Synthesis and antibacterial activity of anacardic acid derivatives

Article abstract of DOI:10.2174/157018011796235167

New anacardic acid derivatives (6a -6u) were prepared from commercially available anacardic acid and tested for Gram positive and Gram negative activities. Most compounds were found to be active compared to ampicillin.

Full text of DOI:10.2174/157018011796235167

626
Letters in Drug Design & Discovery, 2011, 8, 626-632
Synthesis and Antibacterial Activity of Anacardic Acid Derivatives
Subhakara Reddy Nallamillia,b, V. Ravi Kumara, V. Himabindub, B. Rama and
Srinivas Rao Aalapati*,a
aMedicinal chemistry Laboratory, GVK Biosciences PVT Ltd, Plot No 5C, IDA, Uppal, Hyderabad, 500 039, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Hyderabad,500 085, AP, India
Received February 04, 2011: Revised May 17, 2011: Accepted May 24, 2011
Abstract: New anacardic acid derivatives (6a -6u) were prepared from commercially available anacardic acid and tested
for Gram positive and Gram negative activities. Most compounds were found to be active compared to ampicillin.
Keywords: Anacardic acid derivatives, Cashew Nut Shell Liquid, Antibacterial activity, Synthesis, Gram positive bacteria,
Gram negative bacteria.
1. INTRODUCTION
resulted in the formation of the saturated anacardic acid
which was converted to the dialkylated compound by reac-
tion with dimethylsulfate in acetonitrile. The dialkylated
anacardic acid was reduced to alcohol by treatment with
LiAlH4 in tetrahydrofuran and then protected with methane-
sulphonyl chloride in dichloromethane. The resultant mesy-
lated compound was then coupled with various amines in
presence of triethylamine in acetonitrile to obtain derivatives
of anacardic acid (6a-6u) and no dialkylated products were
observed (Scheme 1). Compounds 6a – 6u were tested
against two Gram positive strains viz., i) Escherichia coli,
and ii) Pseudomonas aeruginosa, and two Gram negative
The emergence of drug resistant strains in clinical appli-
cations [1-3] especially to Gram positive bacteria [4-5] has
created a problem of global proportions [6-7]. This phe-
nomenon has led to a resurgence of interest in creating novel
antibacterial agents distinct from existing classes of com-
pounds.
Anacardic acid (pentadecyl salicylic acid, Fig. 1) is a
phenolic constituent present in Cashew Nut Shell Liquid
(CSNL); (Anacardium occidentale L.) and exhibits antimi-
crobial properties [8-9], which have led to the preparation of
a
n=0
n=2
n=4
OH
O
b
c
OH
C15H31-n
d
1
Fig. (1). The anacardic acid mixture.
n=6
various analogues [10-11]. This report describes the synthe-
sis, spectroscopic identification and antibacterial activity of
some novel anacardic acid derivatives (6a-6u) against Es-
cherichia coli, Pseudomonas aeruginosa, Streptococcus
pyogenes and Staphylococcus aureus bacterial strains.
strains viz., i). Streptococcus pyogenes, and ii) Staphylococ-
cus aureus using agar well diffusion method according to the
literature protocol [14]. The anti-bacterial activity of the ana-
logues was compared with standard drug ampicillin (Table
1).
2. SYNTHESIS, RESULTS AND DISCUSSION
2.1. Synthesis and Evaluation
2. RESULTS AND DISCUSSION
Based on the test results it is evident that several synthe-
sized anacardic acid analogues possess moderate to good
activity against the Gram +ve and Gram –ve bacteria. Of all
the compounds prepared entities 6b, 6c, 6e, 6g, 6h, 6j, 6l,
6m, 6o, 6p, 6s and 6u display good to excellent activity
while the remaining compounds showed moderate activity
against Staphylococcus aureus. In case of Streptococcus
pyogenes compounds 6d, 6k, 6l, 6r, 6t showed moderate
activity while the remaining compounds showed good activ-
ity. In case of inhibition of Pseudomonas aeruginosa com-
pounds 6d, 6e, 6f, 6j, 6l, 6o and 6u showed good to excellent
The anacardic acid mixture (Fig. 1, 1a–d) was isolated
[12] from commercially available CNSL as a mixture of
monoene, diene and triene located at (8’), (8’, 11’) and (8’,
11’, 14’) isomers of the C15 alkyl chain, respectively. Hy-
drogenation of the ene mixture of anacardic acid [13]
*Address correspondence to this author at the Medicinal chemistry Labora-
tory, GVK Biosciences PVT Ltd, Plot No 5C, IDA, Uppal, Hyderabad, 500
039, AP, India; Tel: +91-40-67126600; Fax: +91-40-27208866;
E-mail: asrinivas@gvkbio.com
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers Ltd.

