Studies on potential antimicrobial agents Brief...
Transcript of Studies on potential antimicrobial agents Brief...
Studies on potential antimicrobial agents
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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
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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
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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
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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
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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)
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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.
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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.
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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
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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
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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.
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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)
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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,
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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
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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.
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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.
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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
Studies on potential antimicrobial agents
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
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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.
Studies on potential antimicrobial agents
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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
Studies on potential antimicrobial agents
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
Studies on potential antimicrobial agents
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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
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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
R = Different substituents
TABLE 5
Sr. No. -RMolecularFormula
%Yield
M. P.°C
Elemental Analysis
% Carbon % Hydrogen % Nitrogen
Calcd Found Calcd Found Calcd Found
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
Studies on potential antimicrobial agents
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EXPERIMENTAL PROCEDURE
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.
Studies on potential antimicrobial agents
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
Ethanol, NaOHReflux, 10 h
NH2C(=NH)NH2.HNO3
ClCOCH2Cl Chloroform Reflux, 12 h
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
Studies on potential antimicrobial agents
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PHYSICAL CONSTANTS OF N-[6-(2-CHLORO-6-FLUORO(3-QUINOLYL))-4-
(ARYL)PYRIMIDIN-2-YL]-2-MORPHOLIN-4-YLACETAMIDES
N Cl
N N
HN O
N
O
F
R = Different substituents
R
TABLE 6
Sr. No. -RMolecularFormula
%Yield
M. P.°C
Elemental Analysis
% Carbon % Hydrogen % Nitrogen
Calcd Found Calcd Found Calcd Found
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
Studies on potential antimicrobial agents
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EXPERIMENTAL PROCEDURE
Preparation of 6-(2-chloro-6-fluoro(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: 66%; m.p.: 190 °C;
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)
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: 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
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: 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
[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 other compounds of this series were prepared by using the same method
and their physical constants are recorded in TABLE 6.
Studies on potential antimicrobial agents
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
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
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
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Page 86
PHYSICAL CONSTANTS OF N-[6-(2,6-DICHLORO (3-QUINOLYL))-4-
(ARYL)PYRIMIDIN-2-YL]-2-MORPHOLIN-4-YLACETAMIDES
N Cl
N N
HN O
N
O
Cl
R = Different substituents
R
TABLE 7
Sr. No. -RMolecularFormula
%Yield
M. P.°C
Elemental Analysis
% Carbon % Hydrogen % Nitrogen
Calcd Found Calcd Found Calcd Found
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
Studies on potential antimicrobial agents
Page 87
EXPERIMENTAL PROCEDURE
Preparation of 6-(2,6-dichloro(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: 69%; m.p.: 179 °C;
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)
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.: 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-
morpholin-4-ylacetamide (VI) KR7-1
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 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%.
The progress of reaction and purity of compounds IV, V and VI were checked 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 other compounds of this series were prepared by using the same method
and their physical constants are recorded in TABLE 7.
Studies on potential antimicrobial agents
Page 88
SECTION 8
PREPARATION OF N-[6-(2-CHLORO-6-METHYL(3-QUINOLYL))-4-
(ARYL)PYRIMIDIN-2-YL]-2-MORPHOLIN-4-YLACETAMIDES
N Cl
N N
HN
Cl
O
H3C
N Cl
N N
NH2
H3C
N Cl
N N
HN O
N
O
H3C
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
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
Studies on potential antimicrobial agents
Page 89
PHYSICAL CONSTANTS OF N-[6-(2-CHLORO-6-METHYL(3-QUINOLYL))-4-
(ARYL)PYRIMIDIN-2-YL]-2-MORPHOLIN-4-YLACETAMIDES
N Cl
N N
HN O
N
O
H3C
R = Different substituents
R
TABLE 8
Sr. No. -RMolecularFormula
%Yield
M. P.°C
Elemental Analysis
% Carbon % Hydrogen % Nitrogen
Calcd Found Calcd Found Calcd Found
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
Studies on potential antimicrobial agents
Page 90
EXPERIMENTAL PROCEDURE
Preparation of 6-(2-chloro-6-methyl(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 a 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: 69%; m.p.: 179 °C;
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)
An equimolar amount of compound IV (0.01 mol) and chloroacetyl chloride (0.01
mol) in chloroform was refluxed for 12 h in the 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: 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-
morpholin-4-ylacetamide (VI) KR8-1
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: 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%.
The progress of reaction and purity of compounds IV, V and VI were checked 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 other compounds of this series were prepared by using the same method
and their physical constants are recorded in TABLE 8.
Studies on potential antimicrobial agents
Page 91
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