Synthesis and antibacterial activity of sulfonamide derivatives of anacardicacid mixture isolated from a natural product Cashew Nut Shell Liquid (CNSL)

Article abstract of DOI:10.2174/157017812800233660

Abstract: Synthesis and antibacterial activity of some novel sulfonamide derivatives of anacardic acid were (8a-8l) prepared from commercially available anacardic acid mixture (1a-d) isolated from a natural product Cashew Nut Shell Liquid (CNSL).Compounds (8a-8l) were tested for Gram positive and Gram negative bacterial cultures. Most of the compounds were showed active compared with standard drug ampicilline.

Full text of DOI:10.2174/157017812800233660

Letters in Organic Chemistry, 2012, 9, 287-293
287
Synthesis and Antibacterial Activity of Sulfonamide Derivatives of
Anacardicacid Mixture Isolated from a Natural Product Cashew Nut Shell
Liquid (CNSL)
N. Subhakara Reddya,b, A. Srinivas Raoa, M. Adharvana Chari*,c,d, V. Ravi kumara, V. Jyothyc and
V. Himabindub
aMedicinal chemistry Laboratory, GVK Biosciences Pvt Ltd, Plot No 5C, IDA, Uppal, Hyderabad, 500039 AP, India
bCentre for Environment, Institute of Science and Technology, JNT University,Kukatpally, Hyderabad-85, India
cDr.MACS Bio-Pharma Pvt. Ltd., Plot-32/A,Westren Hills, Kukatpally, Hyderabad-85, A.P, India
dDepartment of Complexity Science and Engineering, School of Frontier Sciences, 5-1-5, Kashiwanoha, Kashiwa,
University of Tokyo, Chiba 277-8561, Japan
Received June 19, 2011: Revised October 15, 2011: Accepted January 27, 2012
Abstract: Synthesis and antibacterial activity of some novel sulfonamide derivatives of anacardic acid were (8a-8l)
prepared from commercially available anacardic acid mixture (1a–d) isolated from a natural product Cashew Nut Shell
Liquid (CNSL).Compounds (8a-8l) were tested for Gram positive and Gram negative bacterial cultures. Most of the
compounds were showed active compared with standard drug ampicilline.
Keywords: Anacardic acid, anti-bacterial activity, sulfonamide derivatives, synthesis.
INTRODUCTION
20] has created a problem of global proportions [21, 22].
This phenomenon has led in creating novel antibacterial
agents distinct from existing classes of compounds.
Anacardic acid (pentadecyl salicylic acid) is a phenolic
constituent present in Cashew Nut Shell Liquid (CNSL);
(Anacardium occidentale L.) and exhibits antimicrobial
properties [2, 3] which have led to the preparation of various
analogs [23, 24]. In the present work we wish to report to
synthesize novel cell permeable sulfonamide compounds
from abundantly and cheaply available anacardic acid which
was a major constituent of Cashew Nut Shell Liquid (CNSL)
natural source to evaluate their biological activity by various
antibacterial strains. This report describes the synthesis,
spectroscopic identification and antibacterial activity of
some novel anacardic acid derivatives against Escherichia
coli, Pseudomonas aeruginosa, Staphylococcus aureus and
Streptococcus pyogenes bacterial strains.
Anacardic acid mixture (1a–d) isolated from a natural
product Cashew Nut Shell Liquid (CNSL) which is a by-
product of cashew nut industry and these are salicylic acid
derivatives with a nonisoprenoid alk(en)yl side chain [1].
Anacardic acid and its derivatives exhibits biological
activities like antimicrobial activity [2, 3] and soybean
lipoxygenase-1 inhibitory activity [4, 5]. G.C.Reddy et al.
reported the synthesis of benzamide derivatives of anacardic
acid [6], sildenafil analogs [7], dihydropyridine analogs [8]
as calcium channel blockers, isonicotinoylhydrazones for
antimycobacterial activity [9] starting from anacardic acid.
Kubo et al. 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 cytotoxic activity on BT-20 breast and
HeLa epithelioid cervix carcinoma cells [10]. Recently, a
few anacardic acid derivatives exhibited various activities
like affecting the structure of the enzyme [11], anacardic acid
is a specific activator of kinase activity of Aurora Kinase A
[12], suppresses expression of nuclear factor-kB regulated
gene products leading to potentiation of apoptosis [13]
inhibitor of the HAT activity of recombinant Plasmodium
falciparum GCN5 [14] and as modulators of histone
acetyltransferases [15].
RESULTS AND DISCUSSION
Here, we described the synthesis of various biologically
active novel sulfonamides derivatives using anacardic 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 [25].
Accordingly, CNSL was treated with calcium hydroxide,
during which anacardic acid present in CNSL becomes
calcium anacardate, which was isolated and hydrolyzed with
dil. hydrochloric acid to generate anacardic 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. Saturated anacardic acid was obtained by
The emergence of drug resistant strains in clinical
applications [16-18] especially to Gram positive bacteria [19,
*Address correspondence to this author at the Department of Complexity
Science and Engineering, School of Frontier Sciences, 5-1-5, Kashiwanoha,
Kashiwa, University of Tokyo, Chiba 277-8561, Japan; Tel/Fax: 0091-
4040206647; E-mail: drmac_s@yahoo.com
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

288 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Reddy et al.
a
OH
O
n=0
n=2
OH
O
b
c
OH
C15H31-n
a
OH
n=4
n=6
2
d
1
Anacardic acid mixture 1(a-d)
b
O
O
O
c
O
OH
3
4
d
o
O
O
O
e
S
N3
O
O
6
5
f
O
O
S
g
R
NH2
N
H
O
7
8a-l
Scheme 1. Synthesis of various biologically active sulfonamides from anacardic acid mixture.