Synthesis and Antibacterial Activity of Anacardic Acid Derivatives
OH O
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7 627
OH
O
OH
b
a
OH
1
2
O
O
O
O
OH
c
d
3
4
O
O
O
S
O
e
R
O
5
6a-6u
Scheme 1. Synthesis of anacardic acid derivatives 6a-6u.
Experimental conditions: a) 10% Pd/C, EtOH, H2, 50 psi, rt, 2h; b) Dimethyl sulfate, K2CO3, Acetonitrile, 90 °C, 24h; c) LiAlH4,THF, 0
°C–rt,18h; d) Methanesulfonyl chloride, triethylamine, dichloromethane, 0 °C-rt, 3h; e) amines, triethylamine, acetonitrile, 85 °C, 3-18h
Table 1. Results of Antibacterial Bioassay of Compounds 6a-6u (Concentration Used 250 μg/mL of DMSO) Zones of inhibition of
compounds 6a-6u
Name of the Bacteria
Compound no.
6a
R
E. coli
P. aeruginosa
S. aureus
S. pyogenes
NH2
19
17
16
18
6b
6c
6d
19
20
22
18
18
19
17
18
16
19
20
16
N
N
O
N
S
HN
6e
6f
19
18
20
19
19
16
18
17
OH
O
N
O
OH
6g
6h
16
20
17
18
18
19
18
19
N
O
N
OH

628 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7
Nallamilli et al.
(Table 1). Contd…..
Name of the Bacteria
Compound no.
R
E. coli
P. aeruginosa
S. aureus
S. pyogenes
O
6i
O
21
19
19
16
18
N
NH
6j
19
15
19
15
21
16
N
N
O
O
N
N
6k
21
19
20
6l
20
17
18
17
16
19
N
N
N
O
6m
N
NH
O
N
6n
6o
20
17
15
21
16
17
19
19
O
N
NH
O
N
NH
O
N
N
6p
6q
17
17
18
18
17
15
19
21
O
O
O
N
NH
N
6r
6s
18
16
16
18
16
18
17
18
N
N
N

Synthesis and Antibacterial Activity of Anacardic Acid Derivatives
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7 629
(Table 1). Contd…..
Name of the Bacteria
Compound no.
6t
R
E. coli
P. aeruginosa
S. aureus
S. pyogenes
N
14
15
16
16
N
N
HN
O
O
6u
20
20
20
20
18
18
18
19
N
HO
SD* ampicillin
SD* ampicillin
activity. In case of inhibition of Escherichia coli compounds
6c, 6d, 6h, 6i, 6k, 6m, 6n, and 6u showed good activity with
a zone of inhibition 20, 22, 20, 21, 21, 20, 20, 20 mm. The
most active antibacterial agent against Escherichia coli was
found to be compound 6d having thiomorpholine, compound
6i having 4-amino boc protected piperidine and compound
6k having N-Boc protected piperizine residue as R, while all
the other compounds in the series exhibited moderate to
good activity. These results indicate that compound 6a, 6b,
6c and the remaining compounds in the series might find less
resistance to pass the cell wall in comparison to compounds
6d, 6i and 6k. The activity depends to some extent on the R
substituent, however all the compounds show antibacterial
activity. So other functionalities in the molecule will con-
tribute 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 for all the Escherichia coli, Pseu-
domonas aeruginosa, Streptococcus pyogenes and Staphylo-
coccus aureus bacterial strains.
used for the assays. Discs were soaked in different concen-
trations of the test solution and placed on the inoculated agar
media at regular intervals of 6-7 cm, care was taken to en-
sure that excess solution was not on the discs. All the sam-
ples were taken in triplicates. The plates were incubated at
37 °C in an inverted fashion. Activity was determined by
zones showing complete inhibition (mm). Growth inhibition
was calculated with reference to positive control.
