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Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Novel coumarin isoxazoline derivatives: Synthesis
and study of antibacterial activities
Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu & Kishore
Kaushal
To cite this article: Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu & Kishore
Kaushal (2016) Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial
activities, Synthetic Communications, 46:24, 1972-1980, DOI: 10.1080/00397911.2016.1242748
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1242748
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SYNTHETIC COMMUNICATIONS®
2016, VOL. 46, NO. 24, 1972–1980
http://dx.doi.org/10.1080/00397911.2016.1242748
Novel coumarin isoxazoline derivatives: Synthesis and study
of antibacterial activities
Garbapu Suresha
, Ratnakaram Venkata Nadhb
, Navuluri Srinivasua
, and Kishore Kaushalc
a
Division of Chemistry, Department of Science and Humanities, Vignan’s Foundation for Science, Technology
and Research University, Guntur, India; b
GITAM University, Bengaluru Campus, Karnataka, India; c
API Process
Research and Development, Dr. Reddy’s Laboratories Ltd., Hyderabad, India
ABSTRACT
A highly efficient and mild protocol for the syntheses of ethyl-3-
[7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-
isoxazole carboxylates and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2-
oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole carboxylates in
good yields via [3 þ 2] cycloaddition of in situ–generated nitrile
oxides from 7-benzyloxy-4-methyl-coumarin hydroxymoylchlorides
and 7-benzyloxy-3-chloro-4-methyl-coumarin hydroxymoylchlorides
respectively with ethyl-3-aryl prop-2-enoate has been developed.
The new compounds are screened for antibacterial activity.
GRAPHICAL ABSTRACT
ARTICLE HISTORY
Received 16 July 2016
KEYWORDS
Antibacterial activity;
coumarin isoxazoline;
[3 þ 2] cycloaddition;
1,3-dipolar cycloaddition;
hydroximoyl chloride; nitrile
oxide
Introduction
Coumarins (2H-1-benzopyran-2-ones) are important plant-derived metabolites, which
exhibit interesting biological and pharmacological activities.[1]
Coumarin moiety is used
as an important synthetic intermediate and plays a vital role in the synthesis of numerous
heterocyclic compounds. Most importantly it is well documented that a large number of
pharmaceutical drug products like Novobuocin (antibiotic), Ensaculin (antidementia),
and Warfarin (antithrombotic) are marketed widely in the USA, Canada, and the rest of
the world and contain 7-hydroxy-4-methyl-2-coumarin as an important structural
element.[2]
Coumarins containing heterocyclic moieties have significant medicinal value
because of their potential pharmacological activities such as antibacterial, antifungal, and
antituberculosis activities.[3]
According to the prior literature, compounds containing 2-isoxazoline rings showed
enormous biological activities such as antinociceptive, anticonvulsant, antipsychotic,
CONTACT G. Suresh garbapusuresh@gmail.com Division of Chemistry, Department of Science and Humanities,
Vignan’s Foundation for Science, Technology and Research University, Guntur 522213, India.
Supplemental data (elemental analysis; mass, 1
H NMR, and 13
C NMR spectra; and characterization data for all newly
synthesized coumarin isoxazoline derivatives) can be accessed on the publisher's website
© 2016 Taylor & Francis
antistress, and analgesic effects.[4]
Moreover, isoxazoline derivatives have played important
roles as valuable intermediates in most of the synthetic heterocyclic pharmacological drug
products. The traditional synthesis of isoxazolines involves the base-catalyzed cycloconden-
sation of hydroxyl amine hydrochlorides and chalcones. Kour et al. produce isoxazoline
coumarin derivatives using reaction of various substituted chalcone derivatives with
hydroxyl amines (free base) in the presence of refluxing methanolic NaOH solution.[5]
Desai and coworkers reported the synthesis of isoxazoline coumarin derivatives by
cyclocondensation of hydroxyl amine hydrochlorides and substituted chalcones in the
presence of refluxing methanolic NaOH solution for 7.5 h.[6]
Recently Zghab and
coworkers produced coumarin isoxazoline derivatives by cycloaddition of nitrile oxides
with suitable substituted ethyl cinnamates in the presence of triethylamine and refluxing
toluene.[7]
All these synthesis methods are long and require relatively harsh reaction
conditions to make coumarin isoxazoline derivatives.
1,3-Dipolar cycloaddition was the most effective method for the synthesis of
five-membered heterocycles, which are difficult to prepare by other means.[8]
The
most widely used method for the synthesis of isoxazolines is the 1,3-dipolar cycloaddition
([3 þ 2] cycloaddition) of nitrile oxides to activated dipolarophiles.[9]
Aryl nitrile oxides are
highly reactive and are predominantly generated in situ by either dehydration of primary
nitroalkane derivatives, Mukiyama reaction,[10]
or halogenation of aldoxime followed by an
in situ dehydrohalogenation using a base.[11]
The main advantage of the 1,3-dipolar
cycloaddition of aryl nitrile oxides to activated double bond is high regioselectivity with
good yields. On the basis of this prior evidence, we set out to prepare a new series of
biologically active coumarin appended with isoxazoline pharmacophores 11a–d and
12a–d via [3 þ 2] cycloaddition.
As a part of our research for coumarin isoxazoline derivatives, we proposed to investi-
gate the behavior of coumarin-derived aryl nitrile oxides 8 and 9, which are generated in
situ from hydroximoylchlorides (aldehyde chlorooximes) 6 and 7 under a basic medium,
toward different substituted cinnamates (dipolarophiles) 10. This led to new series
of ethyl-3-[7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole
carboxylates 11a–d and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2-oxo-2H-8-chromenyl]-
5-aryl-4,5-dihydro-4-isoxazole carboxylates 12a–d in good yields. The present study
describes the synthesis, characterization, and antibacterial activities of novel coumarin
isoxazoline derivatives.