Reagents: a) 10% Pd/C, EtOH, 50psi, RT, 2h; b) Dimethyl sulfate, K2CO3, Acetonitrile, 90°C, 24h; c) LAH, THF, 0°C –RT, 18h; d)
Methane sulphonyl chloride, Et3N, DCM, 0°C-rt, 3h; e) NaN3, DMF; f) 10% Pd/C, 50 psi, 2h; g) Different sulphonyl chlorides, TEA, DCM.
hydrogenation of the ene mixture of anacardic acid7 and was
further converted to dialkylated compound by reacting with
dimethylsulfate in acetonitrile. Dialkylated anacardic acid
was reduced to alcohol by treatment with lithium aluminium
hydride in tetrahydrofuran and then protected with methane
sulphonyl chloride in dichloromethane. Resultant mesylated
compound was reacted with sodium azide followed by
reduction with Pd/C under H2 pressure to obtained amine
coupled with various sulphonyl chloride in the presence of
triethylamine in DCM to obtain compounds (8a-8l, Scheme
1) of sulfonamide derivatives were purified by column
chromatography to yield title compounds. The structure of
sulfonamide derivatives 8a-8l was determined by using
and observed that the most of compounds showed high
biological activity. Based on the test results it is evident that
several of the synthesized anacardic acid analogs possess
moderate to good activity against the Gram +ve and Gram –
ve bacteria. Of all the compounds prepared entities 8a, 8k, 8l
of E. coli MTCC443, 8a, 8g, 8h, 8k, 8l of P. aeruginosa
MTCC424, 8f of S. aureus MTCC96 and 8g, 8h of S.
pyogenes MTCC442 display good to excellent activity, while
the remaining compounds showed moderate activity. The
most active antibacterial agent against Escherichia coli
found to be compound 8k and 8l having N-containing
compound and other compounds in the series exhibited
moderate to good activity. The activity depends to some
extent on the R substituent, however all the compounds show
antibacterial activity. So other functionalities in the molecule
will contribute to the activity as well. It may be suggested
that the anacardic acid derivative with a suitable R may lead
to a good antibacterial agent against all the Escherichia coli,
Pseudomonas aeruginosa, Staphylococcus aureus and
Streptococcus pyogenes bacterial strains.
1
different spectroscopic techniques H NMR, IR, Mass. The
resulting compounds are screened for their antibacterial
activity.
Biological Activity
The sulfonamide derivatives 8a-8l were screened for
their antibacterial activity [26] 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 [26]. The anti-bacterial activity of the
analogs was compared with standard drug ampicilline and
the results of investigation have been presented in Table 1
CONCLUSION
In summary, the present study describes a convenient and
efficient protocol for the synthesis of sulfonamide
derivatives by using anacardic acid mixture using various

Synthesis and Antibacterial Activity of Sulfonamide Derivatives
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
289
Table 1. Antibacterial activity of sulfonamide derivatives of anacardic acid
Name of the Bacteria (Conc. 250 µg/ml) & Inhibition Zone in mm
Compound No.
R
E. coli
P. aeruginosa
S. aureus
S. pygenes
MTCC443
MTCC424
MTCC96
MTCC442
8a
8b
22
19
21
17
16
18
16
16
8c
8d
8e
15
16
17
15
18
20
15
16
16
17
16
17
Cl
Cl
8f
15
15
19
18
8g
8h
16
17
21
22
16
15
19
19
8i
8j
19
17
18
19
16
17
18
18
S
Br
S
N
N
8k
21
21
16
16
N
F
N
N
8l
22
20
22
20
15
18
15
19
F
SD* amplicilline (Conc. 250 µg/ml)
SD*

290 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Reddy et al.
reagents and different conditions. We believe that this
procedure is convenient, economic and a user-friendly
process for the synthesis of these various sulphonamide
compounds from anacardic acid mixture. All compounds
structures are supported by physico chemical and IR, NMR,
Mass spectral data. Sulphonamide derivatives were screened
for their antibacterial activity against few bacterial strains
and observed that some of the compounds have shown more
biological activity than the standards used.
3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J = 8
Hz), 7.25 (t, 1H, J = 8 Hz); 13C NMR (100 MHz, CDCl3): δ
14.07, 22.66, 29.32, 29.38, 29.48, 29.51, 29.61, 29.65, 31.12,
31.88, 33.45, 52.04, 55.80, 108.30, 121.45, 123.44, 130.17,
141.35, 156.20, 168.88; EI MS: m/z (rel.abund.%) 377 (M+,
100).
Synthesis of 2-Methoxy-6-pentadecyl-phenyl) - Methanol
(4)
A suspension of LiAlH4 (3.03g, 79.787 m.mol) in Dry
THF (150 mL) was added compound 3 (20g, 53.19 m.mol)
in THF (100 mL) drop wise over a period of 40 min at 0°C.
The content was slowly, stirred at room temp., for 18h.