3.2. Experimental Section
2-hydroxy-6-pentadecyl-benzoic acid (2)
An ethanol solution (500 mL) of 1 (100 g, 0.28 mol) was
hydrogenated in a 1L Parr apparatus at 50 psi in the presence
of 10 % Pd/C (10 g, 10 %) under argon for 2 h. The reaction
mixture was filtered through celite and concentrated to ob-
tain 2 which was recrystallized in pet ether (Yield: 70 g,
68.8%; white solid); M.p: 85-86 °C; IR (KBr): ꢀmax 3071,
3002, 2918, 2851, 1655, 1450, 1246, 1214 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.89 (t, 3H, J = 6.8 Hz), 1.27 (bs,
24H), 1.57-1.63 (m, 2H), 2.98 (t, 2H, J = 8.0 Hz), 6.78 (d,
1H, J = 7.6 Hz), 6.88 (d, 1H, J = 8.4 Hz), 7.37 (t, 1H, J = 8.0
Hz), 11.02 (bs, 1H); EI MS: m/z (rel.abund.%) 349 (M+,
100)
3. GENERAL EXPERIMENT
Melting points were determined in open glass capillaries
on a Mel-temp apparatus and are uncorrected.
Thin-layer chromatography (TLC) was performed on
E.Merk AL silica gel 60 F254 plates and visualized under
UV light. The IR spectra were recorded on a Perkin Elmer
2-Methoxy-6-pentadecyl-benzoic acid methyl ester (3)
An acetonitrile (200 mL) solution of 2 (20 g, 0.57 mol),
K2CO3 (40.8 g, 0.28 mol) and dimethyl sulphate (21.76 mL,
0.22 mol) was refluxed for 24 h. The reaction mixture was
filtered and the filtrate was distilled. The residue was dis-
solved in ethyl acetate and washed with water (2x200 mL),
brine solution (175 mL), dried over anhydrous sodium sul-
phate, filtered and concentrated to obtain 3 (Yield: 18.5 g,
85.5%, pale yellow solid); M.p: 36-37 °C; IR (KBr): ꢀmax
3004, 2921, 2852, 1732, 1589, 1266, 1105 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.8 Hz), 1.25 (bs,
24H), 1.53-1.60 (m, 2H), 2.53 (t, 2H, J = 8.0 Hz), 3.81 (s,
3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J =
8.0 Hz), 7.25 (t, 1H, J = 8.0 Hz); EI MS: m/z (rel.abund.%)
377 (M+, 100).
1
FT-IR spectrometer. The H NMR spectra were recorded in
CDCl3 on a Varian EM-360 spectrometer (400MHz). All
chemical shifts were reported in ꢀ (ppm) using TMS as an
internal standard. The mass spectra were recorded on Agilent
ion trap MS.
3.1. Antibacterial Bioassay
Anacardic acid analogues (6a – 6u) were dissolved in
dimethyl sulphoxide at 250 μg/mL concentration. The com-
position of nutrient agar medium was Bactotryptone (10 g),
yeast extract (5 g), NaCl (10 g), final pH 7.4. After 18h the
exponentially growing cultures of the six bacteria in nutrient
o
broth at 37 C were diluted in sterile broth. From each of
2-Methoxy-6-pentadecyl-phenyl-methanol (4)
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 37 °C for 20h. Paper discs (6mm, punched
from whatmann no 41 paper) were ultraviolet sterilized and
To a suspension of LiAlH4 (3.03 g, 0.08 mol) dry tetra-
hydrofuran (150 mL) was added a pre-mixed of 3 (20 g, 0.05
mol) in tetrahydrofuran (100 mL) drop wise over a period of
40 min at 0 °C and was to slowly brought to room temepra-
ture, and stirred for 18 h. The reaction mixture was quenched

630 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7
Nallamilli et al.
