International Journal of Organic Chemistry, 2011, 1, 167-175
doi:10.4236/ijoc.2011.14025 Published Online December 2011 (http://www.SciRP.org/journal/ijoc)
Copyright © 2011 SciRes. IJOC
167
Synthesis and Antibacterial Activity of Urea and
Thiourea Derivatives at C-8 Alkyl Chain of Anacardic
Acid Mixture Isolated from a Natural Product
Cashew Nut Shell Liquid (CNSL)
N. Subhakara Reddy1,2, A. Srinivas Rao1*, M. Adharvana Chari3,4*, V. Ravi Kumar1, V. Jyothi3,
V. Himabindu2
1Medicinal Chemistry Laboratory, GVK Biosciences Pvt. Ltd., Hyderabad, India
2Centre for Environment, Institute of Science and Technology, JNT University, Hyderabad, India
3Dr. MACS Bio-Pharma Pvt. Ltd., Hyderabad, India
4Department of Complexity Science and Engineering, School of Frontier Sciences,
University of Tokyo, Chib a, Japan
E-mail: drmac_s@yahoo.com
Received August 12, 2011; revised September 23, 2011; accepted October 5, 2011
Abstract
Synthesis and antibacterial activity of some novel urea and thiourea derivatives (7a-7k, 8a-8f) of anacardic
acid prepared from commercially available anacardic acid which is obtained from natural product Cashew
Nut Shell Liquid (CNSL). Compounds (7a-7k, 8a-8f) were tested for Gram positive and Gram negative bac-
terial cultures. Most of the compounds were showed active compared with standard drug ampicilline.
Keywords: Synthesis, Urea and Thiourea Derivatives, Anacardic Acid, Anti-Bacterial Activity
1. Introduction
Among the different families of plants, Anacardiaceae-
shrub family is very important since this plant consist of
Non-isoprenoid phenolic lipids. The cashew tree, Ana-
cardium occidentale L., is a botanical species native of
eastern Brazil and was introduced into other tropical
countries such as India, Africa, Indonesia and South East
Asia in the 16th century [1-2]. Approximately 2 - 3 cm in
length kidney shaped structure is true fruit of cashew is
the nut, which is attached to the end of a fleshy bulb,
generally called the cashew apple. The shell consist of the
raw nut (50% of the weight), the kernel (25%) and the
remaining 25% consists of the natural cashew nut shell
liquid (CNSL), a viscous reddish brown liquid. The CN-
SL is traditionally obtained as a by-product during the iso-
lation of the kernel by roasting the raw nuts. Crude CN-
SL represents one of the major and cheapest sources of
naturally occurring non-isoprenoid phenolic lipids such
as anacardic acids (1), cardols (2), cardanols (3), methy-
lcardols (4) (Figure 1) and polymeric materials. CNSL
has found important commercial usage as the phenolic raw
material for the manufacture of certain resins and plastics
having unusual electric and frictional properties [3-6]. An-
acardic acid mixture (1a-d) isolated from a natural prod-
uct Cashew Nut Shell Liquid (CNSL) which is a by-pro-
duct of cashew nut industry and these are salicylic acid
derivatives with a nonisoprenoid alk(en)yl side chain [7].
Anacardic acid (pentadecyl salicylic acid) is a phenolic
constituent present in Cashew Nut Shell Liquid (CNSL);
(Anacardium occidentale L.) and exhibits antimicrobial
properties [8-14], which have led to the preparation of
various analogues [15-20] and soybean lipoxygenase-1
inhibitory activity [21-22] Kubo et al. [23] reported the
separation of anacardic acid into monoene (15:1), diene
(15:2) and triene (15:3) by preparative HPLC and tested
against cancer cells, and found to show moderate cyto-
toxic activity on BT-20 breast and HeLa epithelioid cer-
vix carcinoma cells. The emergence of drug resistant
strains in clinical applications [24-26] especially to Gram
positive bacteria[27-28] has created a problem of global
proportions [29-30] G. C. Reddy et al. reported the syn-
thesis of benzamide derivatives of anacardic acid [31],
sildenafil analogues [32], dihydropyridine analogues [33]
as calcium channel blockers, isonicotinoylhydrazones for
antimycobacterial activity [34] starting from anacardic
N. S. REDDY ET AL.
168
OH
C15H31-n
a
b
d
n=0
n=2
n=4
n=6
1
OH
C15H31-n
2
OH
C15H31-n
3
OH
C15H31-n
4
HO HO
H3C
14
8
11
8
11
8
c
OH
O
Figure 1. Naturally occurring non-isoprenoid phenolic lip-
ids such as anacardic acids (1), cardols (2), cardanols (3)
and methylcardols (4).
acid. Recently, a few anacardic acid derivatives exhibited
various activities like affect the structure of the enzyme
[35], anacardic acid is a specific activator of kinase ac-
tivity of Aurora Kinase A [36], suppresses expression of
nuclear factor-kB regulated gene products leading to
potentiation of apoptosis [37] inhibitor of the HAT ac-
tiveity of recombinant Plasmodium falciparum GCN5 [38]
and as modulators of histone acetyltransferases [29].
Synthesis of lasiodiplodin from the non-isoprenoid phe-
nolic lipids of CNSL as well as the salicylate macrolac-
tone and other derivatives were reported by santos et al.
