Antibacterial activity of coumarine derivatives synthesized from 4-Chloro-chromen-2-one. The comparison with standard drug

Article abstract of DOI:10.13005/ojc/300433

This work reports the synthesis of some new derivatives from 4-Chloro-chromen-2-one and describe the results of antibacterial activity of purified compounds. Compounds 4-Butylamino-chromen-2-one (1a) , 4-Butylamino-2-oxo-2H-chromene-3-sulfonyl chloride (2

Full text of DOI:10.13005/ojc/300433

ISSN: 0970-020 X
CODEN: OJCHEG
2014, Vol. 30, No. (4):
Pg. 1747-1752
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Antibacterial Activity of Coumarine Derivatives
Synthesized from 4-Chloro-chromen-2-one. The
Comparison with Standard Drug
AZIZ BEHRAMI
Faculty of Food Technology, University of Mitrovica, Kosovo.
*Corresponding author E-mail: a.behrami_chem@live.com
http://dx.doi.org/10.13005/ojc/300433
(Received: August 05, 2014; Accepted: September 26, 2014)
ABSTRACT
This work reports the synthesis of some new derivatives from 4-Chloro-chromen-2-one
and describe the results of antibacterial activity of purified compounds. Compounds 4-Butylamino-
chromen-2-one (1a) , 4-Butylamino-2-oxo-2H-chromene-3-sulfonyl chloride (2a) , 4-Butylamino-
2-oxo-2H-chromene-3-sulfonic acid (2-hydroxy-phenyl)-amide (3a), 4-Butylamino-5-ethyl-2-oxo-
7-(N’-phenyl-hydrazino)-2H-chromene-3-sulfonic acid (2-hydroxy-phenyl)-amide (4a) , have been
synthesized and characterized using melting points , IR spectra , 1H-NMR and 13C-NMR spectra.
The antibacterial activity of synthesized compounds and streptomycin at concentractions of 1mg/
ml, 3mg/ml and 5mg/ml , have been evaluated against three strains of bacterial culture;
Staphylococcus aureus, E.coli and Klebsiella.The compounds show bacteriostatic and bactericidal
activity.
Key words: 4-Chloro-chromen-2-one, Coumarine derivatives,
Antibacterial activity, Staphylococcus aureus, E.coli, Klebsiella, Streptomycin.
INTRODUCTION
(Anthoxanthum odoratum) , woodruff (Galium
odoratum) , mullein (Verbascum spp), and sweet
grass (Hierochloe odorata).Coumarine and their
derivatives have shown varius biological activities.
Their fame has come mainly from their antithrombic,
antiinflammatory, vasodilatory , and antiviral
activities. Other several coumarin derivatives have
antimicrobial properties (Sanghyun ; et al 1996 ;
Mohareb et al 2007; Nofal et al 2000), have urged
us to synthesize some new coumarin derivatives
and to investigate their antibacterial activity against
Starting from 4-Chloro-chromen-2-one (a);
derivatives (1a,2a,3a,4a) are synthesized
Coumarin derivatives are large group of
heterocyclic with oxygen as heteroatom (Govori et
al 1996 ; Govori et al 2002 ; Stanovnik et al
1993).Coumarin is a chemical sompound
(specifically , a benzo--pyrone) found in many
plants (Lee et al 2002) notably in high concentration
in the tonka bean ( Dipteryx odorata), vanilla grass