Results and discussion
The required key intermediates for this study, 7-benzyloxy-4-methyl-coumarin aldehyde
chlorooximes 6a–d and 7-benzyloxy-3-chloro-4-methyl-coumarin aldehyde chlorooximes
7a–d, were prepared as shown in Scheme 1. The first step of the synthesis involves the
preparation of 7-hydroxy-4-methyl coumarins 2a–d via Pechmann condensation of
commercially available resorcinols 1a–d and ethyl acetoacetate in the presence of H2SO4.[12]
Further treatment of 7-hydroxy coumarin derivatives 2a–d with hexamine in acetic acid
make them undergo Duff formylation[13]
to give 8-formyl-7-hydroxy-4-methyl-coumarins
3a–d, which were protected as benzyloxy derivatives 4a–d with benzyl bromide in the
presence of K2CO3 in dimethylformamide (DMF).[14]
Compounds 4a–d treated with
hydroxylamine hydrochloride in the presence of methanol and sodium acetate were
SYNTHETIC COMMUNICATIONS®
1973
converted into oximes 5a–d.[15]
Finally, the key intermediates, coumarin-derived hydroxi-
moyl chlorides 6a–d and 7a–d, were synthesized by the chlorination of oximes 5a–d with
equimolar quantities of N-chlorosuccinimide in DMF at 20–25 °C.[16]
The obtained syrupy
mass on purification by column chromatography gave 7-benzyloxy-4-methyl-coumarin alde-
hyde chloroximes 6a–d and 3-chlorinated products 7a–d as off-white solids. The absence of
oxime proton at δ 11.23 in 1
H NMR indicates the formation of hydroxymoylchloride
derivatives.
Based on our experimental results and in conjunction with known biological properties
for heterocycles as an integral part of the coumarin skeleton, we chose useful and stable cou-
marin-derived hydroximoyl chlorides to synthesize novel coumarin-appended isoxazoline
derivatives as shown in Scheme 2. Treatment of coumarin-derived hydroximoyl chlorides
6a–d and 7a–d with triethylamine in dichloromethane at room temperature causes them
to undergo dehydrohalogenation and results in situ generation of coumarin aryl nitrile
oxides 8a–d and 9a–d,[17]
which reacted instantaneously with different ethyl cinnamates
10 (dipolarophiles) via [3 þ 2] cycloaddition, yielding the corresponding coumarin isoxazo-
line derivatives 11a–d and 12a–d. All these newly synthesized compounds were purified by
column chromatography and characterized by mass, 1
H NMR, and 13
C NMR.
To demonstrate the structure elucidation of the first series of coumarin isoxazoline
derivatives 11a–d, we selected compound 11a, which was obtained by the reaction of
equimolar quantities of 7-benzyloxy-4-methyl-coumarin hydroximoyl chloride 6a and
ethyl-3-phenylprop-2-enoate 10 in the presence of triethylamine in dichloromethane at
room temperature for 24 h. Its positive quasimolecular ion peak was observed at m/z
483.9 (MþH), compatible with the molecular formulae C29H25NO6. In 1
H NMR of 11a
the newly formed isoxazoline ring H-4″ appeared at δ 4.68 (d, J ¼ 8.8 Hz) and H-5″ at
δ 6.07 (d, J ¼ 8.8 Hz). In 13
C NMR of 11a isoxazoline ring carbons appeared at δ 60.5
(C-4″), 88.2 (C-5″), and 158.7 (C-3″).
Scheme 1. Synthesis of coumarin-derived hydroximoyl chlorides 6a–d and 7a–d.
1974 G. SURESH ET AL.
To demonstrate the structure elucidation of the second series of coumarin isoxazoline
derivatives 12a–d, we selected the compound 12a, which was obtained by the reaction
of equimolar quantities of 7-benzyloxy-3-chloro-4-methyl-coumarin hydroximoyl chloride
7a and ethyl-3-phenylprop-2-enoate 10. The compound 12a showed its quasimolecular ion
peaks at m/z 518.1 (MþH) and m/z 520.3 (MþH þ 2), with 3:1 isotopic peak intensities
ratio in mass spectrum confirmed the molecular formulae C29H24ClNO6 with one chlorine
atom. The newly formed isoxazoline ring proton H-4″ appeared at δ 4.64 (d, J ¼ 8.6 Hz)
and H-5″ at δ 6.09 (d, J ¼ 8.6 Hz). In 13
C NMR of 12a isoxazoline ring carbons appeared
at δ 62.3 (C-4″), 88.7 (C-5″), and 159.7 (C-3″).
Antibacterial activity
It is well known that coumarin isoxazoline derivatives possess antibacterial activity.[18]
Furthermore, halogen substituents were introduced into the basic structure, anticipating
an improved biological activity, because their incorporation proved to influence the bio-
logical activity in various heterocycles[19]
as well as coumarins.[20]
Electron-withdrawing
groups like halogens will increase bactericidal potential as they alter the nature of the
compound in such a way as to promote binding to the target(s).[21]
According to Prasad
et al., designing the compounds bearing electron-withdrawing substituents (with high
Scheme 2. Synthesis of coumarin isoxazoline derivatives.
SYNTHETIC COMMUNICATIONS®
1975
degree of binding linearity) results in high molecular weights to exhibit an improved
antibacterial activity.[22]
Similarly, the significant inhibition shown by substituted isoxazo-
lines was attributed to substituents such as hydroxymethyl/hydroxy/methoxy/ethyl ester
groups.[23]
Shah and Desai also reported that the presence of methoxy-, chloro-, and fluoro
groups enhanced the antibacterial activity in isoxazoline derivatives.[24]
All these newly synthesized compounds 11a–d and 12a–d were evaluated for in vitro
antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus MTCC 96)
and Gram-negative bacteria (Escherichia coli MTCC 40) by the agar disc diffusion
method.[25]
The antibacterial screening data showed that most of the compounds 11a–d
and 12a–d showed moderate to excellent activities against the used microorganisms
(Table- 2) compared to the reference drug (chloramphenicol). These results suggested that
the introduction of halogen substituent increased the hydrophobicity of the synthesized
compounds and led to the increase of the antibacterial activity.[26]
In the present study,
it is observed that good activity was shown by the prepared derivatives against the studied
Gram-positive bacteria and very poor activity against Gram-negative bacteria. The outer
cell layers of Gram-positive and Gram-negative bacteria may explain the decent antibacter-
ial activities of these prepared derivatives.[27]
The permeability of drug constituents in
Gram-positive bacteria is due to an ineffective and penetrable outer barrier made of a pep-
tidoglycan layer. On the other hand, outer cell wall of Gram-negative bacteria consists of
multiple impermeable peptidoglycan and phospholipidic layers.[28]
Among the compounds
screened, 12c showed high activity. The observed antibacterial activity profile suggested
that the presence of halogen functional group bromine had enhanced the activity.
Table 2. Antibacterial activity data of the synthesized coumarin isoxazoline derivatives.