[40-43].
In the present work we wish to report to synthesize
novel cell permeable urea and thiourea compounds from
cheaply available anacardic acid which was a major con-
stituent of Cashew Nut Shell Liquid (CNSL) natural sour-
ce to evaluate their biological activity by various anti-
bacterial strains. This report describes the synthesis, spec-
troscopic identification and antibacterial activity of some
novel urea and thiourea derivatives at C-8 alkyl chain of
anacardic acids against Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus and Streptococcus
pyogenes bacterial strains.
2. Results and Discussion
Here we described the synthesis of various biologically
active novel urea and thiourea derivatives using anacar-
dic acid mixture as starting material and various reagents
in the given below conditions (Scheme 1).
The anacardic acid mixture (1a-d) was isolated from
commercially available CNSL by a reported method [44,
45]. Accordingly CNSL was treated with calcium hy-
droxide, during which anacardic acid present in CNSL
becomes calcium anacardate, which was isolated and hy-
drolyzed with dil. hydrochloric acid to generate anacar-
dic acid ene mixture, which was a mixture of monoene,
diene and triene located at (8’), (8’,11’) and (8’,11’,14’)
of the C15 alkyl chain respectively. Anacardic acid ene
mixture was methylated using dimethyl sulphate in
presence of potassium carbonate in acetonitrile to afford
2. Ozonolysis of Compound 2 resulted in the formation
of 3, C8-OH. The compound 3 was converted to 4 using
carbon tetra bromide in Dichloromethane. The com-
pound 4 was reacted with sodium azide followed by re-
duction with Pd/C under H2 pressure to obtaine amine 6
coupled with various isocynate or isothiocynate in chlo-
roform to obtain compounds (7a-7k, 8a-8f, Scheme 1) of
O
O
O
O
O
O
OH
b,c
e
f
6
2
3
4
5
g
7(a-k)
R
d
O
O
O
Br
O
O
O
N3
O
O
O
NH2
OO
O
N
H
CR1
O
OH
OH
O
C15H31-n
a
b
c
d
n=0
n=2
n=4
n=6
1
8(a-f)
OO
O
N
H
CR2
S
h
Scheme 1. Synthesis of various biologically active urea and thiourea (at C8 alky l chain) derivatives from anacardic acid mix-
ture. Reagents: (a) Di methyl sulfate, K2CO3, Acetonitrile, 90˚C, 24 h; (b) Ozonalasis, MeOH, CH2Cl2, –78˚C, 6 h; (c) MeOH,
NaBH4, 18 h, 0˚C, R.T; (d) CBr4, Pyridine, TPP, CH2Cl2, 0˚C, R.T, 8 h; (e) NaN3, DMF, 100˚C, 4 h; (f) 10% Pd/C, 50 psi, 2 h;
(g) different isocyanate, CHCl3; (h) different isothiocyanate, CHCl3.
Copyright © 2011 SciRes. IJOC
169
N. S. REDDY ET AL.
urea and thiourea derivatives were purified by column
chromatography to yield title compounds. The structure
of urea and thiourea derivatives (7a-7k, 8a-8f) was de-
termined by using different spectroscopic techniques 1H
NMR, IR, Mass. The resulting compounds are screened
for their antibacterial activity.
Biological Activity
The urea and thiourea derivatives (7a-7k, 8a-8f) were
screened for their antibacterial activity [27] against some
of the pathogenic bacteria viz. E. coli (MTCC443), P.
aeruginosa (MTCC424), S. aureus, (MTCC96) and S.
pyogenes (MTCC443) using agar well diffusion method
according to the literature protocol [46]. The anti-bacte-
rial activity of the analogues was compared with stan-
dard drug ampicilline and the results of investigation
have been presented in Table 1 and observed that some
of the compounds are showed high biological activity.
Table 1. Antibacterial activity of urea and thiourea derivatives at C-8 alkyl chain of anacardic acid mixture.
Name of the Bacteria (Conc. 250 µg/ml) & Inhibition Zone in mm
Compound No. R E. coli MTCC443 P. aeruginosa MTCC424 S. aureus MTCC96 S.pygenes MTCC442
S* ampicilline SD* amplicilline 20 20 18 19
7a 17 16 17 16
7b
19 19 15 19
7c 21 18 17 17
7d
Cl
19 16 18 15
7e
Cl
Cl
17 16 18 19
7f
F
19 18 17 15
7g
NC
20 17 17 17
7h
CN
17 17 17 19
7i
CF
3
17 16 16 17
7j
O
18 17 17 15
7k
O
16 16 16 16
8a 16 21 17 17
8b
Cl
19 17 17 18
8c
Cl
Cl
17 16 16 18
8d
F
16 20 15 17
8e
CN
22 20 16 17
8f
CF
3
15 16 17 19
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N. S. REDDY ET AL.