1748
BEHRAMI, Orient. J. Chem., Vol. 30(4), 1747-1752 (2014)
staphylococcus aureus, E.coli and Klebsiella.The 500 ‘NMR 1’ spectrometer using DMSO-d6 as the
antibacterial activity of synthesized compounds is solvent andTMS as the internal references standard
compared with antibacterial activity of streptomycin. (  = 0,00 ppm).Chemical shifts are expressed in ´
ppm.Mass spectra were taken on a LKB 9000 mass
MATERIALAND METHODS
spectrometer.
Experimental Chemistry
Element analysze was performed on a
Compounds 4-Butylamino-chromen-2- Perikin-Elmer 240 BCHN analyzer.The purity of the
one (1a) , 4-Butylamino-2-oxo-2H-chromene-3- compounds (synthesized) was routinely checked
sulfonyl chloride (2a) , 4-Butylamino-2-oxo-2H- by TLC using Merck Kieselgel-60 (F-254) and
chromene-3-sulfonic acid (2-hydroxy-phenyl)- benzene,toluene,glacial acetic acid (80:10:10)as
amide (3a), 4-Butylamino-5-ethyl-2-oxo-7-(N’- mobile phase. The spots were exposed in iodine
phenyl-hydrazino)-2H-chromene-3-sulfonic acid (2- vapour for visualization.
hydroxy-phenyl)-amide (4a),are synthesized.
The identification of 2H-chromen-2-one Synthesis of 4-Butylamino-chromen-2-one (1a)
derivatives (1a,2a,3a,4a) , is made by using melting
For this synthesis is used as substrat 4-
point , infrared , H NMR , 13C NMR spectra and Chloro-chromen-2-one in a 100 ml flask mixed 3 g
elemental analysis. Melting point was determinated of 4-Chloro-chromen-2-one with 8ml C2H5OH ,
on a Electrothermal apparatus (Fisher Scientific equivalent amount Butylamino. The mixture was
1
o
2555) in a open capillary tube and are refluxed at 250 C for ca. 90 min. The obtained
uncorrected.Infrared spectra were recorded in cm-1 crystals brown are filtred and rinsed with ethanol
for KBr pellts on a FT-IR Shimadzu 8400S and dried at room temperature.Recrystallization
spectrophotometer with resolution 4 cm-1 . 1H NMR form absolute ethanol gave a red product of 80%
spectra were recorded on a Bruker UNITY plus- yield, melting point 117oC.(Sheme 1)
Cl
H
N
O
CH2CH2CH2CH3
C2H5OH
Butylamino
O
O
O
4-Chloro-chromen-2-one
4-Butylamino-chromen-2-one
1a
a
Scheme 1: Synthesis of Compounds 4-Butylamino-chromen-2-one (1a)
Synthesis of 4-Butylamino-2-oxo-2H-chromene-
3-sulfonyl chloride (2a)
The mixture was refluxed at 80 oC for ca.
1.5 h . The obtained brown crystals are filtred and
In a 100 ml flask were mixed 2.5g of 4- dried at room temperature . Recrystallization form
Butylamino-chromen-2-one, with 5ml CH3CN , 1ml C2H5OH gave brown crystals product of 70%
ClSO3H , 0.3 ml Et3N .
yield,meltingpoint, 287 oC. (Scheme 2) .
H
N
CH2CH2CH2CH3
O
CH2CH2CH2CH3
H
N
S
Cl
ClSO3H
O
CH3CN
Et3N
O
O
O
O
4-Butylamino-chromen-2-one
4-Butylamino-2-oxo-2H-chromene-3-sulfonyl chloride
1a
2a
Scheme 2 - Synthesis of 4-Butylamino-2-oxo-2H-chromene-3-sulfonyl chloride (2a)

BEHRAMI, Orient. J. Chem., Vol. 30(4), 1747-1752 (2014)
1749
Synthesis of 4-Butylamino-2-oxo-2H-chromene-
3-sulfonic acid (2-hydroxy-phenyl) -amide (3a)
In a 100 ml flask were mixed 1.5g 4-
flask was placed in an ice bath for 1h until yellow
crystalline precipitate was formed.
Butylamino – 2 – oxo - 2H- chromene - 3- sulfonyl
chloride with 4 ml Dioxane and 1g aminophenol ,
0.2 ml HCl , 0,2 ml Et3N as katalyzer. The mixture
was refkuxed at 92 oC in water bath for ca. 2 h .The
After
filtration the product was
recrystallized from ethanol .The recrystallizacion
from ethanol gave a yellow product at 70% yield,
melting.point;180oC. (Scheme 3 ).
CH2CH2CH2CH3
O
OH
CH2CH2CH2CH3
O
H
N
H
N
H
N
S
Cl
S
Aminophenol
O
O
Dioxane
HCl
O
O
O
O
4-Butylamino-2-oxo-2H-chromene
4-Butylamino-2-oxo-2H-chromene-3-sulfonic acid (2-
-3-sulfonyl chloride
hydroxy-phenyl)-amide
2a
3a
Scheme 3: Synthesis of 4-Butylamino-2-oxo-2H-chromene-3-sulfonic acid (2-hydroxy-phenyl) -amide (3a)
OH
CH2CH2CH2CH3
O
H
N
H
N
S
O
O
O
4-Butylamino-2-oxo-2H-chromene-3-sulfonic acid
(2-hydroxy-phenyl)-amide
3a
Phenylhydrazino
ClCH2CH3
AlCl3
C2H5OH
HCl
Et3N
OH
CH2CH2CH2CH3
O
S
H
N
CH2CH3
N
O
H
O
H
N
H
N
O
4-Butylamino-5-ethyl-2-oxo-7-(N'-phenyl-hydrazino)-2H-chromene-3-sulfonic acid (2-hydroxy-
phenyl)-amide
4a
Scheme 4: Synthesis of 4-Butylamino-5-ethyl-2-oxo-7-(N’-phenyl-hydrazine)
-2H-chromene-3-sulfonic acid (2-hydroxy-phenyl)-amide (4a)