Compound
Zone of inhibition (mm)a
Escherichia coli (MTCC 40)
(Gram-negative) (Conc. μg/ml)
Staphylococcus aureus (MTCC 96)
(Gram-positive) (Conc. μg/ml)
200 100 50 200 100 50
11a 15 11 5 17 12 5
11b 18 12 8 18 13 10
11c 27 20 19 29 21 19
11d 15 12 11 21 19 4
12a 22 11 6 22 18 7
12b 11 13 14 24 18 26
12c 28 24 20 31 29 24
12d 22 22 16 24 22 20
Chloramphenicol 31 30 21 33 30 23
a
Indicates average of triplicate.
Table 1. Yields of coumarin isoxazoline derivatives.
Entry R R1 Product Yielda
(%)
1 H H 11a 66
2 Cl CF3 11b 74
3 Br CF3 11c 77
4 CH3 3,5-difluoro 11d 69
5 H H 12a 75
6 Cl CF3 12b 74
7 Br CF3 12c 69
8 CH3 3,5-difluoro 12d 72
a
Yields are after column purification.
1976 G. SURESH ET AL.
Conclusion
In conclusion, we have successfully achieved two important aspects in this work. One is a
highly practical method for the synthesis of novel coumarin-appended isoxazoline deriva-
tives 11a–d and 12a–d in a good yield via [3 þ 2] cycloaddition (1,3-diploar cycloaddition)
under mild reaction conditions. The second one is the antibacterial activities of the synthe-
sized compounds. Interestingly all these new compounds are active and show moderate to
good antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. The
observed antibacterial activity profile suggested that the presence of bromine had enhanced
the activity.
Experimental
Melting points were determined in open glass capillaries on a Fisher–Johns melting-point
apparatus and are uncorrected. NMR (1
H 400 MHz; 13
C 125 MHz) were recorded at room
temperature in CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard
(δ ¼ 0 ppm), and the values were reported in the following order: chemical shift (δ in
ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
qq ¼ quartet of quartet), coupling constants (J in Hz), and integration. All the reactions
were monitored by thin-layer chromatography (TLC) on precoated silica gel 60 F254
(mesh); spots were visualized under UV light at 254 nm.
Typical experimental procedure for the synthesis of hydroximoyl chlorides (6a–D)
and (7a–D)
N-Chlorosuccinimide (4.1 g, 31.0 mmol) was added to a stirred solution of 7-benzyloxy-4-
methyl-coumarin aldehyde oxime 5a (8.0 g, 25.8 mmol) in dimethylformamide (DMF,
200.0 mL) at 0 °C, raised to rt over 2 h, quenched with ice cold water (600.0 mL), and
extracted with ethyl acetate (3 � 200.0 mL). The combined organic layer was washed with
saturated NaCl solution (200.0 mL), dried over Na2SO4, concentrated, and purified by col-
umn chromatography to give 6a, 5.6 g (63%). 1
H NMR spectrum (400 MHz, CDCl3), δ,
ppm (J, Hz): 2.41 (3H, s, 4-CH3); 5.37 (s, 2H, OCH2C6H5); 6.13 (s, 1H, H-3); 7.24–7.35
(5H, m, OCH2C6H5); 7.41 (1H, d, J ¼ 8.8 Hz, H-6); 7.8 (1H, d, J ¼ 8.8 Hz, H-6);
12.4 (1H, s, N-OH) and 7a, 2.6 g (27%); 1
H NMR spectrum (400 MHz, CDCl3), δ, ppm
(J, Hz): 2.45 (3H, s, 4-CH3); 5.3 (s, 2H, OCH2C6H5); 7.34–7.46 (5H, m, OCH2C6H5);
7.8 (1H, d, J ¼ 8.8 Hz, H-6); 7.9 (1H, d, J ¼ 8.8 Hz, H-6); 12.4 (1H, s, N-OH).
Following the same procedure as depicted for 6a and 7a, the other hydroximoyl
chlorides 6b–d and 7b–d were prepared from the corresponding aldehyde oximes.
Hydroximoyl chlorides are highly unstable and are readily prepared whenever required.
Typical experimental procedure for the synthesis of coumarin isoxazoline
compounds (11a–D)
The corresponding ethyl-3-phenyl-prop-2-enoate 10 (0.29 g, 1.66 mmol) dissolved in
dichloromethane (DCM, 12.5 mL) was added to a stirred solution of hydroximoyl chloride
6a (0.5 g, 1.45 mmol) in DCM (12.5 mL) and Et3N (0.19 g, 1.89 mmol), and the reaction
SYNTHETIC COMMUNICATIONS®
1977
mixture was stirred for 24 h at room temperature. Water (30.0 mL) was added and
extracted in DCM (2 � 30.0 mL). The combined organic layer was washed with saturated
NaCl solution (60.0 mL), dried over Na2SO4, and concentrated to give the crude isoxazo-
line 11a, which was purified by column chromatography using silica gel in ethyl acetate/
petroleum ether (6:4), 0.46 g, 65.7% yield.
Following the same procedure as illustrated for 11a, the other coumarin
isoxazoline derivatives 11b–d were prepared from the corresponding hydroximoyl
chlorides. The physical, spectral, and analytical data for these compounds are mentioned
as follows.
Ethyl-3-[7-(benzyloxy)-4-methyl-2-oxo-2h-8-chromenyl]-5-phenyl-4,5-dihydro-4-
isoxazole carboxylate (11a)
Off-white solid; yield 0.46 g (66%); mp 130–132 °C; 1
H NMR spectrum (400 MHz, CDCl3),
δ, ppm (J, Hz): 0.95 (3H, t, J ¼ 7.2,OCH2CH3); 2.42 (3H, s, 4-CH3); 3.95 (2H, q, J ¼ 7.2,
OCH2CH3); 4.68 (1H, d, J ¼ 8.8 Hz, H-4″); 5.21 (2H, s, -OCH2C6H5); 6.07 (1H, d, J ¼ 8.8
Hz, H-5″); 6.29 (s, 1H, H-3); 6.91 (1H, d, J ¼ 9.2 Hz, H-6); 7.23–7.38 (5H, m, OCH2C6H5);
7.51–7.62 (5H, m, Ar); 7.72 (1H, d, J ¼ 9.2 Hz, H-5); 13
C NMR spectrum (125 MHz,
CDCl3), δ, ppm: 13.7 (OCH2CH3); 18.7 (CH3); 60.5 (C-4″); 63.1 (OCH2CH3); 70.1
(OCH2C6H5); 88.2 (C-5″); 103.9 (C-6); 104.2 (C-3); 112.6 (C-4a); 113.9 (C-8); 127.1
(C-2′,6′,4′,2″′,6″′,4″′ Ar); 129.5 (C-3′,5′,3″′,5″′ Ar); 142.1 (C-5); 150.3 (C-1″′, 1′); 153.5
(C-8a); 158.7 (C-3″, 4); 166.9 (C-2,7); 167.8 (COOEt); DIPMS: m/z ¼ 483.9 (MþH).