Reaction mixture was quenched with saturated brine solution
(40 mL) at 0°C diluted with ethyl acetate filtered (200 mL)
and washed with ethyl acetate (100 mL), filtrate was washed
with brine solution (200 mL) dried over anhydrous Na2SO4,
filtered and evaporated under vacuum to obtain 2-Methoxy-
6-pentadecyl-phenyl)- methanol (4) (15gm) as off white
solid; Yield: 81%; M.p: 60-62°C; IR (KBr): νmax 3386, 3073,
2917, 2847, 1589, 1465, 1318, 1263, 1197, 1093, 1001, 739
cm-1; H1-NMR (400 MHz, CDCl3): δ 0.89 (t, 3H, J = 7.2
Hz), 1.27 (bs, 24H), 1.53-1.58 (m, 2H), 2.37 (t, 1H, J = 6.4
Hz), 2.68 (t, 2H, J = 6.4 Hz), 3.87 (s, 3H), 4.75 (d, 2H, J =
6.4 Hz) 6.77 (d, 1H, J = 8 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.20
(t, 1H, J = 8 Hz); 13C NMR (100 MHz, CDCl3): δ 14.07,
22.66, 29.32, 29.46, 29.57, 29.61, 29.65, 31.88, 32.10, 33.19,
55.37, 57.30, 108.01, 122.28, 126.83, 128.45, 142.62,
158.22; EI MS: m/z (rel.abund.%) 349 (M+, 100).
EXPERIMENTAL SECTION
All chemicals and solvents were obtained from Aldrich
and Spectrochem., India and used without further
purification. Column chromatographic separations were
carried out on silica gel 60-120 mesh size. Melting points
were determined in open glass capillaries on a Mel-temp
apparatus and are uncorrected. The IR spectra were recorded
on a Thermo Nicolet IR 200 FT-IR spectrometer as KBr
1
pellets and the wave numbers were given in cm−1. The H
and13C 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 100µA.
General Procedure: Synthesis of 2-hydroxy-6-pentadecyl-
benzoic Acid (2)
A solution of compound 1 (100 gm, 287.35 mmol) in
ethanol (500 mL) was taken into a 1L Parr-hydrogenation
vessel and added a suspension of 10 % Pd/C (10g, 10%) in
70 mL of ethanol under argon atmosphere and applied H2-
pressure (50 psi) for 2h. Reaction mixture was filtered
through celite bed and concentrated the filtrate under
reduced pressure to obtain compound recrystallized in pet
ether to get 2-hydroxy-6-pentadecyl-benzoic acid (2) as
white color solid (70g); (Yield:70 g, 68.8%; white solid);
M.p: 85-86 °C; IR (KBr): νmax 3010, 3002, 2918, 2851, 1655,
1450, 1246, 1214 cm-1; H1-NMR (400 MHz, CDCl3): δ 0.89
(t, 3H, J = 6.8 Hz), 1.27 (bs, 24H), 1.57-1.63 (m, 2H), 2.98
(t, 2H, J = 8 Hz), 6.78 (d, 1H, J = 7.6 Hz), 6.88 (d, 1H, J =
8.4 Hz), 7.37 (t, 1H, J = 8 Hz), 11.02 (bs, 1H); EI MS: m/z
(rel.abund.%) 349 (M+, 100)
Synthesis of Methanesulfonic Acid 2-methoxy-6-
pentadecyl-benzyl Ester (5)
To a solution of compound 4 (15g, 45.181m.mol) in
DCM was added TEA (13.92 mL, 99.398 m.mol) followed
by mesyl chloride (4.2 mL, 54.21 m.mol) at 0°C over a
period of 15 min. The content was stirred at room temp., for
3h. Reaction mixture was washed with water (150 mL),
brine solution (200 mL) dried over anhydrous Na2SO4,
filtered and evaporated under vacuum to obtain
methanesulfonic
acid
2-methoxy-6-pentadecyl-benzyl
ester(5) (17g, 92.59%) as off-white color solid.
Synthesis of 2-(azidomethyl)-1-methoxy-3-pentadecyl-
benzene (6)
Synthesis of 2-Methoxy-6-pentadecyl-benzoic Acid
Methyl Ester (3)
To a solution of compound 5 (7.5g, 17.605 mmol) in
DMF (30 mL) was added sodium azide (1.49g, 22.887
mmol), the content was heated at 100°C for 2h. Reaction
mixture was cooled to room temp., and poured into cool
water (150 mL) solid compound was precipitated filtered and
dried to get Azide (6) (6.2g, 94.4%) as white color solid; IR
(KBr): νmax 3087, 3013, 2924, 2854, 2096, 1589, 1463, 1316,
A solution of compound 2 (20g, 57.471 m.mol) in ACN
(200 mL) was added K2CO3 (40.8 g, 287.35 m.mol) and
DMS (21.76 mL, 229.88 m.mol). The content was heated to
reflux for 24h. Reaction mixture was filtered and distilled off
filtrate, obtained residue was re dissolved in ethyl acetate
and washed with water (2x200 mL), brine solution (175
mL), dried over anhydrous Na2SO4, filtered and evaporated
under vacuum to obtain 2-Methoxy-6-pentadecyl-benzoic
acid methyl ester(3) as pale yellow solid 18.5g; Yield:
85.5%; M.p: 36-37°C; IR (KBr): ν max 3004, 2921, 2852,
1732, 1589, 1460, 1266, 1105, 1067, 954, 747 cm-1; H1-
NMR (400 MHz, CDCl3) : δ 0.88 (t, 3H, J = 6.8 Hz), 1.25
(bs, 24H), 1.53-1.60 (m, 2H), 2.53 (t, 2H, J = 8 Hz), 3.81 (s,
1
1262, 1089, 782, 751 cm-1; H NMR (CDCl3, 400 MHz): δ
0.88 (t, 3H, J = 6.8 Hz), 1.25 (bs, 24H), 1.52-1.56 (m, 2H),
2.63 (t, 1H, J = 7.6 Hz), 3.85 (s, 3H), 4.42 (s, 2H) 6.78 (d,
1H, J = 8 Hz), 6.83 (d, 1H, J = 8 Hz), 7.24-7.26 (m, 1H); 13
C
NMR (100 MHz, CDCl3): δ 14.09, 22.67, 29.35, 29.48,
29.56, 29.66, 31.56, 31.91, 32.98, 45.14, 55.49, 108.11,
121.55, 121.97, 129.27, 143.70, 158.28; ESIMS(m/z): 331
(M-N3) (M+H)+.

