Stavudine

N

N

NH2

H2N

OCH3

OCH3

OCH3

Trimethoprim

N

N

NH S

O

O

NH2

Sulfamethazine

Commercially available pyrimidine based analogues

Synthetic study of pyrimidines:

Chalcone derivatives72 are important starting materials for the syntheses of different

classes of heterocyclic compounds such as pyrazolines, thiophenes and pyrimidines

etc. Most of these compounds are highly bioactive and are widely used in

pharmaceutics. Since the late 1980s, tremendous interest in the pyrimidine

derivatives has been observed, as evidenced by the growing number of

publications.73,74 Many biologically active compounds found in the literature have

pyrimidone, pyrazole or quinoline constituents in their structures.75-78 Recently,


Page 71

pyrimidine derivatives were found to be associated with biological activities such as

antimalarial,79,80 antibacterial81 and anticancer82 activities. Numerous methods have

been reported to prepare pyrimidine derivatives.83-86 Deshmukh M B et al87 have

carried out a green, simple and environmentally friendly approach towards one-step

synthesis of 2,6-diamino-4-phenyl pyrimidine-5-carbonitriles (43) by three-

component condensation of aromatic aldehydes, malononitrile and guanidine

hydrochloride in aqueous medium using potassium carbonate in the presence of

tetrabutyl ammonium bromide. Here, tetrabutyl ammonium bromide was used

which helps for the uniform dispersion of organic compounds in water. The same

reaction was also extended for the aliphatic aldehydes like crotonaldehyde but was

not successful.

CHOAr + +H2N NH2

NH

. HCl

K2CO3, reflux

Water, TBAB

N

N

Ar

CN

H2N NH2

NC CN

(43)Ar = Different aryl substituents

Recently, Munawar M A et al72 have reported synthesis and antimicrobial studies of

some quinolinylpyrimidine derivatives (45a-e). They first synthesized chalcones

(44a-e) by the Claisen-Schmidt condensation and then they condensed quinolinyl

chalcones with urea (or thiourea) in basic media under prolonged refluxing

conditions.

N

R

O

OH

CH3

O

+

OHC

R1 N

R

O

OH O

R1

NH2CXNH2

N NH

X

R1N

OH

O

R

(44a-e)

(45a-e)

Butanol/piperidine

reflux

C2H5OH/KOH

refluxa) -

b)

c)

d)

e)

Et -Cl -O

-Me -Cl -O

-Me -H -O

-Ph

-Ph

-Cl -S

-S-OMe

Compd. R R1 X


Page 72

El-Sayed R88 has synthesized 6-(4-octadecyloxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetra-

hydropyrimidine-5-carbonitriles (47) from octadecanol (46). Octadecanol was

converted to appropriate aldehydes to afford desired product (47).

R-OH R-Cl RO CHO

NH

NHR'

NC

S

O

POCl3

PCl5

p-(OH)C6H4CHO

K2CO3 / acetone

NCCH2COOC2H5

NH2CSNH2, EtOH(46)

(47)

R = -(CH2)17-CH3 O (CH2)17CH3R' =

Mulwad V V and Mayekar S A89 have reported the synthesis and antimicrobial

screening of some pyrimidine derivatives (49) from 6-amino coumarines (48).

OO

R1

R2

NH2

i) HCl, NaNO2

ii) CH2(CN)2

OO

R1

R2

NH N

NC CN

1,4-dioxan

Ac2OR1 and R2 = Different substituents

Z= NX

and X= -O, -CH2

O

R1

R2O

NN

CN

NH2

Z

HZ

O

R1

R2O

NN

N NH

Z O

CH3

(48)

(49)

Bhuiyan M M H et al 90 have synthesized some fused pyrimidines (51), (52) and (53).

The starting material, 2-amino-4,5-diphenylfuran-3-carbonitrile (50) was prepared

according to a modified Gewald method.91 Compounds were screened for their

antibacterial and antifungal activities.