Elemental analysis: found (%): C, 71.92; H, 5.18; N, 2.81. C29H25NO6 calculated (%): C,
72.04; H, 5.21; N, 2.90.
Typical experimental procedure for the synthesis of 3-chlorinated coumarin
isoxazoline compounds (12a–D)
The corresponding ethyl-3-phenyl-prop-2-enoate 10 (0.26 g, 1.51 mmol) dissolved in DCM
(10.0 mL) was added to a stirred solution of hydroximoyl chloride 7a (0.5 g, 1.32 mmol) in
DCM (10.0 mL) and triethylamine (0.17 g, 1.71 mmol) and reaction mixture was stirred for
24 h at room temperature. Water (50.0 mL) was added and extracted with DCM (2 � 50.0
mL). The combined organic layer was washed with saturated NaCl solution (60.0 mL),
dried over Na2SO4, and concentrated to give the crude isoxazoline, which was purified
by column chromatography using silica gel in ethyl acetate / petroleum ether (8:2): 12a,
0.51 g, 74.5% yield.
Following the same procedure as illustrated for 12a, coumarin isoxazoline derivatives
12b–d were prepared from the corresponding hydroximoyl chlorides. The physical,
spectral, and analytical data for these compounds are mentioned as follows.
Ethyl-3-[7-(benzyloxy)-3-chloro-4-methyl-2-oxo-2h-8-chromenyl]-5-phenyl-4,5-
dihydro-4-isoxazole carboxylate (12a)
Off-white solid; yield 0.51 g (75%); mp 118–120 °C; 1
H NMR spectrum (400 MHz, CDCl3),
δ, ppm (J, Hz): 1.03 (3H, t, J ¼ 7.3, OCH2CH3); 2.45 (3H, s, 4-CH3); 3.97 (2H, q, J ¼ 7.3,
OCH2CH3); 4.64 (1H, d, J ¼ 8.6 Hz, H-4″); 5.24 (2H, s, OCH2C6H5); 6.09 (1H, d,
1978 G. SURESH ET AL.
J ¼ 8.6 Hz, H-5″); 6.38 (1H, d, J ¼ 9.1 Hz, H-6); 7.28–7.37 (5H, m, OCH2C6H5); 7.51–7.59
(5H, m, Ar); 7.81 (1H, d, J ¼ 9.1 Hz, H-5); 13
C NMR spectrum (125 MHz, CDCl3), δ, ppm:
14.1 (OCH2CH3); 18.9 (CH3); 62.3 (C-4″); 64.7 (OCH2CH3); 72.3 (OCH2C6H5); 88.7 (C-
5″); 105.3 (C-6); 113.7 (C-4a); 115.9 (C-8); 119.3 (C-3); 122.5 (C-2′,6′,4′,2″′,6″′,4″′ Ar);
123.5 (C-3′,5′,3″′,5″′ Ar); 142.6 (C-5); 148.2 (C-1″′, 1′); 151.8 (C-8a); 154.2 (C-3″); 159.7
(C-4); 163.8 (C-7); 166.9 (C-2,); 169.8 (COOEt); DIPMS: m/z ¼ 518.1 (MþH), 520.3
(MþH þ 2). Elemental analysis: Found (%): C, 67.02; H, 4.67; N, 2.69. C29H24ClNO6: Cal-
culated (%): C, 67.25; H, 4.67; N, 2.70.
Screening of antibacterial activity
All these newly synthesized compounds, 11a–d and 12a–d, were evaluated for in vitro
antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus MTCC 96)
and Gram-negative bacteria (Escherichia coli MTCC 40) by the agar disc diffusion
method. All the derivatives at the concentrations of 50 µg/ml, 100 µg/ml, and 200 µg/
ml were tested against Gram-positive bacteria (Staphylococcus aureus MTCC 96) and
Gram-negative bacteria (Escherichia coli MTCC 40). The molten nutrient agar was
inoculated with 100 μl of the inoculum (1 � 108 cfu/ml) and poured into the Petri plate;
the disc (5 mm) (Hi-Media) was saturated with 100 μl of the test compound, allowed to
dry, and introduced on the upper layer of the seeded agar plate. The plates were incu-
bated at about 37 °C and microbial progress was determined by measuring the diameter
of zone of inhibition after 24 h. Pure solvents were used as control and inhibitory zones
were nearly negligible compared to the inhibition zones of the samples. To clarify any
solvent effect on the biological screening, separate studies were carried out using
dimethyl sulfoxide (DMSO) as a control and it showed no activity against any bacterial
strains. Chloramphenicol was used as standard drug for the purpose of comparison of
antibacterial activities of the derivatives. The antibacterial activities were carried out in
triplicate and average values were compiled.