Synthesis and Antibacterial Activity of Sulfonamide Derivatives
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
291
Synthesis of 2-methoxy-6-pentadecyl-benzyl Amine (7)
2962, 2853, 1589, 1465, 1407, 1328, 1265, 1216, 1162,
1
1054, 991, 905, 758, 695cm-1; H NMR (CDCl3, 400 MHz):
A solution of compound 6 (1.5g, 4.021 mmol) in ethanol
(30 mL) was taken into a 500 mL Parr-hydrogenation vessel
and added a suspension of 10 % Pd/C (250 mg, 10%) in 20
mL of ethanol under argon atmosphere and applied H2-
pressure (60 psi) for 2h. Reaction mixture was filtered
through celite bed and concentrated the filtrate under
reduced pressure to obtain 2-methoxy-6-pentadecyl-benzyl
amine (7) (1.1g, 78.8%) as a off-white solid. M.p. 55-56 °C,
IR (neat): ν max 3400, 3066, 2924, 2853, 1583, 1464, 1439,
1374, 1259, 1149, 1121, 1079, 879, 787, 742 cm-1; 1H NMR
(CDCl3, 400 MHz): δ 0.89 (t, 3H, J = 7.2 Hz), 1.26 (brs,
24H), 1.51-1.57 (m, 2H), 1.76 (bs, 2H), 2.65(t,2H, J = 7.6
Hz), 3.84 (s, 5H), 6.74 (d, 1H, J =8 Hz),6.79 (d, 1H, J = 7.6
Hz), 7.15 (t, 1H, J = 7.6 Hz); 13C NMR (100 MHz, CDCl3):
δ 14.06, 22.64, 29.31, 29.49, 29.57, 29.61, 31.88, 32.14,
33.14, 37.54, 55.24, 107.96, 122.02, 127.33, 129.76, 141.62,
157.87; MS(m/z): 348 (M+H)+.
δ 0.9 (t, 3H, J=7.2 Hz), 1.27 (brs, 24H), 1.32-1.402 (m,2H),
2.45 (t, 2H, J=7.6 Hz),2.58 (s, 3H), 3.77 (s, 3H), 4.14 (d, 2H,
J = 6.4 Hz), 5.11 (t, 1H, J = 6 Hz), 6.65-6.71 (m, 2H), 7.14
(t, 1H, J = 7.6Hz), 7.23-7.30 (m,2H), 7.40-7.44 (m,1H), 8.01
(d, 1H, J = 7.6Hz); 13C NMR (100 MHz, CDCl3): δ 14.12,
19.94, 22.69, 29.37, 29.45, 29.50, 29.61, 29.67, 29.70, 31.60,
31.93, 33.00, 38.94, 55.28, 107.74, 122.14, 122.18, 125.93,
128.72, 129.63, 132.20, 132.49, 137.00, 137.88, 142.87,
157.77. ESIMS(m/z): 500 (M-H)+.
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)-4-methyl-
benzenesulfonamide (8d)
Using 7 and para toluene sulfonyl chloride as starting
materials, the title compound 8d was obtained as a light
brown solid (96.9%); M.p. 79-80 °C; IR (KBr pellet): νmax
3293, 2920, 2851, 1591, 1468, 1424, 1329, 1261, 1157,
1
1091, 1049, 816, 787cm-1; H NMR (CDCl3, 400 MHz): δ
0.88 (t, 3H, J=7.2 Hz), 1.26 (brs, 24H), 1.39-1.49 (m,2H),
2.40 (s, 3H), 2.51 (t, 2H, J=8 Hz), 3.71 (s, 3H), 4.13 (d, 2H,
J=6Hz) 4.93 (t, 1H), 6.61 (d, 1H, J=8 Hz), 6.71 (d, 1H,
J=7.6Hz), 7.12 (t, 1H, J=7.6 Hz), 7.23-7.26 (m,2H), 7.70 (d,
2H, J=7.6 Hz); ESIMS(m/z): 500 (M-H)+.
Synthesis of Sulphonamides (8)
A solution of amine 7 (1.0eq) in dry DCM was added
TEA (2.2 eq) followed by sulphonyl chloride (1.1 eq) at 0°C.
The contents were slowly bringing it to r.t and stirred for 2h.
Reaction mixture was diluted with DCM and washed with
water and brine solution dried and distilled off to obtain
crude compound 8 which was purified by column.