Page 73

O

CNPh

Ph NH2 O

Ph

Ph N

N

NH2

O

Ph

Ph N

NH

O

O

Ph

Ph N

N

NH2

PhO

Ph

Ph N

N

O

Ts

N

N

NO

Ph

Ph

PhCNClCH2CHOp-TsCl

HCONH2HCO2H

(50)

(51) (52) (53)

Bhuiyan M M H et al92 have also reported some new fused pyrimidines like

imidazopyrazolopyrimidines (56). Imidazopyrazolopyrimidine (56) was prepared from

o-aminoester (55) and annelating reagent (54). The compounds were screened for

their antibacterial and antifungal activities.

HN

NS O

Ph

EtOCOOEt

CN

N

NH3CS O

Ph

NNH3C NH2

COOEt

N

NNN

NH3C

Ph

O

O

CH3I

K2CO3

CH3NHNH 2

Ethanol (95%)

Dry HAc

(56)

(55)

(54)

116 Co

Abdel-Mohsen S A93 has synthesized 3-amino-4-imino-5-(8-quinolinol-5-yl)-7-

(p-tolyl)-3,4-dihydropyrrolo[2,3-d]pyrimidine (58) from 2-ethoxymethyleneamino-4-

(8-quinolinol-5-yl)-1-(p-tolyl)-pyrrole-3-carbonitrile (57) in the presence of dry

benzene and hydrazine hydrate. They also reported antibacterial and antifungal

activities of the synthesized compounds.


Page 74

N

OH

CN

CN

Br

N

OH

N

Ar NH2

CN

N

OH

N

Ar N

CN

OEt

H

N

OH

N

N

N

NH

NH2

p-toluidine

n-propanol

CH(OEt)3

N2H4.H2O

Ar = 4-(CH3)C6H4

(57)

(58)

Pharma-significance of pyrimidines:

There has been considerable interest in the development of different types of

synthesis for the production of pyrimidines. This is because pyrimidines represent

one of the most active classes of compounds, possessing a wide spectrum of

biological activity.94-96 Pyrimidines and their fused ring derivatives have a broad

spectrum of biological activity; best known as heterocyclic core of the nucleic acid

bases. These ring systems are often incorporated into drugs designed for

anticancer,97,98 antiviral,99 antihypertensive,100 analgesic,101 antipyretic,102 anti-

inflammatory,103 antipsoriasis104 agents. Some of them are active in the blood

circulatory system105 and can stimulate the skin preparative regeneration and

increase the efficacy of antibiotic therapy of staphylococcus and proteus infected

wounds.106

Pirisino R et al107 have studied 2-phenylpyrazolo-4-ethyl-4,7-dihydro[1,5-

a]pyrimidine-7-one, FPP028 (59), for its analgesic, antipyretic and anti-inflammatory

activities. The anti-inflammatory property of FPP028 was evaluated by carrageenan-

induced paw oedema and cotton pellet-induced granuloma methods and found to


Page 75

possess activity similar to indomethacin, phenylbutazone and isoxicam. Similarly

FPP028 was shown to possess analgesic and antipyretic activities comparable to

former drugs. Modica M et al108 have synthesized some new

thiadiazolothienopyrimidinones and tested them for anti-inflammatory and analgesic

activities and found encouraging results. Cenicola et al109 evaluated some

imidazolo[1,2-c]pyrimidines (60) for anti-inflammatory, analgesic and antipyretic

activities. Desai et al110 have synthesized some new 4-(4-(4-aminophenyl)-6-(aryl)-

1,6-dihydropyrimidin-2-ylthio)butanenitriles (61) and tested them for antimicrobial

activity.

NN

N

C2H5

O(59)FPP028

N N

N

R1

R2

CH3

R1= -Cl, -OCH3, -CH3

R2= -COOH, -CH2COOH

(60)

N NH

S CN

H2N RR = Different substituents

(61)

Nargund L V G et al111 reported the synthesis of few substituted 2-mercapto-3-(N-

alkyl)pyrimido[5,4-c]cinnolin-4-(3H)-ones (62) and screened them for anti-

inflammatory and antimicrobial activities. The compounds showed moderate to good

antimicrobial activity against various Gram-positive and Gram-negative bacteria.