with brine solution (40 mL) at 0 °C diluted with ethyl ace-
tate, filtered (200 mL) and washed with ethyl acetate (100
mL), the filtrate was washed with brine solution (200 mL)
dried over anhydrous sodium sulphate, filtered and evapo-
rated under vacuum to obtain 4 (Yield: 15 g, 81%, off-white
solid); M.p: 60-62 °C; IR (KBr): ꢀmax 3386, 3073,
2917,2847, 1465,1263, 1093 cm-1; H1-NMR (400 MHz,
CDCl3) ꢀ: 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 = 8.0
Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.20 (t, 1H, J = 8.0 Hz); EI
MS: m/z (rel.abund.%) 349 (M+, 100).
4-(2-methoxy-6-pentadecylbenzyl)thiomorpholine (6d)
White coloured solid; Yield: 295 mg, 58.1%; M.p: 50-51
°C; IR (neat): ꢀmax 3066, 2922, 2853, 1585, 1462, 1257 cm-1;
H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.8 Hz), 1.26
(brs, 24H), 1.56-1.60 (m, 2H), 2.58-2.71 (m, 10H), 3.53 (s,
2H), 3.78 (s, 3H), 6.70 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J =
7.6 Hz), 7.16 (t, 1H, J = 8.0 Hz); EI MS: m/z (rel.abund.%)
434 (M+, 100).
N-(2-methoxy-6-pentadecylbenzyl)cyclohexanamine (6e)
Light yellow liquid, Yield: 260 mg, 51.6%; IR (neat):
ꢀmax 2923, 2853, 1585, 1459, 1254, 1089 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.0 Hz), 1.12-1.40 (m,
29H), 1.52-1.61 (m, 4H), 1.72-1.75 (m, 2H), 1.89-1.92 (m,
2H), 2.45 (m, 1H), 2.64 (t, 2H, J = 8.0 Hz ), 3.78 (s, 2H),
3.81 (s, 3H), 6.70 (d, 1H, J = 8.4 Hz), 6.77 (d, 1H, J = 7.6
Hz), 7.12 (t, 1H, J = 8.0 Hz); EI MS: m/z (rel.abund.%) 430
(M+, 100).
Methanesulfonic acid 2-methoxy-6-pentadecyl-benzyl ester
(5)
To a solution of 4 (15 g, 0.04 mol) in dichloromethane
was added triethyl amine (13.92 mL, 0.09 mol) followed by
methanesulfonyl chloride (4.2 mL, 0.05 mol) at 0 °C over a
period of 15 min. The content was stirred at room tempera-
ture for 3 h. The reaction mixture was washed with water
(150 mL), brine solution (200 mL) dried over anhydrous
sodium sulphate, filtered and evaporated under vacuum to
obtain 5 (Yield: 17g, 92.59%, off-white solid).
1-(2-methoxy-6-pentadecylbenzyl)piperidine-2-carboxylic
acid (6f)
Light yellow liquid; Yield: 389 mg, 72.3%; IR (neat):
ꢀmax 3400, 2923, 2853, 1585, 1463, 1266 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.21-1.42 (m,
28H), 1.51-1.55 (m, 2H), 2.74 (t, 2H, J = 8.0 Hz), 3.61-3.66
(m, 5H), 3.88 (s, 3H), 4.63 (s, 2H), 6.82 (d, 1H, J = 8.4 Hz),
6.95 (d, 1H, J = 8.0 Hz), 7.39 (t, 1H, J = 8.0 Hz);
ESIMS(m/z): EI MS: m/z (rel.abund.%) 458 (M-, 100).