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)-2,5-dimet-
hylbenzenesulfonamide (8e)
Using 7 and 2,5 dimethyl benzenesulfonyl chloride as
starting materials, the title compound 8e was obtained as a
light yellow semi solid (96.6%); IR (DCM film): νmax 3241,
3050, 2924, 2854, 1588, 1406, 1324, 1265, 1218, 1154,
1083, 1056, 901, 820, 781cm-1; 1H NMR (CDCl3, 400 MHz):
δ 0.9 (t, 3H, J=6.8 Hz), 1.27 (brs, 24H), 1.32-1.41 (m,2H),
2.35 (s, 3H) , 2.46 (t, 2H, J=7.2 Hz),2.52 (s, 3H), 3.77 (s,
3H), 4.14 (d, 2H, J=6.4 Hz), 5.11 (t, 1H, J=6 Hz), 6.65 (d,
2H, J=8 Hz), 6.69 (d, 2H, J=7.6 Hz), 7.10-7.21 (m, 2H), 7.78
(s, 1H); ESIMS(m/z): 514 (M-H)+.
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)methanesul-
fonamide (8a)
Using 7 and methane sulfonyl chloride as starting
materials, the title compound 8a was obtained as a white
color solid (59.8%); MP: 77-78 °C; IR (DCM film): ν max
3287, 3020, 2918, 2849, 1588, 1467, 1512, 1322, 1268,
1224, 1144, 1096, 1046, 1002, 871, 773, 714 cm-1; 1H NMR
(CDCl3, 400 MHz): δ 0.87 (t, 3H, J=6.8 Hz), 1.25 (brs,
24H), 1.52-1.56 (m, 2H), 2.72 (t, 2H, J=7.2 Hz), 2.77 (s,
3H), 3.85 (s, 3H), 4.35 (d, 1H, J=6), 4.87 (bs, 1H), 6.76 (d,
1H, J=8.4 Hz), 6.82 (d, 1H, J=7.2 Hz), 7.22 (t, 1H, J=8 Hz);
13C NMR (100 MHz, CDCl3): δ 14.09, 22.66, 29.33, 29.49,
29.53, 29.57, 29.65, 31.84, 31.89, 33.06, 39.22, 40.45, 55.49,
108.07, 122.40, 122.77, 128.95, 142.85, 157.90;
ESIMS(m/z): 424 (M-H)+.
Synthesis of 2,5-dichloro-N-(2-methoxy-6-pentadecylben-
zyl)benzenesulfonamide (8f)
Using 7 and 2,5-dichloro-benzene sulfonyl chloride as
starting materials, the title compound 8f was obtained as a
off white solid (87.3%); M.p. 66-77°C; IR (KBr pellet): νmax
3338, 3286, 3087, 3007, 2920, 2850, 1589, 1464, 1405,
1
1341, 1262, 1164, 1096, 1035, 982, 891 cm-1; H NMR
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)benzenesul-
fonamide (8b)
(CDCl3, 400 MHz): δ 0.88 (t, 3H, J=6.4 Hz), 1.25 (brs,
24H), 1.38-1.42 (m,2H), 2.53 (t, 2H, J=8 Hz), 3.76 (s, 3H),
4.26 (d, 2H, J=6.4 Hz), 5.90 (t, 1H, J=8 Hz), 6.54 (d, 1H,
J=8.4 Hz), 6.57 (d, 1H, J=8Hz), 7.01 (t, 1H, J=7.6 Hz),
7.152 (d, 1H, J=8.4 Hz), 7.25-7.27 (m,1H), 7.92 (s,1H);
ESIMS(m/z): 554 (M-H)+. 556 (chloro isotope).
Using 7 and benzene sulfonyl chloride as starting
materials, the title compound 8b was obtained as a light
brown solid (90.2%); M.p.: 68-69°C; IR (KBr pellet): νmax
3286, 3079, 2921, 2851, 1587, 1464, 1418, 1344, 1310,
1269, 1156, 1089, 1044, 921 cm-1; H NMR (CDCl3, 400
1
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)-1-phenyl-
methanesulfonamide (8g)
MHz): δ 0.88 (t, 3H, J=6.8 Hz), 1.25 (brs, 24H), 1.39-1.44
(m,2H), 2.518 (t, 2H, J=8 Hz), 3.69 (s, 3H), 4.17 (d, 2H,
J=6.4 Hz), 4.99 (t, 1H), 6.602 (d, 1H, J=8 Hz), 6.69 (d, 1H,
J=8 Hz), 7.11 (t, 1H, J=8 Hz), 7.44 (t, 2H, J=7.8 Hz), 7.50-
7.52 (m, 1H), 7.79-7.81 (m, 2H); ESIMS(m/z): 486 (M-H)+.
Using 7 and phenylmethanesulfonyl chloride as starting
materials, the title compound 8g was obtained as a light
brown solid (64.6%); M.p.58-59 °C; IR (KBr pellet): νmax
3285, 3078, 3023, 2919, 2851, 1588, 1466, 1407, 1322,
1268, 1226, 1152, 1081, 1052, 992, 835, 784 cm-1; 1H NMR
(CDCl3, 400 MHz): δ 0.88 (t, 3H, J=6.8 Hz), 1.25 (brs,
24H), 1.51-1.547 (m,2H), 2.72 (t, 2H, J=7.2 Hz), 3.74 (s,
3H), 4.1 (s, 2H), 4.33 (d, 2H, J=6 Hz), 4.82 (t, 1H), 6.74 (d,
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)-2-methyl-
benzenesulfonamide (8c)
Using 7 and 2-methyl benzene sulfonyl chloride as
starting materials, the title compound 8c was obtained as a
yellow liquid (78.5%); IR (DCM film): ν max 3305, 3062,

292 Letters in Organic Chemistry, 2012, Vol. 9, No. 4
Reddy et al.