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Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial activities

  • 1. Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=lsyc20 Download by: [Florida Atlantic University] Date: 09 December 2016, At: 07:15 Synthetic Communications An International Journal for Rapid Communication of Synthetic Organic Chemistry ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20 Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial activities Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu & Kishore Kaushal To cite this article: Garbapu Suresh, Ratnakaram Venkata Nadh, Navuluri Srinivasu & Kishore Kaushal (2016) Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial activities, Synthetic Communications, 46:24, 1972-1980, DOI: 10.1080/00397911.2016.1242748 To link to this article: http://dx.doi.org/10.1080/00397911.2016.1242748 View supplementary material Accepted author version posted online: 07 Oct 2016. Published online: 07 Oct 2016. Submit your article to this journal Article views: 49 View related articles View Crossmark data
  • 2. SYNTHETIC COMMUNICATIONS® 2016, VOL. 46, NO. 24, 1972–1980 http://dx.doi.org/10.1080/00397911.2016.1242748 Novel coumarin isoxazoline derivatives: Synthesis and study of antibacterial activities Garbapu Suresha , Ratnakaram Venkata Nadhb , Navuluri Srinivasua , and Kishore Kaushalc a Division of Chemistry, Department of Science and Humanities, Vignan’s Foundation for Science, Technology and Research University, Guntur, India; b GITAM University, Bengaluru Campus, Karnataka, India; c API Process Research and Development, Dr. Reddy’s Laboratories Ltd., Hyderabad, India ABSTRACT A highly efficient and mild protocol for the syntheses of ethyl-3- [7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4- isoxazole carboxylates and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2- oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole carboxylates in good yields via [3 þ 2] cycloaddition of in situ–generated nitrile oxides from 7-benzyloxy-4-methyl-coumarin hydroxymoylchlorides and 7-benzyloxy-3-chloro-4-methyl-coumarin hydroxymoylchlorides respectively with ethyl-3-aryl prop-2-enoate has been developed. The new compounds are screened for antibacterial activity. GRAPHICAL ABSTRACT ARTICLE HISTORY Received 16 July 2016 KEYWORDS Antibacterial activity; coumarin isoxazoline; [3 þ 2] cycloaddition; 1,3-dipolar cycloaddition; hydroximoyl chloride; nitrile oxide Introduction Coumarins (2H-1-benzopyran-2-ones) are important plant-derived metabolites, which exhibit interesting biological and pharmacological activities.[1] Coumarin moiety is used as an important synthetic intermediate and plays a vital role in the synthesis of numerous heterocyclic compounds. Most importantly it is well documented that a large number of pharmaceutical drug products like Novobuocin (antibiotic), Ensaculin (antidementia), and Warfarin (antithrombotic) are marketed widely in the USA, Canada, and the rest of the world and contain 7-hydroxy-4-methyl-2-coumarin as an important structural element.[2] Coumarins containing heterocyclic moieties have significant medicinal value because of their potential pharmacological activities such as antibacterial, antifungal, and antituberculosis activities.[3] According to the prior literature, compounds containing 2-isoxazoline rings showed enormous biological activities such as antinociceptive, anticonvulsant, antipsychotic, CONTACT G. Suresh garbapusuresh@gmail.com Division of Chemistry, Department of Science and Humanities, Vignan’s Foundation for Science, Technology and Research University, Guntur 522213, India. Supplemental data (elemental analysis; mass, 1 H NMR, and 13 C NMR spectra; and characterization data for all newly synthesized coumarin isoxazoline derivatives) can be accessed on the publisher's website © 2016 Taylor & Francis
  • 3. antistress, and analgesic effects.[4] Moreover, isoxazoline derivatives have played important roles as valuable intermediates in most of the synthetic heterocyclic pharmacological drug products. The traditional synthesis of isoxazolines involves the base-catalyzed cycloconden- sation of hydroxyl amine hydrochlorides and chalcones. Kour et al. produce isoxazoline coumarin derivatives using reaction of various substituted chalcone derivatives with hydroxyl amines (free base) in the presence of refluxing methanolic NaOH solution.[5] Desai and coworkers reported the synthesis of isoxazoline coumarin derivatives by cyclocondensation of hydroxyl amine hydrochlorides and substituted chalcones in the presence of refluxing methanolic NaOH solution for 7.5 h.[6] Recently Zghab and coworkers produced coumarin isoxazoline derivatives by cycloaddition of nitrile oxides with suitable substituted ethyl cinnamates in the presence of triethylamine and refluxing toluene.[7] All these synthesis methods are long and require relatively harsh reaction conditions to make coumarin isoxazoline derivatives. 1,3-Dipolar cycloaddition was the most effective method for the synthesis of five-membered heterocycles, which are difficult to prepare by other means.[8] The most widely used method for the synthesis of isoxazolines is the 1,3-dipolar cycloaddition ([3 þ 2] cycloaddition) of nitrile oxides to activated dipolarophiles.[9] Aryl nitrile oxides are highly reactive and are predominantly generated in situ by either dehydration of primary nitroalkane derivatives, Mukiyama reaction,[10] or halogenation of aldoxime followed by an in situ dehydrohalogenation using a base.[11] The main advantage of the 1,3-dipolar cycloaddition of aryl nitrile oxides to activated double bond is high regioselectivity with good yields. On the basis of this prior evidence, we set out to prepare a new series of biologically active coumarin appended with isoxazoline pharmacophores 11a–d and 12a–d via [3 þ 2] cycloaddition. As a part of our research for coumarin isoxazoline derivatives, we proposed to investi- gate the behavior of coumarin-derived aryl nitrile oxides 8 and 9, which are generated in situ from hydroximoylchlorides (aldehyde chlorooximes) 6 and 7 under a basic medium, toward different substituted cinnamates (dipolarophiles) 10. This led to new series of ethyl-3-[7-benzyloxy-4-methyl-2-oxo-2H-8-chromenyl]-5-aryl-4,5-dihydro-4-isoxazole carboxylates 11a–d and ethyl-3-[7-benzyloxy-3-chloro-4-methyl-2-oxo-2H-8-chromenyl]- 5-aryl-4,5-dihydro-4-isoxazole carboxylates 12a–d in good yields. The present study describes the synthesis, characterization, and antibacterial activities of novel coumarin isoxazoline derivatives. Results and discussion The required key intermediates for this study, 7-benzyloxy-4-methyl-coumarin aldehyde chlorooximes 6a–d and 7-benzyloxy-3-chloro-4-methyl-coumarin aldehyde chlorooximes 7a–d, were prepared as shown in Scheme 1. The first step of the synthesis involves the preparation of 7-hydroxy-4-methyl coumarins 2a–d via Pechmann condensation of commercially available resorcinols 1a–d and ethyl acetoacetate in the presence of H2SO4.[12] Further treatment of 7-hydroxy coumarin derivatives 2a–d with hexamine in acetic acid make them undergo Duff formylation[13] to give 8-formyl-7-hydroxy-4-methyl-coumarins 3a–d, which were protected as benzyloxy derivatives 4a–d with benzyl bromide in the presence of K2CO3 in dimethylformamide (DMF).[14] Compounds 4a–d treated with hydroxylamine hydrochloride in the presence of methanol and sodium acetate were SYNTHETIC COMMUNICATIONS® 1973