Inhibitory activity of pyrazolo[1,5-a]pyrimidine derivatives (63) against c-Src kinase

for the treatment of acute ischemic stroke was also reported by Mukaiyama H et

al112. One of the synthesized compounds inhibited c-Src selectively and exhibited

satisfactory central nervous system penetration.

NN

NHN

R

O

S

R= -H, -CH3 , R1= -H, -2-CH3, -4-CH3, -4-Cl

(62)(63)

HN NN

N

CH3

NH R3

NH2

O

R1

R2

R1 = -H, -3-OMe, -4-OMe R2 = -H, -5-OMe

R3 = Different substituents

R


Page 76

Looking to the literature survey and pharmacological importance of quinoline and

pyrimidine, we have synthesized the following heterocyclic compounds.

Section 5: N-[6-(2-chloro(3-quinolyl))-4-(aryl)pyrimidin-2-yl]-2-morpholin-4-

ylacetamides.

Section 6: N-[6-(2-chloro-6-fluoro(3-quinolyl))-4-(aryl)pyrimidin-2-yl]-2-morpholin-

4-ylacetamides.

Section 7: N-[6-(2,6-dichloro(3-quinolyl))-4-(aryl)pyrimidin-2-yl]-2-morpholin-4-

ylacetamides.

Section 8: N-[6-(2-chloro-6-methyl(3-quinolyl))-4-(aryl)pyrimidin-2-yl]-2-morpholin

-4-ylacetamides.


Page 77

EXPERIMENTAL PROCEDURE

DMF/POCl3

R' = -H, -4-F, -4-Cl, -4-CH3

(I) (IIa-d)80 oC, Reflux 3 h

NHCOCH3

R'

N Cl

CHO

R' +

COCH3

Ethanol, NaOHStirring, 24 h

N Cl

O

R' R

R

(III)

R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,

-2-F, -3-F, -4-F, -2-NO2, -3-NO2, -4-NO2

Preparation of substituted 2-chloroquinoline-3-carbaldehyde (IIa-d)

Dimethylformamide (0.0125 mol) was charged in a three-necked round bottom flask

equipped with a thermometer, a drying tube and mechanical stirrer and cooled to

0 °C. To it, phosphorous oxychloride (0.035 mol) was added drop wise with stirring

at 0-10 °C. To the solution, corresponding substituted acetanilides (0.05 mol) I

(0.1 mol) was added and mixture was refluxed for 3 h at 80 °C. Reaction mass was

cooled to room temperature and poured onto crushed ice. Solid separated was

filtered, washed with water and recrystallized from ethyl acetate.

Preparation of 3-(2-chloro(3-quinolyl))-1-phenylprop-2-en-1-one (III)

A mixture of 2-chloroquinoline-3-carbaldehyde IIa (0.01 mol) and acetophenone

(0.01 mol) was stirred in ethanolic sodium hydroxide for 24 h at room temperature.

The yellow crystals formed were filtered off, washed with water and recrystallized

from ethanol (95%). Yield: 70%; m.p.: 177 °C; Anal. calcd. for C18H12ClNO: C-73.60,

H-4.77, N-17.02; Found: C-73.67, H-4.71, N-17.08%.

The progress of reaction and purity of compounds IIa-d and III were checked on TLC

[Aluminium sheet silica gel 60 F245 (E. Merck)] plates using n-hexane:ethyl acetate

(7:3) as an irrigator and plates were visualized with ultraviolet (UV) light, or iodine


Page 78

vapour. All compounds were prepared by using the same method and their physical

constants are recorded in TABLE A.

TABLE A

Sr. No.

-RMolecularFormula

%Yield

M. P.°C

Elemental Analysis

% Carbon % Hydrogen % Nitrogen

Calcd Found Calcd Found Calcd Found

IIa -H C10H6ClNO 67 141 62.68 62.74 3.16 3.21 7.31 7.37

IIb -4-F C10H5ClFNO 68 168 57.30 57.24 2.40 2.47 6.82 6.77

IIc -4-Cl C10H5Cl2NO 64 177 53.13 53.19 2.23 2.28 6.20 6.27

IId -4-CH3 C11H8ClNO 76 189 64.25 64.31 3.92 3.86 6.81 6.75


Page 79

SECTION 5

PREPARATION OF N-[6-(2-CHLORO(3-QUINOLYL))-4-(ARYL)PYRIMIDIN-2-YL]-2-

MORPHOLIN-4-YLACETAMIDES

N Cl

N N

HN

Cl

O

N Cl

N N

NH2

N Cl

N N

HN O

N

O

Ethanol, NaOHReflux, 10 h

NH2C(=NH)NH2.HNO3

ClCOCH2Cl Chloroform Reflux, 12 h

Morpholine

Dry toluene

Reflux 8 h

(IV)