170
Based on the test results it is evident that several of syn-
thesized anacardic acid analogues possess moderate to
good activity against the Gram +ve and Gram –ve bacte-
ria. Of all the compounds prepared entities 7a, 7b, 7c, 7d,
7f, 7g, 8b and 8e activity against E. coli, MTCC443, 7a,
7b, 8a, 8d and 8e activity against P. aeruginosa, MT-
CC424; display good to excellent activity while the re-
maining compounds showed moderate activity. The most
active antibacterial agent against Escherichia coli found
to be compound 7c, 7f, 7g, and 8e having -CN,F groups
and other compounds in the series exhibited moderate to
good activity. The compounds 7d, 7e, 8b and 8f showed
good activity against S. aureus MTCC96 and 7a, 7b, 7e,
7h, 8b, 8c and 8f showed good activity against S. pyo-
genes MTCC442. This indicates chloro, dichloro, flouro,
cyano and methoxy substituted compounds showed bet-
ter activity when compared to other substituted groups.
Here seems to be, thiourea substituted novel compounds
are exhibiting better activity than urea substituted com-
pounds. The activity depends to some extent on the R
substituent, however all the compounds showed antibac-
terial activity. It may be suggested that the anacardic acid
derivative with a suitable R may lead to a good antibac-
terial agent against all the Escherichia coli, Pseudomonas
aeruginosa, Staphylococcus aureus and Streptococcus
pyogenes bacterial strains.
3. Conclusions
In summary, the present study describes a convenient
and efficient protocol for the synthesis of sulfonamide
derivatives by using anacardic acid mixture using various
reagents and different conditions. We believe that this
procedure is convenient, economic and a user-friendly
process for the synthesis of these various novel urea and
thiourea compounds from anacardic acid mixture. All
compounds structures are supported by physico chemical
and IR, NMR, Mass spectral data. Urea and thiourea de-
rivatives were screened for their antibacterial activity ag-
ainst few bacterial strains and observed that some of the
compounds are showed more biological activity than stan-
dards used.
4. Experimental Section
4.1. General Reagents and Equipment
All chemicals and solvents were obtained from Aldrich
and Spectrochem., India and used without further purifi-
cation. Column chromatographic separations were carri-
ed out on silica gel 60 - 120 mesh size and eluting with a
gradient of hexane: ethyl acetate. Analytical thin layer
chromatography was performed on precoated Merck si-
lica gel (60F254/0.2 mm) plates using UV light, 5% eth-
anolic phosphomolybdic acid or iodine vapours to visu-
alize the spots. Melting points were determined in open
glass capillaries on a Mel-temp apparatus and are uncorr-
ected. The IR spectra were recorded on a Thermo Ni-
colet IR 200 FT-IR spectrometer as KBr pellets and the
wave numbers were given in cm1. The 1H and 13C NMR
spectra of samples were recorded on a Varian EM-360,
NMR spectrometer using TMS as an internal standard in
CDCl3.The mass spectra were recorded on Jeol JMS-D
300 and Finnigan Mat b at 70 eV with an emission current
of 100 µA. The oxidative cleavages were performed with
a Welsbach T-408 ozonizator and the catalytic hydroge-
nations in a Parr apparatus.
4.2. General Procedure: Isolation of Anacardic
Acids (1)
The shells (500 g) of cashew nuts from Anacardiumoc-
cidentale were extracted in a Soxhletextractor with com-
mercial 95% ethanol (2.0 L) during 6 h, yielding a crude
extract (CNSL, 157 g, 31% by weight). Anacardic acids (1)
were removed in 61% from CNSL (15.25 g) either by
precipitation with lead nitrate or calcium hydroxide ac-
cording to protocols described in the literature [44,45].
The spectral properties were identical to those reported
in the literature [44,45].
Preparation of Methyl anacardate methyl ethers
ene mixture (2): To a solution of Compound 1 (65 g,
186.78 mmol) in acetone was added K2CO3 (103.1 g,
747.12 mmol), Di methyl sulfate (44.3 mL, 466.95
mmol). The contents were heated at 65˚C for 5 h. Reac-
tion mixture was cooled to room temperature, filtered
and washed with ethyl acetate. Filtrate was distilled off,
crude compound was re dissolved in ethyl acetate (300
mL). Organic layer was washed with water, brine solu-
tion and dried over anhydrous sodium sulphate and dis-
tilled off ethyl acetate. Crude compound was purified by
60 - 120 silica pet ether pack column compound was
eluted with 5% ethyl acetate: pet ether to get compound
2, Yield: 58 g, light yellow liquid.