  • 4. converted into oximes 5a–d.[15] Finally, the key intermediates, coumarin-derived hydroxi- moyl chlorides 6a–d and 7a–d, were synthesized by the chlorination of oximes 5a–d with equimolar quantities of N-chlorosuccinimide in DMF at 20–25 °C.[16] The obtained syrupy mass on purification by column chromatography gave 7-benzyloxy-4-methyl-coumarin alde- hyde chloroximes 6a–d and 3-chlorinated products 7a–d as off-white solids. The absence of oxime proton at δ 11.23 in 1 H NMR indicates the formation of hydroxymoylchloride derivatives. Based on our experimental results and in conjunction with known biological properties for heterocycles as an integral part of the coumarin skeleton, we chose useful and stable cou- marin-derived hydroximoyl chlorides to synthesize novel coumarin-appended isoxazoline derivatives as shown in Scheme 2. Treatment of coumarin-derived hydroximoyl chlorides 6a–d and 7a–d with triethylamine in dichloromethane at room temperature causes them to undergo dehydrohalogenation and results in situ generation of coumarin aryl nitrile oxides 8a–d and 9a–d,[17] which reacted instantaneously with different ethyl cinnamates 10 (dipolarophiles) via [3 þ 2] cycloaddition, yielding the corresponding coumarin isoxazo- line derivatives 11a–d and 12a–d. All these newly synthesized compounds were purified by column chromatography and characterized by mass, 1 H NMR, and 13 C NMR. To demonstrate the structure elucidation of the first series of coumarin isoxazoline derivatives 11a–d, we selected compound 11a, which was obtained by the reaction of equimolar quantities of 7-benzyloxy-4-methyl-coumarin hydroximoyl chloride 6a and ethyl-3-phenylprop-2-enoate 10 in the presence of triethylamine in dichloromethane at room temperature for 24 h. Its positive quasimolecular ion peak was observed at m/z 483.9 (MþH), compatible with the molecular formulae C29H25NO6. In 1 H NMR of 11a the newly formed isoxazoline ring H-4″ appeared at δ 4.68 (d, J ¼ 8.8 Hz) and H-5″ at δ 6.07 (d, J ¼ 8.8 Hz). In 13 C NMR of 11a isoxazoline ring carbons appeared at δ 60.5 (C-4″), 88.2 (C-5″), and 158.7 (C-3″). Scheme 1. Synthesis of coumarin-derived hydroximoyl chlorides 6a–d and 7a–d. 1974 G. SURESH ET AL.
  • 5. To demonstrate the structure elucidation of the second series of coumarin isoxazoline derivatives 12a–d, we selected the compound 12a, which was obtained by the reaction of equimolar quantities of 7-benzyloxy-3-chloro-4-methyl-coumarin hydroximoyl chloride 7a and ethyl-3-phenylprop-2-enoate 10. The compound 12a showed its quasimolecular ion peaks at m/z 518.1 (MþH) and m/z 520.3 (MþH þ 2), with 3:1 isotopic peak intensities ratio in mass spectrum confirmed the molecular formulae C29H24ClNO6 with one chlorine atom. The newly formed isoxazoline ring proton H-4″ appeared at δ 4.64 (d, J ¼ 8.6 Hz) and H-5″ at δ 6.09 (d, J ¼ 8.6 Hz). In 13 C NMR of 12a isoxazoline ring carbons appeared at δ 62.3 (C-4″), 88.7 (C-5″), and 159.7 (C-3″). Antibacterial activity It is well known that coumarin isoxazoline derivatives possess antibacterial activity.[18] Furthermore, halogen substituents were introduced into the basic structure, anticipating an improved biological activity, because their incorporation proved to influence the bio- logical activity in various heterocycles[19] as well as coumarins.[20] Electron-withdrawing groups like halogens will increase bactericidal potential as they alter the nature of the compound in such a way as to promote binding to the target(s).[21] According to Prasad et al., designing the compounds bearing electron-withdrawing substituents (with high Scheme 2. Synthesis of coumarin isoxazoline derivatives. SYNTHETIC COMMUNICATIONS® 1975
  • 6. degree of binding linearity) results in high molecular weights to exhibit an improved antibacterial activity.[22] Similarly, the significant inhibition shown by substituted isoxazo- lines was attributed to substituents such as hydroxymethyl/hydroxy/methoxy/ethyl ester groups.[23] Shah and Desai also reported that the presence of methoxy-, chloro-, and fluoro groups enhanced the antibacterial activity in isoxazoline derivatives.[24] All these newly synthesized compounds 11a–d and 12a–d were evaluated for in vitro antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus MTCC 96) and Gram-negative bacteria (Escherichia coli MTCC 40) by the agar disc diffusion method.[25] The antibacterial screening data showed that most of the compounds 11a–d and 12a–d showed moderate to excellent activities against the used microorganisms (Table- 2) compared to the reference drug (chloramphenicol). These results suggested that the introduction of halogen substituent increased the hydrophobicity of the synthesized compounds and led to the increase of the antibacterial activity.[26] In the present study, it is observed that good activity was shown by the prepared derivatives against the studied Gram-positive bacteria and very poor activity against Gram-negative bacteria. The outer cell layers of Gram-positive and Gram-negative bacteria may explain the decent antibacter- ial activities of these prepared derivatives.[27] The permeability of drug constituents in Gram-positive bacteria is due to an ineffective and penetrable outer barrier made of a pep- tidoglycan layer. On the other hand, outer cell wall of Gram-negative bacteria consists of multiple impermeable peptidoglycan and phospholipidic layers.[28] Among the compounds screened, 12c showed high activity. The observed antibacterial activity profile suggested that the presence of halogen functional group bromine had enhanced the activity. Table 2. Antibacterial activity data of the synthesized coumarin isoxazoline derivatives. Compound Zone of inhibition (mm)a Escherichia coli (MTCC 40) (Gram-negative) (Conc. μg/ml) Staphylococcus aureus (MTCC 96) (Gram-positive) (Conc. μg/ml) 200 100 50 200 100 50 11a 15 11 5 17 12 5 11b 18 12 8 18 13 10 11c 27 20 19 29 21 19 11d 15 12 11 21 19 4 12a 22 11 6 22 18 7 12b 11 13 14 24 18 26 12c 28 24 20 31 29 24 12d 22 22 16 24 22 20 Chloramphenicol 31 30 21 33 30 23 a Indicates average of triplicate. Table 1. Yields of coumarin isoxazoline derivatives. Entry R R1 Product Yielda (%) 1 H H 11a 66 2 Cl CF3 11b 74 3 Br CF3 11c 77 4 CH3 3,5-difluoro 11d 69 5 H H 12a 75 6 Cl CF3 12b 74 7 Br CF3 12c 69 8 CH3 3,5-difluoro 12d 72 a Yields are after column purification. 1976 G. SURESH ET AL.