(V)

(VI)

Et3N

Anhyd. K2CO3

N Cl

O

R

(III)

R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,

-2-F, -3-F, -4-F, -2-NO2, -3-NO2, -4-NO2

R

RR

SYNTHETIC SCHEME 5


Page 80

PHYSICAL CONSTANTS OF N-[6-(2-CHLORO(3-QUINOLYL))-4-(ARYL)PYRIMIDIN-

2-YL]-2-MORPHOLIN-4-YLACETAMIDES

N Cl

N N

HN O

N

O

R


TABLE 5

Sr. No. -RMolecularFormula

%Yield

M. P.°C

Elemental Analysis



KR5-1 -H C25H22ClN5O2 52 200 65.29 65.22 4.82 4.76 15.23 15.28

KR5-2 -2-OH C25H22ClN5O3 56 184 63.09 63.15 4.66 4.60 14.71 14.75

KR5-3 -4-OH C25H22ClN5O3 53 214 63.09 63.02 4.66 4.71 14.71 14.66

KR5-4 -4-OCH3 C26H24ClN5O3 55 197 63.74 63.79 4.93 4.97 14.29 14.24

KR5-5 -2-Cl C25H21Cl2N5O2 51 168 60.74 60.79 4.28 4.22 14.17 14.13

KR5-6 -4-Cl C25H21Cl2N5O2 58 194 60.74 60.68 4.28 4.27 14.17 14.23

KR5-7 -2-F C25H21ClFN5O2 55 234 62.83 62.89 4.43 4.50 14.65 14.69

KR5-8 -3-F C25H21ClFN5O2 59 170 62.83 62.77 4.43 4.38 14.65 14.71

KR5-9 -4-F C25H21ClFN5O2 52 211 62.83 62.88 4.43 4.47 14.65 14.60

KR5-10 -2-NO2 C25H21ClN6O4 57 183 59.47 59.52 4.19 4.13 16.64 16.70

KR5-11 -3-NO2 C25H21ClN6O4 53 233 59.47 59.42 4.19 4.25 16.64 16.60

KR5-12 -4-NO2 C25H21ClN6O4 50 197 59.47 59.55 4.19 4.27 16.64 16.72


Page 81


Preparation of 6-(2-chloro(3-quinolyl))-4-phenylpyrimidine-2-ylamine (IV)

A mixture of compound III (0.01 mol) and guanidine nitrate (0.01 mol) in ethanol

(95%) was refluxed, while a solution of sodium hydroxide (0.05 mol) in water was

added dropwise for 2 h. Refluxing was continued for further 10 h and mixture was

poured into ice-cold water. Solid product formed was separated by filtration. Crude

product was dried and recrystallized from ethanol (95%). Yield: 68%; m.p.: 163 °C;

Anal. calcd. for C19H13ClN4: C-68.57, H-3.94, N-16.83; Found: C-68.64, H-3.88,

N-16.87%.

Preparation of 2-chloro-N-[6-(2-chloro(3-quinolyl))-4-phenylpyrimidin-2-

yl]acetamide (V)

An equimolar amount of compound IV (0.01 mol) and chloroacetyl chloride (0.01

mol) in chloroform was refluxed for 12 h in presence of catalytic amount of

triethylamine. Excess of solvent was removed under reduced pressure and residue

was stirred with water. Crude product was dried and recrystallized from ethanol

(95%). Yield: 64%; m.p.: 198 °C; Anal. calcd. for C21H14Cl2N4O: C-61.63, H-3.45,

N-13.69; Found: C-61.69, H-3.40, N-13.77%.