Synthesis of 2-(8-Hydroxy-octyl)-6-methoxybenzo-
ic acid methyl ester (3): A solution of compound 2 (15
g, 40.540 mmol) in dichloro methane: methanol (1:1, 500
mL) was added a pinch of Sudan red catalyst and cooled
to –78˚C. Ozone gas purged through reaction mixture
until starting material was completed (8 h). Nitrogen gas
was purged through reaction mixture for 30 min (to re-
move excess O3 gas), dimethyl sulfide was added few
drops and stirred for 20 min at –15˚C. Sodium boro-
hydride (9.970 g, 263.51 mmol) was added portion wise
over a period of 45 min. Reaction mixture was slowly
bring it to room temperature and stirred at this tempera-
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171
N. S. REDDY ET AL.
ture for 18 h. Reaction mixture was quenched with cold
water (400 mL), dichloro methane and methanol distilled
off and crude compound was diluted with water and ex-
tracted with ethyl acetate (2 × 200 mL). The combined
organic layer was washed with brine solution (150 mL)
dried over anhydrous sodium sulphate, filtered and eva-
porated under vacuum, to obtaine crude compound was
purified by neutral alumina pet ether packed column,
compound was eluted with 20% ethyl acetate: pet ether
to obtain compound (3) as yellow liquid (7.1 g, 59.5%);
IR (DCM film): 3401, 2930, 1728, 1586, 1467, 1268,
1110, 1071, 954, 749 cm–1; 1H NMR (CDCl3, 400 MHz):
δ 1.31 (bs, 8H), 1.53 - 1.59 (m, 4H), 2.53 (t, 2H, J = 8.0
Hz), 3.63 (t, 2H, J = 6.8 Hz), 3.81 (s, 3H), 3.90 (s, 3H),
6.75 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.26 -
7.28 (m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ:
25.58, 29.16, 29.23, 29.63, 31.00, 32.62, 33.35, 52.10,
55.73, 62.81, 108.23, 121.37, 123.26, 130.18, 141.17,
156.10, 168.93 ppm; ESIMS (m/z): 295 (M + H)+.
Synthesis of 2-(8-bromo-octyl)-6-methoxy-benzoic
acid methyl ester (4): A solution of compound 2 (15 g,
51.02 mmol) in Dichloro methane (150 mL) was added
dry pyridine (42 mL, 510.2 mmol) tri phenyl phosphene
(22.73 g, 86.734 mmol) at 0˚C. Carbon tetra bromide
(25.4 g, 76.53 mmol) was added portion wise over a pe-
riod of 15 min. The contain were slowly bring it to rt and
stirred at rt for 6 h. Reaction mixture was diluted with
DCM (100 mL) washed with 2N HCl (2 × 150 mL), wa-
ter (200 mL), brine solution (175 mL), dried over anhy-
drous Na2SO4, filtered and evaporated under vacuum, Cru-
de compound was purified by 100 - 200 silica pet ether
column compound was eluted with 10% ethyl acetate:
pet ether and distilled off solvent to obtain compound 4
(16.5 g, 90.8%) as yellow liquid; IR (DCM film): 3071,
3002, 2931, 2854, 1732, 1588, 1464, 1437, 1268, 1109,
1072, 960, 749 cm–1; 1H NMR (CDCl3, 400 MHz): δ
1.29 - 1.42 (m, 8H), 1.52 - 1.59 (m, 4H), 1.80 - 1.87 (m,
2H), 2.53 (t, 2H, J = 8.0 Hz), 3.40 (t, 2H, J = 7.2 Hz),
3.82 (s, 3H), 3.90 (s, 3H), 6.76 (d, 1H, J = 8.4 Hz), 6.81
(d, 1H, J = 7.6 Hz), 7.24 - 7.28 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3), δ: 28.05, 28.56, 29.12, 29.26, 31.02,
32.72, 33.36, 34.02, 52.13, 55.78, 108.27, 121.39, 123.32,
130.20, 141.14, 156.14, 168.90 ppm; ESIMS(m/z): 357
(M + H)+, 359 (bromo).
Synthesis of 2- (8-aza-octyl)-6 -methoxy-b enzoic acid
methyl ester (5): A solution of compound 3 (2.0 g,
5.617 mmol) in DMF (10 mL) was added Sodium azide
(548 mg, 8.426). The contain were heated at 100˚C for 3 h,
reaction mixture was poured into cool water (70 mL) and
extracted with diethyl ether (2 × 40 mL), the organic
layer was washed with water (50 mL), brine solution (30
mL), dried over anhydrous Na2SO4, filtered and evapo-
rated under vacuum to obtain compound 5 as yellow liq-
uid (1.5 g, 83.7%); IR (DCM film): 3087, 3002, 2932,
2856, 2095, 1731, 1588, 1464, 1266, 1109, 1071, 753
cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H), 1.59
(bs, 4H), 2.53 (t, 2H, J = 7.6 Hz), 3.25 (t, 2H, J= 7.2 Hz),
3.82 (s, 3H), 3.91 (s, 3H), 6.76 (d, 1H, J = 8.4 Hz), 6.82
(d, 1H, J = 8.0 Hz), 7.25 - 7.29 (m, 1H) ppm; ESIMS
(m/z): 320 (M + H)+.
Synthesis of 2-(8-Amino-octyl)-6-methoxy-benzoic
acid methyl ester (6): A solution of compound 4 (2.0 g,
mmol) in ethanol (30 mL) was taken into a 500 mL Parr-
hydrogenation vessel and added a suspension of 10% Pd/C
(220 mg, 10%) in 20 mL of ethanol under argon atmos-
phere and applied H2-pressure (60 psi) for 2 h. Reaction
mixture was filtered through celite bed and concentrated
the filtrate under reduced pressure to obtain 2-(8-Ami-
no-octyl)-6-methoxy-benzoic acid methyl ester (6) (1.7 g,
92.5%) as a yellow liquid. IR (neat): 3436, 2931, 2857,
1729, 1587, 1467, 1438, 1268, 1111, 1073, 829, 753
cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.273 (bs, 8H),
1.54 (bs, 2H), 1.65 - 1.79 (m,2H), 2.51 (t, 2H, J = 7.6
Hz), 2.94 (t, 2H, J = 8.0 Hz), 3.79 (s, 3H), 3.89 (s, 3H),
6.74 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H, J = 8.0 Hz), 7.23 -
7.27 (m, 1H) ppm ; ESIMS (m/z): 294 (M + H)+.