Representative procedure for the synthesis of amines (6)
To a acetonitrile solution containing 5 (500 mg, 1.17
mmol) was added triethylamine (3.52 mmol) and the appro-
priate amine (1.17 mmol). The contents were heated at 85 °C
for 3h-18 h. The reaction mixture was distilled and the crude
compounds obtained were dissolved in ethyl acetate, washed
with water, brine solution dried over anhydrous sodium sul-
phate, filtered and evaporated under vacuum to obtain the
crude amines which were purified by column chromatogra-
phy.
1-(2-methoxy-6-pentadecylbenzyl)piperidine-3-carboxylic
acid (6g)
Light yellow liquid; Yield: 410 mg, 76%; IR (neat): ꢀmax
3428, 2926, 2856, 1720, 1588, 1462, 1263cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.23-1.41 (m,
28H), 1.50-1.55 (m, 2H), 2.74 (t, 2H, J = 8.0 Hz), 3.60-3.61
(m, 5H), 3.88 (s, 3H), 4.61 (s, 2H), 6.82 (d, 1H, J = 7.6 Hz),
6.95 (d, 1H, J = 7.6 Hz), 7.39 (t, 1H, J = 8.0 Hz); EI MS:
m/z (rel.abund.%) 460 (M+, 100).
2-methoxy-6-pentadecylphenylmethanamine (6a)
White coloured solid; Yield: 320 mg, 78.8%; M.p: 55-56
°C; IR (KBr): ꢀmax 3400, 3066, 2924, 1583, 1464,1259 cm-1;
H1-NMR (400 MHz, CDCl3) ꢀ: 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 = 8.0 Hz),6.79 (d, 1H, J
= 7.6 Hz), 7.15 (t, 1H, J = 7.6 Hz); EI MS: m/z
(rel.abund.%) 348 (M+, 100).
1-(2-methoxy-6-pentadecylbenzyl)piperidine-4-carboxylic
acid (6h)
Light yellow liquid; Yield: 380 mg, 70.6%; IR (neat):
ꢀmax 3397, 2923, 2854, 1462, 1263 cm-1; H1-NMR (400
MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.24-1.41 (m,
28H), 1.53-1.55 (m, 2H), 2.75 (t, 2H, J = 7.6 Hz), 3.61-3.66
(m, 5H), 3.88 (s, 3H), 4.62 (s, 2H), 6.82 (d, 1H, J = 8.4 Hz),
6.95 (d, 1H, J = 7.6 Hz), 7.26-7.29 (m, 1H); EI MS: m/z
(rel.abund.%) 458 (M-, 100).
1-(2-methoxy-6-pentadecylbenzyl)pyrrolidine (6b)
Pale brown liquid; Yield: 325 mg, 69.1%; IR (neat): ꢀmax
3013, 2921, 2848, 1589, 1473, 1273, 1092 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.8 Hz), 1.25 (bs,
24H), 1.50-1.53 (m, 2H), 2.05-2.16 (m, 4H), 2.67 (t, 2H, J =
8.0 Hz ), 2.94 (bs, 2H), 3.74 (bs, 2H), 3.89 (s, 3H), 4.33 (s,
2H), 6.79 (d, 1H, J = 8.4 Hz), 6.87 (d, 1H, J = 8.0 Hz), 7.32
(t, 1H, J = 8.0 Hz); EI MS: m/z (rel.abund.%) 402 (M+, 100).
tert-butyl 1-(2-methoxy-6-pentadecylbenzyl)piperidin-4-
ylcarbamate (6i)
4-(2-methoxy-6-pentadecylbenzyl)morpholine (6c)
Brown coloured semi solid; Yield: 435 mg, 70%; IR
(neat): ꢀmax 3339, 3079, 2925, 2854, 1706, 1462, 1256, 1172
cm-1; H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 7.2
Hz), 1.25 (bs, 24H), 1.43 (s, 9H), 1.50-1.59 (m, 2H), 1.53
(brs, 2H ), 1.85 (bs, 2H), 2.20 (bs, 2H), 2.65- 2.82 (m, 4H),
3.49 (bs, 2H), 3.79 (s, 3H), 4.42 (bs, 1H), 6.71 (d, 1H, J =
8.0 Hz), 6.81 (d, 1H, J = 7.2 Hz), 7.16-7.18 (m, 1H); EI MS:
m/z (rel.abund.%) 531 (M+, 100).