  • 7. Conclusion In conclusion, we have successfully achieved two important aspects in this work. One is a highly practical method for the synthesis of novel coumarin-appended isoxazoline deriva- tives 11a–d and 12a–d in a good yield via [3 þ 2] cycloaddition (1,3-diploar cycloaddition) under mild reaction conditions. The second one is the antibacterial activities of the synthe- sized compounds. Interestingly all these new compounds are active and show moderate to good antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. The observed antibacterial activity profile suggested that the presence of bromine had enhanced the activity. Experimental Melting points were determined in open glass capillaries on a Fisher–Johns melting-point apparatus and are uncorrected. NMR (1 H 400 MHz; 13 C 125 MHz) were recorded at room temperature in CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard (δ ¼ 0 ppm), and the values were reported in the following order: chemical shift (δ in ppm), multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, qq ¼ quartet of quartet), coupling constants (J in Hz), and integration. All the reactions were monitored by thin-layer chromatography (TLC) on precoated silica gel 60 F254 (mesh); spots were visualized under UV light at 254 nm. Typical experimental procedure for the synthesis of hydroximoyl chlorides (6a–D) and (7a–D) N-Chlorosuccinimide (4.1 g, 31.0 mmol) was added to a stirred solution of 7-benzyloxy-4- methyl-coumarin aldehyde oxime 5a (8.0 g, 25.8 mmol) in dimethylformamide (DMF, 200.0 mL) at 0 °C, raised to rt over 2 h, quenched with ice cold water (600.0 mL), and extracted with ethyl acetate (3 � 200.0 mL). The combined organic layer was washed with saturated NaCl solution (200.0 mL), dried over Na2SO4, concentrated, and purified by col- umn chromatography to give 6a, 5.6 g (63%). 1 H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 2.41 (3H, s, 4-CH3); 5.37 (s, 2H, OCH2C6H5); 6.13 (s, 1H, H-3); 7.24–7.35 (5H, m, OCH2C6H5); 7.41 (1H, d, J ¼ 8.8 Hz, H-6); 7.8 (1H, d, J ¼ 8.8 Hz, H-6); 12.4 (1H, s, N-OH) and 7a, 2.6 g (27%); 1 H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 2.45 (3H, s, 4-CH3); 5.3 (s, 2H, OCH2C6H5); 7.34–7.46 (5H, m, OCH2C6H5); 7.8 (1H, d, J ¼ 8.8 Hz, H-6); 7.9 (1H, d, J ¼ 8.8 Hz, H-6); 12.4 (1H, s, N-OH). Following the same procedure as depicted for 6a and 7a, the other hydroximoyl chlorides 6b–d and 7b–d were prepared from the corresponding aldehyde oximes. Hydroximoyl chlorides are highly unstable and are readily prepared whenever required. Typical experimental procedure for the synthesis of coumarin isoxazoline compounds (11a–D) The corresponding ethyl-3-phenyl-prop-2-enoate 10 (0.29 g, 1.66 mmol) dissolved in dichloromethane (DCM, 12.5 mL) was added to a stirred solution of hydroximoyl chloride 6a (0.5 g, 1.45 mmol) in DCM (12.5 mL) and Et3N (0.19 g, 1.89 mmol), and the reaction SYNTHETIC COMMUNICATIONS® 1977
  • 8. mixture was stirred for 24 h at room temperature. Water (30.0 mL) was added and extracted in DCM (2 � 30.0 mL). The combined organic layer was washed with saturated NaCl solution (60.0 mL), dried over Na2SO4, and concentrated to give the crude isoxazo- line 11a, which was purified by column chromatography using silica gel in ethyl acetate/ petroleum ether (6:4), 0.46 g, 65.7% yield. Following the same procedure as illustrated for 11a, the other coumarin isoxazoline derivatives 11b–d were prepared from the corresponding hydroximoyl chlorides. The physical, spectral, and analytical data for these compounds are mentioned as follows. Ethyl-3-[7-(benzyloxy)-4-methyl-2-oxo-2h-8-chromenyl]-5-phenyl-4,5-dihydro-4- isoxazole carboxylate (11a) Off-white solid; yield 0.46 g (66%); mp 130–132 °C; 1 H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 0.95 (3H, t, J ¼ 7.2,OCH2CH3); 2.42 (3H, s, 4-CH3); 3.95 (2H, q, J ¼ 7.2, OCH2CH3); 4.68 (1H, d, J ¼ 8.8 Hz, H-4″); 5.21 (2H, s, -OCH2C6H5); 6.07 (1H, d, J ¼ 8.8 Hz, H-5″); 6.29 (s, 1H, H-3); 6.91 (1H, d, J ¼ 9.2 Hz, H-6); 7.23–7.38 (5H, m, OCH2C6H5); 7.51–7.62 (5H, m, Ar); 7.72 (1H, d, J ¼ 9.2 Hz, H-5); 13 C NMR spectrum (125 MHz, CDCl3), δ, ppm: 13.7 (OCH2CH3); 18.7 (CH3); 60.5 (C-4″); 63.1 (OCH2CH3); 70.1 (OCH2C6H5); 88.2 (C-5″); 103.9 (C-6); 104.2 (C-3); 112.6 (C-4a); 113.9 (C-8); 127.1 (C-2′,6′,4′,2″′,6″′,4″′ Ar); 129.5 (C-3′,5′,3″′,5″′ Ar); 142.1 (C-5); 150.3 (C-1″′, 1′); 153.5 (C-8a); 158.7 (C-3″, 4); 166.9 (C-2,7); 167.8 (COOEt); DIPMS: m/z ¼ 483.9 (MþH). Elemental analysis: found (%): C, 71.92; H, 5.18; N, 2.81. C29H25NO6 calculated (%): C, 72.04; H, 5.21; N, 2.90. Typical experimental procedure for the synthesis of 3-chlorinated coumarin isoxazoline compounds (12a–D) The corresponding ethyl-3-phenyl-prop-2-enoate 10 (0.26 g, 1.51 mmol) dissolved in DCM (10.0 mL) was added to a stirred solution of hydroximoyl chloride 7a (0.5 g, 1.32 mmol) in DCM (10.0 mL) and triethylamine (0.17 g, 1.71 mmol) and reaction mixture was stirred for 24 h at room temperature. Water (50.0 mL) was added and extracted with DCM (2 � 50.0 mL). The combined organic layer was washed with saturated NaCl solution (60.0 mL), dried over Na2SO4, and concentrated to give the crude isoxazoline, which was purified by column chromatography using silica gel in ethyl acetate / petroleum ether (8:2): 12a, 0.51 g, 74.5% yield. Following the same procedure as illustrated for 12a, coumarin isoxazoline derivatives 12b–d were prepared from the corresponding hydroximoyl chlorides. The physical, spectral, and analytical data for these compounds are mentioned as follows. Ethyl-3-[7-(benzyloxy)-3-chloro-4-methyl-2-oxo-2h-8-chromenyl]-5-phenyl-4,5- dihydro-4-isoxazole carboxylate (12a) Off-white solid; yield 0.51 g (75%); mp 118–120 °C; 1 H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 1.03 (3H, t, J ¼ 7.3, OCH2CH3); 2.45 (3H, s, 4-CH3); 3.97 (2H, q, J ¼ 7.3, OCH2CH3); 4.64 (1H, d, J ¼ 8.6 Hz, H-4″); 5.24 (2H, s, OCH2C6H5); 6.09 (1H, d, 1978 G. SURESH ET AL.