Preparation of N-[6-(2-chloro(3-quinolyl))-4-phenylpyrimidin-2-yl]-2-morpholin-

4-ylacetamide (VI) KR5-1

A mixture of compound V (0.01 mol), anhydrous potassium carbonate (0.02 mol)

and morpholine (0.01 mol) in dry toluene was refluxed for 8 h. After completion of

reaction, potassium carbonate was removed by filtration and excess of solvent was

removed under reduced pressure. The obtained residue was filtered, dried and

recrystallized from DMF. Yield: 52%; m.p.: 200 °C; Anal. calcd. for C25H22ClN5O2:

C-65.29, H-4.82, N-15.23; Found: C-65.22, H-4.76, N-15.28%.

The progress of reaction and purity of compounds IV, V and VI were checked

similarly on TLC [Aluminium sheet silica gel 60 F245 (E. Merck)] plates using

n-hexane:ethyl acetate (8:2) as an irrigator and plates were visualized with

ultraviolet (UV) light, or iodine vapour. All compounds of this series were prepared

by using the same method and their physical constants are recorded in TABLE 5.


Page 82

SECTION 6

PREPARATION OF N-[6-(2-CHLORO-6-FLUORO(3-QUINOLYL))-4-

(ARYL)PYRIMIDIN-2-YL]-2-MORPHOLIN-4-YLACETAMIDES

N Cl

N N

HN

Cl

O

F

N Cl

N N

NH2

F

N Cl

N N

HN O

N

O

F


NH2C(=NH)NH2.HNO3


Morpholine

Dry toluene

Reflux 8 h

R

(IV)

(V)

(VI)

Et3N

Anhyd. K2CO3

N Cl

O

F

R

(III)

R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,

-2-F, -3-F, -4-F, -2-NO2, -3-NO2, -4-NO2

RR

SYNTHETIC SCHEME 6


Page 83

PHYSICAL CONSTANTS OF N-[6-(2-CHLORO-6-FLUORO(3-QUINOLYL))-4-


N Cl

N N

HN O

N

O

F


R

TABLE 6


%Yield

M. P.°C

Elemental Analysis



KR6-1 -H C25H21ClFN5O2 50 169 62.83 62.87 4.43 4.48 14.65 14.71

KR6-2 -2-OH C25H21ClFN5O3 54 189 60.79 60.83 4.28 4.34 14.18 14.11

KR6-3 -4-OH C25H21ClFN5O3 52 227 60.79 60.72 4.28 4.21 14.18 14.25

KR6-4 -4-OCH3 C26H23ClFN5O3 58 180 61.48 61.44 4.56 4.61 13.79 13.84

KR6-5 -2-Cl C25H20Cl2FN5O2 54 213 58.60 58.54 3.93 3.99 13.67 13.62

KR6-6 -4-Cl C25H20Cl2FN5O2 52 192 58.60 58.68 3.93 3.87 13.67 13.72

KR6-7 -2-F C25H20ClF2N5O2 58 188 60.55 60.62 4.07 4.14 14.12 14.06

KR6-8 -3-F C25H20ClF2N5O2 55 200 60.55 60.50 4.07 4.01 14.12 14.16

KR6-9 -4-F C25H20ClF2N5O2 57 218 60.55 60.61 4.07 4.11 14.12 14.19

KR6-10 -2-NO2 C25H20ClFN6O4 56 197 57.42 57.49 3.85 3.93 16.07 16.10

KR6-11 -3-NO2 C25H20ClFN6O4 51 177 57.42 57.50 3.85 3.91 16.07 16.01

KR6-12 -4-NO2 C25H20ClFN6O4 58 201 57.42 57.47 3.85 3.80 16.07 16.12


Page 84


Preparation of 6-(2-chloro-6-fluoro(3-quinolyl))-4-phenylpyrimidine-2-ylamine

(IV)






Anal. calcd. for C19H12ClFN4: C-66.06, H-3.45, N-15.97; Found: C-65.13, H-3.40,

N-15.90%.