Synthesis of urea and thio urea compounds: A so-
lution of amine (300 mg, 1.023 mmol) in dry CHCl3 was
taken in seal tube was added isocynate or iso thiocynate
(1.22 mmol) at rt and stirred at rt for 3 h to 8 h and dis-
tilled off solvent and crude compound was purified by
column.
Synthesis of methyl 2-(8-(3-ethylureido)octyl)-6-me-
thoxybenzoate (7a): Using 6 and ethyl isocyanate as
starting materials, the title compound 7a was obtained as
a off white solid (Yield = 44.4%); m.p. 71˚C - 72˚C; IR
(KBr): 3338, 2929, 2854, 1729, 1625, 1579, 1466, 1269,
1108, 1072, 738 cm–1; 1H NMR (CDCl3, 400 MHz): δ
1.11 - 1.15 (m, 3H), 1.28 (bs, 8H), 1.45 - 1.59 (m, 4H),
2.53 (t, 2H, J = 8.0 Hz), 3.12 - 3.24 (m, 4H), 3.82 (s, 3H),
3.91 (s, 3H), 4.23 (s, 2H), 6.76 (d, 1H, J = 8.4 Hz), 6.81
(d, 1H, J =7.2 Hz), 7.25 - 7.29 (m, 1H) ppm; 13C NMR
(100 MHz, CDCl3), δ: 15.46, 26.73, 29.07, 29.18, 29.21,
30.14, 30.94, 33.35, 35.01, 40.25, 52.10, 55.78, 108.33,
121.43, 123.30, 130.24, 141.17, 156.15, 158.65, 169.05
ppm; ESIMS (m/z): 365 (M + H)+.
Synthesis of methyl 2-(8-(3-cyclopentylureido)octyl)
-6-methoxybenzoate (7b): Using 6 and cyclopentyl iso-
cyanate as starting materials, the title compound 7b was
obtained as a white solid (Yield = 60.4%); m.p. 80˚C -
81˚C; IR (DCM film): 3339, 2932, 2858, 1731, 1630,
1574, 1466, 1267, 1110, 1073, 749 cm–1; 1H NMR (CD-
Cl3, 400 MHz): δ 1.28 - 1.65 (m, 18H), 1.92 - 2.00 (m,
2H), 2.53 (t, 2H, J = 7.6 Hz), 3.12 - 3.16 (q, 2H), 3.81 (s,
3H), 3.90 (s, 3H), 3.91 - 3.95 (m, 1H), 4.31 (s, 1H), 6.75
(d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.25 - 7.29
Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL.
172
(m, 1H) ppm; 13C NMR (100 MHz, CDCl3), δ: 23.51,
26.78, 29.09, 29.19, 29.23, 30.21, 30.96, 33.35, 33.51,
40.24, 51.86, 52.09, 55.77, 108.31, 121.42, 123.30,
130.23, 141.16, 156.15, 158.34, 169.01 ppm; ESIMS
(m/z): 405 (M + H)+.
Synthesis of methyl 2-methoxy-6-(8-(3-phenylur-
eido)octyl) benzoate (7c): Using 6 and phenyl isocy-
anate as starting materials, the title compound 7c was ob-
tained as a cream color semi solid (Yield = 66.2%); IR
(DCM film): 3345, 3298, 3085, 3008, 2929, 2853, 1729,
1637, 1589, 1552, 1467, 1270, 1111, 1071, 735 cm–1; 1H
NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.43 - 1.55 (m,
4H), 2.53 (t, 2H, J = 8.0 Hz), 3.17 - 3.22 (q, 2H), 3.80 (s,
3H), 3.91 (s, 3H), 5.07 (bs, 1H), 6.76 (d, 1H, J = 8.4 Hz),
6.81 (d, 1H, J = 8.0 Hz), 7.01 - 7.05 (m, 1H), 7.24 - 7.31
(m, 5H) ppm; ESIMS (m/z): 413 (M + H)+.
Synthesis of methy l 2-(8-(3-(3-chlorophenyl)ureido)
octyl)-6-methoxybenzoate (7d): Using 6 and 3-chlor-
ophenyl isocyanate as starting materials, the title com-
pound 7d was obtained as a white color solid (Yield =
35%); m.p. 102˚C - 103˚C; IR (DCM film): 3347, 3080,
3004, 2930, 2855, 1729, 1659, 1590, 1549, 1473, 1429,
1268, 1110, 1073, 766 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.27 (bs, 8H), 1.40 - 1.60 (m, 4H), 2.54 (t, 2H, J
= 7.6 Hz), 3.19 - 3.24 (q, 2H), 3.80 (s, 3H), 3.92 (s, 3H),
5.04 (s, 1H), 6.76 - 6.85 (m, 3H), 6.97 (d, 1H, 7.2 Hz),
7.14 - 7.37 (m, 4H) ppm ; ESIMS (m/z): 447 (M + H)+.