1750
BEHRAMI, Orient. J. Chem., Vol. 30(4), 1747-1752 (2014)
Table 1: Antibacterial activity- Staphylococcus
aureus and the comparison with Streptomycine
Table 2: Antibacterial activity E.coli and
the comparison with Streptomycine
Compound
Inhibition zone (mm)
2mg/ml 3mg /ml 5mg/ml
Compound
Inhibition zone (mm)
2mg/ml 3mg /ml 5mg/ml
1a
2a
3a
4a
10
18
19
11
20
13
20
21
13
20
15
24
25
1a
2a
3a
4a
5
9
14
21
23
10
12
11
23
15
17
15
23
18
20
Streptomycine
20 10 µg
Streptomycine
23 10µg
Table 3: Antibacterial activity Klebsiella
and the comparison with Streptomycine
Synthesis of 4 – Butylamino – 5 – ethyl -2 – oxo -
7 - ( N’ – phenyl – hydrazine )- 2H-chromene-3-
sulfonic acid (2-hydroxy-phenyl)-amide (4a)
In a 100 ml flask were mixed 1g of 4-
Butylamino-2-oxo-2H-chromene-3-sulfonic acid (2-
hydroxy-phenyl) – amide , 0.8g phenylhidrazine with
4ml C2H5OH ,0.5ml ClCH2CH3, 0.2 ml Et3N and 0.2
ml HCl. The mixture was refluxed at 95 oC in water
bath for ca. 2 h .The obtained red crystals are filtred
and rinsed with CH3CN and dried at room
temperature.Recrystallization from ethanol gave a
Compound
Inhibition zone (mm)
2mg/ml 3mg /ml 5mg/ml
1a
2a
3a
4a
12
13
13
10
23
19
18
19
17
23
23
25
24
21
Streptomycine
23 10µg
Table 4
1H NMR ppm
Compound
IR (cm-1)
13C NMR ppm
1a
3370 (NH), 3010(C-H) ar,
2962(C-H)alifatic
1720(C=O),1570(C=C)ar,
1385(C-O),750(C-H)ar
.0.96 s(3H,CH3)
. 166(C-NH),162(C,COO),
150(C-O),121-128(5C,ar)
88.9(C=C-H),46.3(C-NH)
34.8(C,CH2),20.6(C,CH2)
13.7(C,CH3)
.167(C-NH),162(COO),
150.8(C-O),121-128(6C,ar)
89(C-SO2),46.3(C-NH)
34.8(C,CH2),20.6(C,CH2)
13.7(C,CH3)
.167(C-NH),162(COO),
150(C-O),144(C-O),
134(C-NH),116-127(9C,ar)
46.2(C-NH)20.6(C,CH2)
13.7(C,CH3)
1.33 d(,4H,2CH2)
1.55-2.0 d(,H,NH-CH2)
2.65 s(,H,NH),
7.20-7.60m(,5H,ar)
.0.96 s(,3H,CH3)
1.33-1.55,d(4H,2CH2)
2.65 s(H,NHCH2)
3.0 s(H,NH)ar
7.20-7.63m(4H,ar)
. 0.96s(3H,CH3)
1.33-1.55d(4H,2CH2)
2.65s(H,NHCH2)3.0s
(H,NH),4.0s(H,NHSO2)
5.0s(H,OH)
6.29-6.63m(8H,ar)
.0.96-1.24d(6H,2CH3)
1.33-1.55d(4H,2CH2)2.0s (C-O),144(C-O),142(C-NH),
(H,NH),2.65s(H,NH)2.59s 102-138(17C,ar),89(C-SO2)
(H,CH2),4.0t(H,NH)5.0s
(H,OH)6.29-7.18m(11H,ar) 13.7(C,CH3),10.5(C,CH3)
2a
3a
3370(N-H),3008(C-H)ar
2960(CH)alifatic,
1740(C=O),1600(C=C)
1380(SO2Cl),1285(C-O)
720(C-H)ar
3400(OH),3300(NH),
3265(SO2NH),3009
(C-H)ar, 2850 (C-H)al,
1730(C=O),1528(C=C) ar,
1280(N-H),1275(C-O),
1250(C-O),740(C-H)ar
3387(O-H),3330(N-H)
3270(SO2NH),3010(C-H)ar
2900(C-H)al ,1728(C=O)
1600(C=C)ar,1280(N-H)
1270(C-O),750(C-H)ar
4ª
. 167(C-NH),162(COO),151
46.3(C-NH),22.5(C,CH2)