Pale yellow liquid; Yield: 366 mg, 75%; IR (neat): ꢀmax
3071, 2922, 2849, 1584, 1467, 1261, 1115 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.8 Hz), 1.25 (bs,
24H), 1.58-1.64 (m, 2H), 2.44 (t, 4H, J = 4.8 Hz ), 2.65 (t,
2H, J = 8.0 Hz), 3.54 (s, 2H), 3.63 (t, 4H, J = 4.8 Hz), 3.78
(s, 3H), 6.70 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 8.0 Hz),
7.16 (t, 1H, J = 7.6 Hz); EI MS: m/z (rel.abund.%) 418 (M+,
100).

Synthesis and Antibacterial Activity of Anacardic Acid Derivatives
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7 631
1-(2-methoxy-6-pentadecylbenzyl)-4-methylpiperazine (6j)
tert-butyl 4-(2-methoxy-6-pentadecylbenzyl)-1,4-diazepane-
1-carboxylate (6p)
Pale brown liquid; Yield: 340 mg, 67.4%; IR (neat): ꢀmax
3068, 2924, 2852, 1585, 1460, 1258 cm-1; H1-NMR (400
MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.25-1.36 (bs,
24H), 1.55-1.63 (m, 2H), 2.25 (s, 3H), 2.36-2.57 (m, 8H),
2.68 (t, 2H, J = 8.0 Hz), 3.54 (s, 2H), 3.78 (s, 3H), 6.70 (d,
1H, J = 8.7 Hz), 6.80 (d, 1H, J = 9.6Hz), 7.15 (t, 1H, J = 8.0
Hz); EI MS: m/z (rel.abund.%) 431 (M+, 100).
Yellow liquid; Yield: 360 mg, 57.8%; IR (neat): ꢀmax
2925, 2855, 1695, 1467, 1251, 1168 cm-1; H1-NMR (400
MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.25 (bs, 24H),
1.45 (s, 9H), 1.51-1.61 (m, 2H), 1.76-1.84 (m, 2H), 2.61 (bs,
2H), 2.71 (t, 2H, J = 7.6 Hz), 3.32-3.45 (m, 6H), 3.62 (s,
2H), 3.78 (s, 3H), 6.71 (d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J =
7.6 Hz), 7.16 (t, 1H, J = 7.6 Hz); EI MS: m/z (rel.abund.%)
531(M+, 100).
tert-butyl 4-(2-methoxy-6-pentadecylbenzyl)piperazine-1-
carboxylate (6k)
tert-butyl 8-(2-methoxy-6-pentadecylbenzyl)-8-azabicyclo
[3,2,1]octan-3-ylcarbamate (6q)
Pale yellow liquid; Yield: 427 mg, 70.6%; IR (neat): ꢀmax
3070, 2924, 2855, 1698, 1463, 1249, 1172, 1124, 1085cm-1;
H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.8 Hz), 1.25
(brs, 24H), 1.45 (s, 9H), 1.55-1.61 (m, 2H), 2.38 (bs, 4H),
2.68 (t,2H, J = 7.6 Hz), 3.34 (bs, 4H), 3.53 (s, 2H), 3.78 (s,
3H), 6.71 (d, 1H, J =8.4 Hz),6.82 (d, 1H, J = 7.6 Hz), 7.17 (t,
1H, J = 7.6 Hz); EI MS: m/z (rel.abund.%) 517 (M+, 100).
Brown coloured solid; Yield: 429 mg, 65.9%; M.p: 50-51
°C; IR (KBr): ꢀmax 3350, 2925, 2855, 1709, 1463, 1250,
1171 cm-1; H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J =
7.2 Hz), 1.21-1.46 (m, 35H), 1.59-1.75 (m, 6H), 2.04-2.09
(m, 2H), 2.76 (t, 2H, J = 8Hz), 3.14 (s, 2H), 3.54 (s, 2H),
3.77 (s, 3H), 4.24-4.26 (m, 1H), 6.69 (d, 1H, J = 8.0 Hz),
6.82 (d, 1H, J = 7.8 Hz), 7.15 (t, 1H, J = 8.0 Hz); EI MS:
m/z (rel.abund.%) 557 (M+, 100).