Synthesis of methyl 2-(8-(3-(3,4-dichlorophenyl)ur-
eido)octyl)-6-methoxybenzoate (7e): Using 6 and 3, 4
dichlorophenyl isocyanate as starting materials, the title
compound 7e was obtained as a light brown solid (Yield
= 65%); m.p. 80˚C - 82˚C; IR (DCM film): 3351, 3099,
2930, 2855, 1729, 1661, 1587, 1542, 1470, 1381, 1270,
1115, 1072, 1028, 820, 746 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.25 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J
= 8.0 Hz), 3.17 - 3.22 (q, 2H), 3.80 (s, 3H), 3.93 (s, 3H),
5.15 (s, 1H), 6.77 (d, 1H, J = 8.0 Hz), 6.82 (d, 1H, J =
7.6 Hz), 7.08 - 7.19 (m, 2H), 7.20 - 7.31 (m, 2H), 7.48 (s,
1H) ppm; ESIMS (m/z): 481 (M + H)+. 483 (chloro).
Synthesis of methyl 2-(8-(3-(2-fluorophenyl)ureido)
octyl)-6-methoxybenzoate (7f): Using 6 and 2-fluoro-
phenyl isocyanate as starting materials, the title com-
pound 7f was obtained as a light brown solid (Yield =
68.2%); m.p. 92˚C - 93˚C; IR (DCM film): 3348, 3073,
3006, 2930, 2855, 1730, 1658, 1551, 1457, 1265, 1188,
1109, 1073, 810 cm–1; 1H NMR (CDCl3, 400 MHz): δ
1.28 (bs, 8H), 1.42 - 1.60 (m, 4H), 2.54 (t, 2H, J = 7.6
Hz), 3.21 - 3.25 (q, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 5.04
(s, 1H), 6.67 (s, 1H), 6.75 (d, 1H, J = 8.0 Hz), 6.81 (d,
1H, J = 8.0 Hz), 6.92 - 6.98 (m, 1H), 7.01 - 7.10 (m, 2H),
7.24 - 7.29 (m, 1H), 8.01 - 8.10 (m, 1H) ppm; ESIMS
(m/z): 431 (M + H)+.
Synthesis of methyl 2-(8-(3-(2-cyanophenyl)ureido)
octyl)-6-methoxybenzoate (7g): Using 6 and 2-cyano-
phenyl isocyanate as starting materials, the title com-
pound 7g was obtained as a light green semi solid (Yield
= 26.7%); IR (DCM film): 3346, 3078, 3000, 2930, 2855,
2221, 1728, 1662, 1581, 1546, 1452, 1268, 1110, 1072,
758 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H),
1.51 - 1.57 (m, 4H), 2.54 (t, 2H, J = 7.6 Hz), 3.23 - 3.28
(q, 2H), 3.80 (s, 3H), 3.91 (s, 3H), 5.33 (s, 1H), 6.75 (d,
1H, J = 8 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.02 (t, 1H, J =
7.6 Hz), 7.11 (s, 1H), 7.24 - 7.28 (m, 1H), 7.49 - 7.54 (m,
2H), 8.31 (d, 1H, J = 8.0 Hz) ppm; ESIMS (m/z): 436 (M
+ H)+.
Synthesis of methyl 2-(8-(3-(3-cyanophenyl)ureido)
octyl)-6-methoxybenzoate (7h): Using 6 and 3-cyano
phenyl isocyanate as starting materials, the title compound
7h was obtained as a pale yellow solid (Yield = 33.5%);
m.p. 75˚C - 76˚C; IR (DCM film): 3355, 3083, 3006,
2930, 2855, 2230, 1728, 1664, 1587, 1552, 1470, 1431,
1271, 1111, 1072, 791, 747 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.26 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J
= 8.0 Hz), 3.19 - 3.24 (q, 2H), 3.80 (s, 3H), 3.93 (s, 3H),
5.2 (s, 1H), 6.78 - 6.84 (m, 2H), 7.22 - 7.33 (m, 3H),
7.57(s, 1H), 7.63 - 7.65 (m, 1H) ppm; ESIMS (m/z): 438
(M + H)+.
Synthesis of methyl 2-methoxy-6-(8-(3-(3-(trifluo-
romethyl)phenyl)ureido)octyl)benzoate (7i): Using 6
and 3-trifluromethyl phenyl isocyanate as starting mate-
rials, the title compound 7i was obtained as a white solid
(Yield = 42.6%); m.p. 99˚C - 101˚C; IR (DCM film):
3349, 3096, 3005, 2932, 2856, 1730, 1660, 1564, 1442,
1335, 1266, 1120, 1072 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.26 (bs, 8H), 1.41 - 1.58 (m, 4H), 2.55 (t, 2H, J
= 7.6 Hz), 3.19 - 3.24 (q, 2H), 3.79 (s, 3H), 3.93 (s, 3H),
5.12 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J =
8.0 Hz), 7.075 (s, 1H), 7.22 - 7.36 (m, 3H), 7.55 - 7.59
(m, 2H) ppm; ESIMS (m/z): 481 (M + H)+.