1H, J=8.4 Hz), 6.84 (d, 1H, J=7.6 Hz), 7.10 (d, 2H, J=6.4
33.07, 39.34, 55.37,107.82, 113.87, 113.93, 121.80, 122.16,
124.79, 125.91, 126.11, 128.59, 128.79, 135.89, 136.15,
140.05, 143.01, 146.54, 157.30, 157.73, 159.84;
ESIMS(m/z): 573 (M-H)+.
Hz), 7.22-7.4 (m,4H); ESIMS(m/z): 500 (M-H)+.
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)naphthal-
ene-2-sulfonamide (8h)
Synthesis of 1-(4-fluorophenyl)-N-(2-methoxy-6-penta-
decylbenzyl) -1H-pyrazole-4-sulfonamide (8l)
Using 7 and Naphthalene-2-sulfonyl chloride as starting
materials, the title compound 8h was obtained as an light
brown solid (75.4%); M.p.60-61°C; IR (KBr pellet): νmax
3299, 3056, 3014, 2921, 2850, 1589, 1507, 1467, 1405,
1343, 1318, 1269, 1160, 1123, 1072, 1034, 913, 864, 825
cm-1; 1H NMR (CDCl3, 400 MHz): δ 0.88 (t, 3H, J=6.8 Hz),
1.19 (bs, 24H), 1.30-1.41 (m, 2H), 2.48 (t, 2H, J=8 Hz), 3.64
(s, 3H), 4.20 (d, 2H, J=6 Hz), 5.07 (t, 1H, J=7.6 Hz), 6.54 (d,
1H, J=8.4 Hz), 6.61 (d, 1H, J=7.6 Hz), 7.02(t, 1H, J=8Hz),
7.57-7.65 (m,2H), 7.73-7.76 (m,1H), 7.86-7.92 (m, 3H), 8.37
(s, 1H); ESIMS(m/z): 536 (M-H)+.
Using 7 and 1-(4-fluorophenyl)-1H-pyrazole-4-sulfonyl
chloride as starting materials, the title compound 8l was
obtained as an off white solid (Yield = 54.5%); M.p. 118-
119°C; IR (KBr): νmax 3257, 3134, 3079, 2921, 2851, 1651,
1591, 1524, 1470, 1422, 1320, 1241, 1175, 1145, 1087,
1
1045, 999, 952cm-1; H NMR (CDCl3, 400 MHz): δ 0.88 (t,
3H, J =6.8 Hz), 1.24 (brs, 24H), 1.43-1.47 (m,2H), 2.62 (t,
2H, J =7.6 Hz), 3.75 (s, 3H), 4.29 (d, 2H, J=6 Hz), 5.14 (t,
1H, J=6.4 Hz), 6.59-6.73(m, 2H), 7.06-7.20 (m, 3H), 7.54-
7.57 (m, 2H), 7.81 (s, 1H), 7.95 (s, 1H); ESIMS(m/z): 572
(M+H)+.
Synthesis of N-(2-methoxy-6-pentadecylbenzyl)thiophene-
2-sulfonamide (8i)
Using 7 and thiophene-2-sulfonyl chloride as starting
materials, the title compound 8i was obtained as an off white
solid (51.6%); M.p.67-68°C; IR (KBr pellet): νmax 3273,
3100, 2920, 2848, 1585, 1543, 1466, 1410, 1338, 1267,
Antibacterial Bioassay
Sulfonamide derivatives of Anacardic acid (8a – 8l) were
dissolved in dimethyl sulphoxide at 250 µg/mL
concentration. The composition of nutrient agar medium was
Bactotryptone (10 g), yeast extract (5g), NaCl (10 g), final
pH 7.4. After 18 h the exponentially growing cultures of the
six bacteria in nutrient broth at 37oC were diluted in sterile
broth. From each of these diluted cultures, 1mL was added to
100 mL sterilized and cooled nutrient agar media to give a
final bacterial count of 1 x 106 cell/ml. The plates were set at
room temperature and later dried at 37oC for 20h. Paper discs
(6mm, punched from Whatmann no. 41 paper) were
ultraviolet sterilized and used for the assays. Discs were
soaked in different concentration 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 incubated at 37oC in an inverted fashion.
Activity was determined by zones showing complete
inhibition (mm). Growth inhibition was calculated with
reference to positive control.
1
1230, 1159, 1090, 1023, 920, 780 cm-1; H NMR (CDCl3,
400 MHz): δ 0.88 (t, 3H, J=6.8 Hz), 1.25 (brs, 24H), 1.40-
1.42 (m,2H), 2.58 (t, 2H, J=5.6 Hz), 3.73 (s, 3H), 4.24 (d,
2H, J=5.6 Hz), 5.06 (t, 1H, J=7.2 Hz), 6.65 (d, 1H, J=8.4
Hz), 6.74 (d, 1H, J=7.2Hz), 7.02 (t, 1H, J=4.4 Hz), 7.14 (t,
1H, J=8 Hz), 7.52-7.54 (m,2H); ESIMS(m/z): 492 (M-H)+.