Preparation of 2-chloro-N-[6-(2-chloro-6-fluoro(3-quinolyl))-4-phenylpyrimidin-

2-yl]acetamide (V)





(95%). Yield: 62%; m.p.: 178 °C; Anal. calcd. for C21H13Cl2FN4O: C-59.03, H-3.07, N-

13.11; Found: C-59.09, H-3.13, N-13.17%.

Preparation of N-[6-(2-chloro-6-fluoro(3-quinolyl))-4-phenylpyrimidin-2-yl]-2-

morpholin-4-ylacetamide (VI) KR6-1





recrystallized from DMF. Yield: 50%; m.p.: 169 °C; Anal. calcd. for C25H21ClFN5O2: C-

62.83, H-4.43, N-14.65; Found: C-62.87, H-4.48, N-14.71%.

The progress of reaction and purity of compounds IV, V and VI were checked on TLC



vapour. All other compounds of this series were prepared by using the same method

and their physical constants are recorded in TABLE 6.


Page 85

SECTION 7

PREPARATION OF N-[6-(2,6-DICHLORO (3-QUINOLYL))-4-(ARYL)PYRIMIDIN-2-

YL]-2-MORPHOLIN-4-YLACETAMIDES

N Cl

N N

HN

Cl

O

Cl

N Cl

N N

NH2

Cl

N Cl

N N

HN O

N

O

Cl


NH2C(=NH)NH2.HNO3


Morpholine

Dry toluene

Reflux 8 h

(IV)

(V)

(VI)

Et3N

Anhyd. K2CO3

N Cl

O

Cl

R

(III)

R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,

-2-F, -3-F, -4-F, -2-NO2, -3-NO2, -4-NO2

R

RR

SYNTHETIC SCHEME 7


Page 86

PHYSICAL CONSTANTS OF N-[6-(2,6-DICHLORO (3-QUINOLYL))-4-


N Cl

N N

HN O

N

O

Cl


R

TABLE 7


%Yield

M. P.°C

Elemental Analysis



KR7-1 -H C25H21Cl2N5O2 52 200 60.74 60.80 4.28 4.22 14.17 14.23

KR7-2 -2-OH C25H21Cl2N5O3 56 184 58.83 63.79 4.15 4.22 13.72 13.77

KR7-3 -4-OH C25H21Cl2N5O3 53 214 58.83 58.89 4.15 4.19 13.72 13.67

KR7-4 -4-OCH3 C26H23Cl2N5O3 55 197 59.55 59.62 4.42 4.47 13.35 13.29

KR7-5 -2-Cl C25H20Cl3N5O2 51 168 56.78 56.72 3.81 3.75 13.24 13.17

KR7-6 -4-Cl C25H20Cl3N5O2 58 194 56.78 56.83 3.81 3.86 13.24 13.28

KR7-7 -2-F C25H20Cl2FN5O2 55 234 58.60 58.67 3.93 3.90 13.67 13.64

KR7-8 -3-F C25H20Cl2FN5O2 59 170 58.60 58.54 3.93 3.88 13.67 13.62

KR7-9 -4-F C25H20Cl2FN5O2 52 211 58.60 58.64 3.93 3.97 13.67 13.73

KR7-10 -2-NO2 C25H20Cl2N6O4 57 183 55.67 55.62 3.74 3.68 15.58 15.64

KR7-11 -3-NO2 C25H20Cl2N6O4 53 233 55.67 55.72 3.74 3.70 15.58 16.52

KR7-12 -4-NO2 C25H20Cl2N6O4 50 197 55.67 55.60 3.74 3.78 15.58 15.62


Page 87


Preparation of 6-(2,6-dichloro(3-quinolyl))-4-phenylpyrimidine-2-ylamine (IV)






Anal. calcd. for C19H12Cl2N4: C-62.14, H-3.29, N-15.25; Found: C-62.21, H-3.35, N-

15.32%.

Preparation of 2-chloro-N-[6-(2,6-dichloro(3-quinolyl))-4-phenylpyrimidin-2-

yl]acetamide (V)





(95%). Yield: 64%; m.p.: 163 °C; Anal. calcd. for C21H13Cl3N4O: C-56.84, H-2.95, N-

12.63; Found: C-56.90, H-2.89, N-12.67%.