Synthesis of methyl 2-methoxy-6-(8-(3-(3-methoxy
phenyl)ureido)octyl)benzoate (7j): Using 6 and 3-me-
thoxy phenyl isocyanate as starting materials, the title
compound 7j was obtained as a off white solid (Yield =
88.4%); m.p. 82˚C - 83˚C; IR (DCM film): 3343, 2935,
2861, 1726, 1567, 1466, 1266, 1109, 1072, 772 cm–1; 1H
NMR (CDCl3, 400 MHz): δ 1.26 (bs, 8H), 1.40 - 1.58 (m,
4H), 2.53 (t, 2H, J = 8.0 Hz), 3.19 - 3.22 (q, 2H), 3.77 (s,
3H), 3.80 (s, 3H), 3.91 (s, 3H), 5.08 (s, 1H), 6.59 - 6.60
(m, 1H), 6.75 - 6.82 (m, 3H), 7.05 (s, 1H), 7.12 - 7.18 (m,
1H), 7.25 - 7.30 (m, 1H) ppm; ESIMS (m/z): 443 (M +
H)+.
Synthesis of methyl 2-(8-(3-(2,2-dimethyl-2,3-dihy-
dro benzofuran-7-yl)ureido)octyl)-6-methoxybenzoate
(7k): Using 6 and 7-isocyanato-2, 2-dimethyl-2, 3-dihy-
dro benzofuran as starting materials, the title com- pound
7k was obtained as a light brown color solid (Yield:
Copyright © 2011 SciRes. IJOC
173
N. S. REDDY ET AL.
44.4%); m.p. 96˚C - 97˚C; IR (DCM film): 3347, 3050,
2929, 2855, 1730, 1658, 1565, 1441, 1374, 1300, 1267,
1111, 1070, 877, 765, 738 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.28 (bs, 8H), 1.46 (s,6H), 1.46 - 1.60 (m, 4H),
2.53 (t, 2H, J = 7.6 Hz), 3.03 (s, 2H), 3.21 - 3.26 (q, 2H),
3.81 (s, 3H), 3.90 (s, 3H), 4.85 (s, 1H), 6.21 (s, 1H), 6.74
- 6.85 (m, 4H), 7.24 - 7.28 (m, 1H), 7.54 (d, 1H, J = 8.0
Hz) ppm; 13C NMR (100 MHz, CDCl3), δ: 26.78, 28.20,
29.09, 29.20, 29.26, 30.01, 30.98, 33.39, 40.30, 43.32,
52.13, 55.80, 87.56, 108.33, 119.50, 119.69, 120.59,
121.46, 122.97, 123.36, 126.89, 130.22, 141.24, 148.55,
155.82, 156.20, 168.97 ppm; ESIMS (m/z): 483 (M +
H)+.
Synthesis of methyl 2-methoxy-6-(8-(3-phenyl thi-
oure ido)octyl) benzoate (8a): Using 6 and phenyl thio-
isocyanate as starting materials, the title compound 8a
was obtained as a light brown liquid (Yield = 50.2%); IR
(DCM film): 3280, 3054, 3005, 2930, 2854, 1728, 1590,
1536, 1502, 1465, 1304, 1267, 1110, 1072, 753 cm–1; 1H
NMR (CDCl3, 400 MHz): δ 1.29 (bs, 8H), 1.57 (bs, 4H),
2.54 (t, 2H, J = 8.0 Hz), 3.60 - 3.64 (m, 2H), 3.82 (s, 3H),
3.91 (s, 3H), 6.02 (s, 1H), 6.77 (d, 1H, J = 8 Hz), 6.82 (d,
1H, J = 8.0 Hz), 7.22 - 7.34 (m, 4H), 7.43 - 7.47 (m, 2H),
7.59 (s, 1H) ppm; ESIMS (m/z): 429 (M + H)+.
Synthesis of methyl 2-(8-(3-(3-chlorophenyl) thioure
ido)octyl)-6-methoxybenzoate (8b): Using 6 and 3-
chloro phenyl thioisocyanate as starting materials, the
title compound 8b was obtained as a off white solid
(Yield = 80.3%); m.p. 103˚C - 104˚C; IR (DCM film):
3349, 3083, 3004, 2930, 2855, 1730, 1660, 1592, 1544,
1473, 1429, 1269, 1110, 1073, 773, 741 cm–1; 1H NMR
(CDCl3, 400 MHz): δ 1.25 (bs, 8H), 1.44 - 1.60 (m, 4H),
2.54 (t, 2H, J = 7.6 Hz), 3.18 - 3.20 (m, 2H), 3.8 (s, 3H),
3.92 (s, 3H), 5.2 (s, 1H), 6.77 (d, 1H, J = 8.4 Hz), 6.82 (d,
1H, J = 7.6 Hz), 6.95 (d, 1H, J = 8.0 Hz), 7.12 - 7.21 (m,
2H), 7.28 - 7.35 (m, 2H) ppm; ESIMS (m/z): 463 (M +
H)+.