BEHRAMI, Orient. J. Chem., Vol. 30(4), 1747-1752 (2014)
1751
Table 5: Analytical data
Compd
Yield(%)
m.p
M.F
Elemental analysis. Calculated (found) (%)
C
H
N
O
Cl
S
1a
2a
3a
4a
80
70
70
60
117oC
C13H15NO2
71.87
72.00
49.45
50.00
58.75
60.00
62.05
61.50
6.96
7.11
4.47
5.00
5.19
4.90
5.79
5.20
6.45
6.15
4.44
4.11
7.21
7.10
10.72
10.0
14.73
14.32
20.27
20.00
20.59
19.92
15.31
15.00
287oC C13H14ClNO4S
11.23 10.15
11.00
9.80
8.20
8.00
6.14
6.00
180oC
204oC
C19H20N2O5S
C27H30N4O5S
o
red product at 60 % yield , melting point 204 C.
(Scheme 4)
that compounds (1a,2a,3a,4a) obviously inhibit the
growth of Staphyllococcus auerus, E.coli and
Klebsiella.
Antibacterial activity
The purified synthesized compounds
(1a,2a,3a,4a) was subjected to test in vitro its
antibacterial activity against three bacterial cultures
; Staphylococcus aureus,E.Coli and Klebsiella.
Antibacterial activity of compounds was
investigated applying the Kirby-Bayer method 14 or
disc method (d=5.5 mm max. capacity 10 µg)
The compounds (1a,2a,3a,4a) compared
with the antibacterial activity of Streptomycine in
S.aureus , and Klebsiella.
The chemical structures of synthesizen compounds
were determined according to extensive NMR
experiments and published data.
ACKNOWLEDGEMENTS
CONCLUSION
The authors thank Prof.Branko
Stanovnik,University of Ljubljana and its laboratory
staff for 1H NMR spectrum and elemental analyses.
From the results the followin conclusion
were drawn:The study provides the first evidence
REFERENCES
1.
2.
S.Govori,V.Kalaj,V.Rapic,L.Kalaj and
S.Dakovic,Heterocycel.Commun., 2002;
8,129.
6.
7.
M.D.Aytemir , R.C.Hider , D.D.Erol , M.Ozalp
and M.Ekizoglu .Turk.J.chem., 2003; 27 :
445.
M.M.El.Saghier,M.B.Naili,B.Kh.Rammash,
N.A.Saleh and K.M.Kreddan, Arkivoc, 2007;
83.
Z.M.Nofal ,M.El-Zahar and S.Abd El
Karim,Molecules, 2000; 5: 99.
Chaluvaraju KC and Ishwarbhat K.Asian ,J
Chem 2008; 20, 4335.
Rajan Ra Kali , Jubie S,Grworamma B, and
Suresh B,Asian J Chem 2008: 20: 5289.
Ali Mohammed Ashraf and Sharayar
Mohammed . Boorg Med Chem. Lett 2009;
17: 3314.
B.Stanovnik, H.Susachitzky
and
E.F.Scriven, Progress in Heterocyclic
Chemistry, Pergamon Press ,Oxford , 1993;
5,pp.75-146.
S.H.Lee, D.-S.Shin, J.-S,Kim, K.-B. Oh and
S.S.Kan, Arch. Pharm. Res, 2003; 26.
K.B.Vyas, K.S.Nimavat, G.R.Jani and M.V.
Hathi, Orbital, 2009; 1, 183.
A.Z.Abyshev, V.A.Gimdein, E.V. Semenov,
E.M, E.MAgev, A.A. Abdulla - Zade and
A.B.Gueseinov,Pharm.Chem.J., 2206;
40.607.
8.
3.
4.
5.
9.
10.
11.

1752
12.
BEHRAMI, Orient. J. Chem., Vol. 30(4), 1747-1752 (2014)
Nofal ZM, El-Zahar M, Abd El-Karim S, Novel 13.
coumarin derivatives with expected
Vyas KB,Nimavat KS,Jani GR,Hathi MV,
Synthesis and microbial activity of coumarin
derivatives metal complex: An in vitro
evaluation.Orbital, 2009; 1: 183-192.
biological activity, Molecules. 2000; 5: 99-
113.