Preparation of N-[6-(2,6-dichloro(3-quinolyl))-4-phenylpyrimidin-2-yl]-2-





removed under reduced pressure. The obtained residues were filtered, dried and

recrystallized from DMF. Yield: 52%; m.p.: 200 °C; Anal. calcd. for C25H21Cl2N5O2:

C-60.74, H-4.28, N-14.17; Found: C-60.80, H-4.22, N-14.23%.







Page 88

SECTION 8

PREPARATION OF N-[6-(2-CHLORO-6-METHYL(3-QUINOLYL))-4-


N Cl

N N

HN

Cl

O

H3C

N Cl

N N

NH2

H3C

N Cl

N N

HN O

N

O

H3C


NH2C(=NH)NH2.HNO3


Morpholine

Dry toluene

Reflux 8 h

(IV)

(V)

(VI)

Et3N

Anhyd. K2CO3

N Cl

O

H3C

R

(III)

R = -H, -2-OH, -4-OH, -4-OCH3, -2-Cl, -4-Cl,

-2-F, -3-F, -4-F, -2-NO2, -3-NO2, -4-NO2

R

RR

SYNTHETIC SCHEME 8


Page 89

PHYSICAL CONSTANTS OF N-[6-(2-CHLORO-6-METHYL(3-QUINOLYL))-4-


N Cl

N N

HN O

N

O

H3C


R

TABLE 8


%Yield

M. P.°C

Elemental Analysis



KR8-1 -H C26H24ClN5O2 57 189 65.89 65.83 5.10 5.16 14.78 14.85

KR8-2 -2-OH C26H24ClN5O3 54 175 63.73 63.78 4.94 4.90 14.29 14.35

KR8-3 -4-OH C26H24ClN5O3 58 200 63.73 63.68 4.94 4.99 14.29 14.24

KR8-4 -4-OCH3 C27H26ClN5O3 56 216 64.35 64.41 5.20 5.27 13.90 13.96

KR8-5 -2-Cl C26H23Cl2N5O2 50 198 61.42 61.37 4.56 4.61 13.77 13.83

KR8-6 -4-Cl C26H23Cl2N5O2 52 231 61.42 61.49 4.56 4.51 13.77 13.71

KR8-7 -2-F C26H23ClFN5O2 54 175 63.48 63.55 4.71 4.77 14.24 14.20

KR8-8 -3-F C26H23ClFN5O2 51 188 63.48 63.42 4.71 4.74 14.24 14.29

KR8-9 -4-F C26H23ClFN5O2 55 224 63.48 63.54 4.71 4.66 14.24 14.31

KR8-10 -2-NO2 C26H23ClN6O4 56 192 60.18 60.27 4.47 4.43 16.19 16.14

KR8-11 -3-NO2 C26H23ClN6O4 54 182 60.18 60.13 4.47 4.52 16.19 16.12

KR8-12 -4-NO2 C26H23ClN6O4 58 166 60.18 60.24 4.47 4.41 16.19 16.25


Page 90


Preparation of 6-(2-chloro-6-methyl(3-quinolyl))-4-phenylpyrimidine-2-ylamine

(IV)



added dropwise for 2 h. Refluxing was continued for a further 10 h and mixture was



Anal. calcd. for C20H15ClN4: C-69.26, H-4.36, N-16.15; Found: C-69.21, H-4.43, N-

16.22%.

Preparation of 2-chloro-N-[6-(2-chloro-6-methyl(3-quinolyl))-4-phenylpyrimidin-

2-yl]acetamide (V)


mol) in chloroform was refluxed for 12 h in the presence of catalytic amount of



(95%). Yield: 67%; m.p.: 217 °C; Anal. calcd. for C22H16Cl2N4O: C-62.42, H-3.81, N-

13.23; Found: C-62.48, H-3.87, N-13.27%.

Preparation of N-[6-(2-chloro-6-methyl(3-quinolyl))-4-phenylpyrimidin-2-yl]-2-






recrystallized from DMF. Yield: 57%; m.p.: 189 °C; Anal. calcd. for C26H24ClN5O2:

C-65.89, H-5.10, N-14.78; Found: C-65.83, H-5.16, N-14.85%.







Page 91

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