1-Benzyl-4-(2-methoxy-6-pentadecylbenzyl)piperazine (6l)
Light yellow liquid; Yield: 410 mg, 69.1%; IR (neat):
ꢀmax 3028, 2923, 2853, 1458, 1340, 1259, 1084, 738 cm-1;
H1-NMR (400 MHz, CDCl3) ꢀ: 0.87 (t, 3H, J = 6.8 Hz), 1.25
(brs, 24H), 1.56-1.60 (m, 2H), 2.48 (bs, 8H), 2.67 (t, 2H, J =
8.0 Hz), 3.47 (s, 2H), 3.53 (s, 2H), 3.76 (s, 3H), 6.91 (d, 1H,
J = 8.4 Hz), 6.80 (d, 1H, J = 7.6 Hz), 7.15 (t, 1H, J = 7.6
Hz), 7.22-7.30 (m, 5H); EI MS: m/z (rel.abund.%) 507 (M+,
100).
1-(2-methoxy-6-pentadecylbenzyl)-1H-pyrazole (6r)
Off white solid; Yield: 283 mg, 60.7%; M.p: 58-59 °C;
IR (KBr): ꢀmax 3009, 2918, 2846, 1465, 1263, 1088 cm-1; H1-
NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 6.0 Hz), 1.25
(brs, 24H), 1.39-1.46 (m, 2H), 2.71 (t, 2H, J = 7.2 Hz), 3.83
(s, 3H), 5.40 (s, 2H), 6.14 (s, 1H), 6.78 (d, 1H, J = 8.0 Hz),
6.84 (d, 1H, J = 7.6 Hz), 7.22-7.27 (m, 2H), 7.47 (s, 1H); EI
MS: m/z (rel.abund.%) 399 (M+, 100).
6-(dimethylamino)-1-(2-methoxy-6-pentadecylbenzyl)-1,4-
diazepan-5-one (6m)
1-(2-methoxy-6-pentadecylbenzyl)-1H-imidazole (6s)
Pale brown coloured solid; Yield: 368 mg, 64.5%; M.p:
82-83 °C; IR (KBr): ꢀmax 3185, 3065, 2919, 1679, 1466,
1317, 1261 cm-1; H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H,
J = 6.8 Hz), 1.25 (bs, 24H), 1.55-1.63 (m, 2H), 2.28 (s, 6H),
2.54 (brs, 2H ), 2.65- 2.77 (m, 4H), 3.05-3.15 (m, 2H), 3.55-
3.65 (m, 3H), 3.787 (s, 3H), 5.73 (bs, 1H), 6.71 (d, 1H, J =
8.4 Hz), 6.82 (d, 1H, J = 7.6 Hz), 7.18 (t, 1H, J = 8.0 Hz); EI
MS: m/z (rel.abund.%) 488 (M+, 100).
Light brown coloured solid; Yield: 266 mg, 57.1%; M.p:
45-46 °C; IR (KBr): ꢀmax 3107, 2922, 2854, 1588, 1460,
1265, 1080 cm-1; H1-NMR (400 MHz, CDCl3) ꢀ: ꢀ 0.88 (t,
3H, J = 6.8 Hz), 1.25 (brs, 24H), 1.40-1.49 (m, 2H), 2.64 (t,
2H, J = 8.0 Hz), 3.82 (s, 3H), 5.15 (s, 2H), 6.76-6.87 (m,
3H), 6.97 (s, 1H), 7.23-7.27 (m, 1H), 7.46 (s, 1H); EI MS:
m/z (rel.abund.%) 399 (M+, 100).