Synthesis of 5-bromo-N-(2-methoxy-6-pentadecylbenzyl)
thiophene-2-sulfonamide (8j)
Using 7 and 5-bromo-thiophene-2-sulfonyl chloride as
starting materials, the title compound 8j was obtained as an
off white solid (68.9%); M.p.71-72°C; IR (KBr pellet): νmax
3291, 3111, 2920, 2850, 1589, 1517, 1467, 1407, 1323,
1267, 1155, 1082, 1051, 964, 921, 797cm-1; 1H NMR
(CDCl3, 400 MHz): δ 0.88 (t, 3H, J=6.8 Hz), 1.26 (brs,
24H), 1.43-1.49 (m,2H), 2.59 (t, 2H, J=7.6 Hz), 3.75 (s, 3H),
4.25 (d, 2H, J=6 Hz), 5.10 (t, 1H), 6.69 (d, 1H, J=8.4 Hz),
6.75 (d, 1H, J=7.6Hz), 6.96 (d, 1H, J=4.4 Hz), 7.16 (t, 1H,
J=8 Hz), 7.24 (d, 1H, J=4.4 Hz); 13C NMR (100 MHz,
CDCl3): δ 14.10, 22.67, 29.34, 29.48, 29.53, 29.59, 29.64,
29.67, 31.64, 31.90, 33.08, 39.51, 55.38, 107.86, 119.44,
121.51, 122.22, 128.95, 129.95, 132.00, 142.08, 143.04,
157.78; ESIMS(m/z): 570 (M-H)+. 572 ( bromo isotope).
CONFLICT OF INTEREST
Declared none.
Synthesis of 1-(5-fluoropyridin-2-yl)-N-(2-methoxy-6-pent-
adecylbenzyl) -1H-pyrazole-4-sulfonamide (8k)
ACKNOWLEDGEMENTS
We thank GVK Biosciences Private Limited for the
financial support and encouragement. We are also thankful
to the analytical department for their analytical data and to
Dr. Balaram Patro for his helpful suggestions.
Using
7
and 1-(5-fluoropyridin-2yl)-1H-pyrazole-4-
sulfonyl chloride as starting materials, the title compound 8k
was obtained as an off white solid (Yield = 90.9%); M.p.
103-104°C; IR (DCM film): νmax 3285, 3145, 3072, 2924,
2854, 1590, 1524, 1478, 1331, 1263, 1234, 1179, 1143,
1091, 1043, 954, 836 cm-1; H NMR (CDCl3, 400 MHz): δ
1
REFERENCES
0.87 (t, 3H, J =6.4 Hz), 1.25 (brs, 24H), 1.41-1.57 (m,2H),
2.62 (t, 2H, J = 7.6 Hz), 3.75 (s, 3H), 4.27 (d, 2H, J =6 Hz),
5.07 (t, 1H, J =6 Hz), 6.62(d, 1H, J = 8.4 Hz), 6.70 (d, 1H, J
=7.6 Hz), 7.1 (t, 1H, J =8 Hz), 7.56-7.59 (m, 1H), 7.61 (d,
1H, J =2.8 Hz), 7.95-7.98 (m, 1H), 8.29 (d, 1H, J =2.8Hz),
8.74 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 14.08, 22.66,
29.33, 29.46, 29.52, 29.58, 29.63, 29.66, 30.89, 31.64, 31.89,
[1]
Tyman, J.H.P. Non-isoprenoid long chain phenols. Chem. Soc.
Rev., 1979, 8(4), 499-533.
[2]
Kubo, I.; Muroi, H.; Himejima, M.; Yamigiwa, Y. Structure-
antibacterial activity relationships of anacardic acids. J. Agric.
Food Chem. 1993, 41(6), 1016-1019.
[3]
Gillerman, J.L.; Walsh, N.J.; Werner, N.K.; Schlenk, H.
Antimicrobial effects of anacardic acids. Can. J. Microbiol., 1969,
15(10), 1219-1223.

Synthesis and Antibacterial Activity of Sulfonamide Derivatives
Letters in Organic Chemistry, 2012, Vol. 9, No. 4
293
[4]
Shobha, S.V.; Ramadoss, C.S.; Ravindranath, B. Inhibition of
Soybean Lipoxygenase-1 by Anacardic Acids, Cardols, and
Cardanols. J. Nat. Prod., 1994, 57(12), 1755-1757.
Ha, T.J.; Kubo, I. Lipoxygenase Inhibitory Activity of Anacardic
Acids. J. Agric. Food Chem., 2005, 53(11), 4350-4354.
Chandregowda, V.; Kush, A.; Reddy, G.C. Synthesis of benzamide
derivatives of anacardic acid and their cytotoxic activity. European
J. Med. Chem., 2009, 44(6), 2711-2719.
Paramashivappa, R.; Phani kumar, P.; Subba Rao, P.V.; Srinivasa
Rao, A. Synthesis of Sildenafil Analogues from Anacardic Acid
and Their Phosphodiesterase-5 Inhibition. J. Agric. Food Chem.,
2002, 50(26), 7709-7713.