  • 9. J ¼ 8.6 Hz, H-5″); 6.38 (1H, d, J ¼ 9.1 Hz, H-6); 7.28–7.37 (5H, m, OCH2C6H5); 7.51–7.59 (5H, m, Ar); 7.81 (1H, d, J ¼ 9.1 Hz, H-5); 13 C NMR spectrum (125 MHz, CDCl3), δ, ppm: 14.1 (OCH2CH3); 18.9 (CH3); 62.3 (C-4″); 64.7 (OCH2CH3); 72.3 (OCH2C6H5); 88.7 (C- 5″); 105.3 (C-6); 113.7 (C-4a); 115.9 (C-8); 119.3 (C-3); 122.5 (C-2′,6′,4′,2″′,6″′,4″′ Ar); 123.5 (C-3′,5′,3″′,5″′ Ar); 142.6 (C-5); 148.2 (C-1″′, 1′); 151.8 (C-8a); 154.2 (C-3″); 159.7 (C-4); 163.8 (C-7); 166.9 (C-2,); 169.8 (COOEt); DIPMS: m/z ¼ 518.1 (MþH), 520.3 (MþH þ 2). Elemental analysis: Found (%): C, 67.02; H, 4.67; N, 2.69. C29H24ClNO6: Cal- culated (%): C, 67.25; H, 4.67; N, 2.70. Screening of antibacterial activity All these newly synthesized compounds, 11a–d and 12a–d, were evaluated for in vitro antimicrobial activity against Gram-positive bacteria (Staphylococcus aureus MTCC 96) and Gram-negative bacteria (Escherichia coli MTCC 40) by the agar disc diffusion method. All the derivatives at the concentrations of 50 µg/ml, 100 µg/ml, and 200 µg/ ml were tested against Gram-positive bacteria (Staphylococcus aureus MTCC 96) and Gram-negative bacteria (Escherichia coli MTCC 40). The molten nutrient agar was inoculated with 100 μl of the inoculum (1 � 108 cfu/ml) and poured into the Petri plate; the disc (5 mm) (Hi-Media) was saturated with 100 μl of the test compound, allowed to dry, and introduced on the upper layer of the seeded agar plate. The plates were incu- bated at about 37 °C and microbial progress was determined by measuring the diameter of zone of inhibition after 24 h. Pure solvents were used as control and inhibitory zones were nearly negligible compared to the inhibition zones of the samples. To clarify any solvent effect on the biological screening, separate studies were carried out using dimethyl sulfoxide (DMSO) as a control and it showed no activity against any bacterial strains. Chloramphenicol was used as standard drug for the purpose of comparison of antibacterial activities of the derivatives. The antibacterial activities were carried out in triplicate and average values were compiled. References [1] (a) Quezada, E.; Delogu, G.; Picciau, C.; Santana, L.; Podda, G.; Borges, F.; Gracia-Morales, V.; Vinna, D.; Orallo, F. Molecules 2010, 15(1), 270–279; (b) Fylaktakidou, K. C.; Hadjipavlou- Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr. Pharm. Des. 2004, 10(30), 3813; (c) Curir, P.; Galeotti, F.; Dolci, M.; Barile, E.; Lanzotti, V. J. Nat. Prod. 2007, 70(10), 1668; (d) Lafitte, D.; Lamour, V.; Tsvetkov, P.; Makarov, A.; Klich, M.; Deprez, P.; Moras, D.; Briand, C.; Gilli, R. Biochemistry 2002, 41(23), 7217; (e) Hwu, J.; Singha, R.; Hong, S.; Chang, Y.; Das, A.; Vliegen, I.; De Clerk, E.; Neyts, J. Antivir. Res. 2008, 77, 157; (f) Maucher, A.; Von Angerer, E. J. Cancer Res. Clin. Oncol. 1994, 120(8), 502; (g) Kirkiacharian, S.; Thuy, D.; Sicsic, S.; Bakhchinian, R.; Kurkjian, R.; Tonnaire, T. Farmaco 2002, 57, 703; (h) Vukovic, N.; Sukdolak, S.; Solujic, S.; Niciforovic, N. Food Chem. 2010, 120, 1011; (i) Lee, Y.; Lee, S.; Jin, J.; Yun-Choi, H. Arch. Pharm. Res. 2003, 26, 7236; (j) Grimm, E.; Brideau, C.; Chauret, N.; Chan, C.; Delorme, D.; Ducharme, Y.; Ethier, D.; Falgueyret, J.; Friesen, R.; Guay, J.; Hamel, P.; Riendeau, D.; Breau, C.; Tagari, P.; Girard, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2528; (k) Fylaktakidou, K.; Hadjipavlou-Litina, D.; Litinas, K.; Nicolaides, D. Curr. Pharm. Des. 2004, 10(30), 3813. [2] (a) Yogesh, K. T.; Shvetambari, T.; Hanumantharao, G. R.; Rajinder, K. G. Sci. Pharm. 2008, 76, 395; (b) Johansson, I.; Ingelman-Sundberg, M. Toxicol. Sci. 2011, 120, 1; (c) Patel, K. C.; Patel, H. D. e-J. Chem. 2011, 8(1), 113. SYNTHETIC COMMUNICATIONS® 1979
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