Synthesis of methyl 2-(8-(3-(3,4-dichlorphenyl)thi-
oureido)octyl)-6-methoxybenzoate (8c): Using 6 and
phenyl thioisocyanate as starting materials, the title com-
pound 8c was obtained as a pale brown color liquid
(Yield = 98.4%); IR (DCM film): 3298, 3055, 3008,
2930, 2855, 1725, 1588, 1533, 1470, 1269, 1115, 1072,
1030, 822, 736 cm–1; 1H NMR (CDCl3, 400 MHz): δ
1.37 (bs, 8H), 1.58 (s, 4H), 2.55 (t, 2H, J = 7.2 Hz), 3.60
(bs, 2H), 3.81 (s, 3H), 3.91 (s, 3H), 6.06 (s, 1H), 6.77 (d,
1H, J = 8.0 Hz), 6.82 (d, 1H, J = 7.2 Hz), 7.13 (d, 1H, J =
8.4 Hz), 7.26 - 7.30 (m, 1H), 7.38 (s, 1H), 7.48 (d, 1H, J
= 8.8 Hz), 7.67 (s, 1H) ppm; ESIMS (m/z): 497 (M + H)+.
499 (chloro).
Synthesis of methyl 2-(8-(3-(2-fluorophenyl)thiour-
eido)octyl)-6-methoxybenzoate (8d): Using 6 and 2-
fluorophenyl thioisocyanate as starting materials, the title
compound 8d was obtained as a pale brown liquid (Yield
= 74.3%); IR (DCM film): 3259, 3050, 3006, 2931, 2855,
1728, 1587, 1541, 1505, 1465, 1268, 1110, 1072, 956,
752 cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.30 (bs, 8H),
1.58 (bs, 4H), 2.54 (t, 2H, J = 8.0 Hz), 3.63 (bs, 2H),
3.82 (s, 3H), 3.92 (s, 3H), 6.04 (s, 1H), 6.77 (d, 1H, J =
8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 7.19 - 7.41 (m, 5H)
ppm; ESIMS (m/z): 447 (M + H)+.
Synthesis of methyl 2-(8-(3-(3-cyanophenyl)thiour-
eido)octyl)-6-methoxybenzoate (8e): Using 6 and 3-
cyanophenyl thioisocyanate as starting materials, the title
compound 8e was obtained as a yellow solid (Yield =
36.6%); m.p. 114˚C - 115˚C; IR (DCM film): 3334, 2939,
2862, 2223, 1725, 1639, 1549, 1466, 1265, 1109, 1071
cm–1; 1H NMR (CDCl3, 400 MHz): δ 1.33 (bs, 8H), 1.58
(bs, 4H), 1.80 - 1.82 (m, 2H), 2.53 (t, 2H, J = 8.0 Hz),
3.81 (s, 3H), 3.91 (s, 3H), 4.6 (s, 1H), 6.75 (d, 1H, J =
8.4 Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.95 (d, 1H, J = 8.0 Hz),
7.23 - 7.28 (m, 3H), 7.47 - 7.51 (m, 1H) ppm; ESIMS
(m/z): 454 (M + H)+.
Synnthesis of methyl 2-methoxy-6-(8-(3-(3-(trifluoro
methyl)phenyl)thioureido)octyl) benzoate (8f): Using 6
and 3-trifluromethylphenyl thioisocyanate as star- ting
materials, the title compound 8f was obtained as a light
yellow liquid (Yield = 46.7%); IR (DCM film): 3325,
3070, 3013, 2931, 2856, 1725, 1666, 1582, 1459, 1331,
1269, 1119, 1073, 894 cm–1; 1H NMR (CDCl3, 400
MHz): δ 1.288 (bs, 8H), 1.58 (bs, 4H), 2.53 (t, 2H, J =
8.0 Hz), 3.61 (bs, 2H), 3.79 (s, 3H), 3.90 (s, 3H), 6.06 (s,
1H), 6.75 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz),
7.25 - 7.29 (m, 1H), 7.46 - 7.55 (m, 4H), 7.74 (s, 1H)
ppm; ESIMS (m/z): 495(M – H)+.
Antibacterial Bioassay [27]: Urea and thiourea deriva-
tives of Anacardic acid (7a-7k, 8a-8f) were dissolved in
dimethyl sulphoxide at 250 μg/mL concentration. The
composition of nutrient agar medium was Bactotryptone
(10 g), yeast extract (5 g), NaCl (10 g), final pH 7.4. Af-
ter 18 h the exponentially growing cultures of the six
bacteria in nutrient broth at 37˚C were diluted in sterile
broth. From each of these diluted cultures, 1mL was
added to 100 mL sterilized and cooled nutrient agar me-
dia to give a final bacterial count of 1 × 106 cell/ml. The
plates were set at room temperature and later dried at
37˚C for 20 h. Paper discs (6 mm, punched from What-
mann no. 41 paper) were ultraviolet sterilized and used
for the assays. Discs were soaked in different concentra-
tion of the test solution and placed on the inoculated agar
media at regular intervals of 6 - 7 cm, care was taken to
ensure that excess solution was not on the discs. All the
samples were taken in triplicates. The plates were incu-
bated at 37˚C in an inverted fashion. Activity was deter-
mined by zones showing complete inhibition (mm). Gr-
owth inhibition was calculated with reference to positive
Copyright © 2011 SciRes. IJOC
N. S. REDDY ET AL.
174
control.
5. Acknowledgements
We thank GVK Biosciences Private Limited for the fi-
nancial support and encouragement. We also thankful to
the analytical department for their analytical data and to
Dr. Balaram Patro for his helpful suggestions.
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