1-(2-methoxy-6-pentadecylbenzyl)-1H-1,2,4-triazole (6t)
tert-butyl 1-(2-methoxy-6-pentadecylbenzyl)-6-morpholino-
1,4-diazepan-5-one (6n)
Off white solid; Yield: 349 mg, 74.7%; M.p: 65-66 °C;
IR (KBr): ꢀmax 3000, 2918, 2850, 1589, 1468, 1264 cm-1; H1-
NMR (400 MHz, CDCl3) ꢀ: ꢀ 0.88 (t, 3H, J = 6.8 Hz), 1.24
(brs, 24H), 1.46-1.52 (m, 2H), 2.74 (t, 2H, J = 8.0 Hz), 3.83
(s, 3H), 5.39 (s, 2H), 6.78 (d, 1H, J = 8.4 Hz), 6.86 (d, 1H, J
= 7.2 Hz), 7.26 (t, 1H, J = 7.2 Hz), 7.89 (s, 1H), 7.92 (s, 1H);
EI MS: m/z (rel.abund.%) 400 (M-, 100).
Cream coloured solid; Yield: 348 mg, 56.1%; M.p: 80-81
°C; IR (KBr): ꢀmax 3232, 2924, 2853, 1672, 1462, 1348,
1257, 1117 cm-1; H1-NMR (400 MHz, CDCl3) ꢀ: 0.88 (t, 3H,
J = 7.2 Hz), 1.25 (bs, 24H), 1.53-1.59 (m, 2H), 2.21-3.12 (m,
12H), 3.50-3.53 (m, 2H), 3.63-3.66 (m, 5H), 3.77 (s, 3H),
5.88 (s, 1H), 6.72 (d, 1H, J = 8.4 Hz), 6.80 (d, 1H, J = 7.2
Hz), 7.18 (t, 1H, J = 8.0 Hz); EI MS: m/z (rel.abund.%) 530
(M+, 100).
tert-butyl-4-hydroxy-4-((2-methoxy-6-pentadecylbenzyl-
amino)methyl)piperidine-1-carboxylate (6u)
Yellow liquid; Yield: 320 mg, 48.7%; IR (neat): ꢀmax
3445, 2925, 2854, 1691, 1465, 1365, 1088 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.880 (t, 3H, J = 7.2 Hz), 1.21-1.61
(m, 39H), 2.54 (s, 2H), 2.64 (t, 2H, J = 8.0 Hz), 3.13-3.19
(m, 2H), 3.82 (bs, 7H), 6.73 (d, 1H, J = 8.0 Hz), 6.80 (d, 1H,
J = 7.2 Hz), 7.16 (t, 1H, J = 8.4 Hz); EI MS: m/z
(rel.abund.%) 561 (M+, 100).
1-(2-methoxy-pentadecylbenzyl)-3,4-dihydro-1H-
benzo[e][1,4]diazepin-5(2H)-one (6o)
Light yellow liquid; Yield: 375 mg, 65%; IR (neat): ꢀmax
3402, 2923, 2853, 1659,1463, 1256, 1089 cm-1; H1-NMR
(400 MHz, CDCl3) ꢀ: 0.88 (t, 3H, J = 7.2 Hz), 1.25 (m,
24H), 1.41-1.49 (m, 2H), 2.54 (t, 2H, J = 8.0 Hz), 3.11 (t,
2H, J = 6.0 Hz), 3.23 (t, 2H, J = 6.0 Hz), 3.81 (s, 2H), 4.38
(s, 3H), 6.09 (t, 1H, J = 6.0 Hz), 6.73 (d, 1H, J = 8.0 Hz),
6.82 (d, 1H, J = 7.2 Hz), 7.01 (t, 1H, J = 7.8 Hz), 7.15-7.21
(m, 2H), 7.42 (t, 1H, J = 7.2 Hz), 7.68 ( d, 1H, J = 7.6 Hz);
EI MS: m/z (rel.abund.%) 493 (M+, 100).
ACKNOWLEDGEMENTS
We thank GVK Biosciences Private Limited for the fi-
nancial support and encouragement. Help from the analytical

632 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 7
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