Phanikumar, P.; Stotz, S.C.; Paramashivappa, R.; Beedle, M.;
Zamponi, G.W.; Srinivasa Rao, A. Synthesis and Evaluation of a
New Class of Nifedipine Analogs with T-Type Calcium Channel
Blocking Activity. Mol. Pharmacol., 2002, 61(3), 649-658.
Narayana Swamy, B.; Suma, T.K.; Venkateswara Rao, G.;
[14]
[15]
[16]
Cui, L.; Miao, J.; Furuya, T.; Fan, Q.; Li, X.; Rathod, P.K.; Su,
X.Z.; Cui, L. Histone acetyltransferase inhibitor anacardic acid
causes changes in global gene expression during in vitro
Plasmodium falciparum development. Eukaryotic Cell 2008, 7(7),
1200-1210.
Sbardella, G.; Castellano, S.; Vicidomini, C.; Rotili, D.; Nebbioso,
A.; Miceli, M.; Altucci, L.; Mai, A. Identification of long chain
alkylidenemalonates as novel small molecule modulators of histone
acetyltransferases. Bioorg. Med. Chem. Lett., 2008, 18(9), 2788-
2792.
Rybak, M.J.; Akins, R.L. Emergence of methicillin-resistant
Staphylococcus aureus with intermediate glycopeptide resistance:
clinical significance and treatment options. Drugs 2001, 61(1), 1-7.
Lipsitch, M.ꢀ The rise and fall of antimicrobial resistance. Trends
Microbiol. 2001, 9(9), 438-444.
Cunha, B.A. Antibiotic resistance. Drugs Today 1998, 34(8), 691-
698.
Marchese, A.; Schito, G.C.; Debbia, E.A. Evolution of Antibiotic
Resistance in Gram-Positive Pathogens. J. Chemother., (Firenze)
2000, 12, 459-462.
Cetinkaya, Y.; Falk, P.; Mayhall, C.G. Vancomycin-Resistant
Enterococci. Clin. Microbiol. Rev., 2000, 13(4), 686.
Cassell, G.H.; Mekalanos, J. Development of Antimicrobial Agents
in the Era of New and Reemerging Infectious Diseases and
Increasing Antibiotic Resistance. J. Am. Med. Assoc., 2001, 285(5),
601-605.
Chu, D.T.W.; Plattner, J.J.; Katz, L. New Directions in
Antibacterial Research. J. Med. Chem., 1996, 39(20), 3853-3874.
Gulati, A.S.; Subba Rao, B.C. Drug analogues from the phenolic
constituents of cashewnut shell liquid. Indian J. Chem., 1964, 2,
337-338.
[5]
[6]
[7]
[8]
[9]
[17]
[18]
[19]
Chandrasekara Reddy, G.
ꢀ
Synthesis of isonicotinoylhydrazones
from anacardic acid and their in vitro activity against
Mycobacterium smegmatis. Eur. J. Med. Chem., 2007, 42(3), 420-
424.
[20]
[21]
[10]
[11]
Kubo, I.; Ochi, M.; Viera, P.C.; Komatsu, S. Antitumor agents
from the cashew (Anacardium occidentale) apple juice. J. Agric.
Food Chem., 1993, 41(6), 1012-1015.
Mantelingu, K.; Kishore, A.H.; Balasubramanyam, K.; Kumar,
G.V.; Altaf, M.; Swamy, S.N.; Selvi, R.; Das, C.; Narayana, C.;
Rangappa, K.S.; Kundu, T.K. Activation of p300 Histone
Acetyltransferase by Small Molecules Altering Enzyme Structure:ꢀ
Probed by Surface-Enhanced Raman Spectroscopy. J. Phys. Chem.
B 2007, 111(17), 4527-4534.
Hari Kishore, A.; Vedamurthy, B.M.; Mantelingu, K.; Agrawal, S.;
Ashok Reddy, B.A.; Roy, S.; Rangappa, K.S.; Kundu, T.K.
Specific Small-Molecule Activator of Aurora Kinase A Induces
Autophosphorylation in a Cell-Free System. J. Med. Chem., 2008,
51(4), 792-797.
Sung, B.; Pandey, M.K.; Ahn, K.S.; Yi, T.; Chaturvedi, M.M.; Liu,
M.; Aggarwal, B.B. Anacardic acid (6-nonadecyl salicylic acid), an
inhibitor of histone acetyltransferase, suppresses expression of
nuclear factor-κB–regulated gene products involved in cell
survival, proliferation, invasion, and inflammation through
inhibition of the inhibitory subunit of nuclear factor-κBα kinase,
leading to potentiation of apoptosis. Blood 2008, 111(10), 4880-
4891.
[22]
[23]
[12]
[13]
[24]
[25]
[26]
EISholy, M.A.; Adawadkar, P.D.; Benigni, D.A.; Watson, E.S.;
Little, T.L. Jr. Analogs of poison ivy urushiol. Synthesis and
biological activity of disubstituted n-alkylbenzenes. J. Med. Chem.,
1986, 29(5), 606-611.
Paramashivappa, R.; Phanikumar, P.; Vithayathil, P.J.; Srinivasa
Rao, A. Novel Method for Isolation of Major Phenolic Constituents
from Cashew (Anacardium occidentale L.) Nut Shell Liquid. J.
Agric. Food Chem., 2001, 49(5), 2548-2551.
Rahman, A.; Choudhary, M.I.; Thomsen, W.J. “Bioassay
Techniques for Drug Development” Harwood Academic
Publishers, The Netherlands, 2001, pp. 16.