Synthesis and antibacterial activity of 6-substituted anacardic acid derivatives

Article abstract of DOI:10.2174/157018011797655278

New anacardic acid derivatives (5a -5s) were prepared from commercially available anacardic acid and tested for Gram positive and Gram negative bacteria. Most compounds were found to be active compared to ampicillin drug.

Full text of DOI:10.2174/157018011797655278

972
Letters in Drug Design & Discovery, 2011, 8, 972-979
Synthesis and Antibacterial Activity of 6-Substituted Anacardic Acid
Derivatives
Subhakara Reddy Nallamillia,b, Ravi Kumar Va, Himabindu Vb, 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 June 29, 2011: Revised August 24, 2011: Accepted September 15, 2011
Abstract: New anacardic acid derivatives (5a -5s) were prepared from commercially available anacardic acid and tested
for Gram positive and Gram negative bacteria. Most compounds were found to be active compared to ampicillin drug.
Keywords: Ampicillin, Anacardic acid derivatives, Antibacterial activity, Cashew Nut Shell Liquid, Ozonolysis, Synthesis.
1. INTRODUCTION
published recently [24], here in we are reporting the
synthesis and antibacterial activity of some novel 6-
substituted anacardic acid derivatives (5a-5s) prepared from
commercially available anacardic acid. The structures of all
the synthesized compounds were determined by
spectroscopic methods. In view of reports on the
antibacterial activities of anacardic acid derivatives, we
screened the compounds 5a – 5s for evaluation of their
antibacterial effects against Escherichia coli, Pseudomonas
aeruginosa, Streptococcus pyogenes and Staphylococcus
aureus bacterial strains.
With the discovery of antibiotics people were convinced
that infectious diseases might some day be wiped out.
Almost all the major classes of antibiotics have encountered
resistance in clinical applications [1-5]. The emergence of
bacterial resistance to ꢀ-lactam antibiotics, macrolides,
quinolones, and vancomycin is becoming a major worldwide
health problem [4-8]. In particular, antibiotic resistance
among Gram-positive bacteria (staphylococci, enterococci,
and streptococci) is becoming increasingly serious [9-12].
Enterococci, which are frequently resistant to most
antibiotics including penicillin, cephalosporin and
aminoglycosides, are often treated with either a combination
of two antibiotics or vancomycin. However, with the recent
increased use of vancomycin in methicillin-resistance
Staphylococcus aureus (MRSA) infections and colitis due to
Clostridium difficile, multiple resistant Enterococcus
faecium has been spreading. As such, the last resort for anti-
infective diseases, the Vancomycin family of antibiotics, has
now been gravely challenged in recent years due to the
emergence of Vancomycin resistance in clinical practice [11,
13]. Thus scientists are working to find new ways to defeat
bacteria that are increasingly resistant to the antibiotic
already available.
2. RESULTS AND DISCUSSION
2.1. Synthesis
The anacardic acid mixture (Fig. 1, 1a–d) was isolated
from 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 C-15 alkyl chain respectively. Anacardic acid
ene mixture was methylated using dimethyl sulphate in the
presence of potassium carbonate in acetonitrile to afford 2.
Ozonolysis of the ene mixture of anacardic acid 2 resulted in
the formation of 3, C8-OH [26]. The compound 3 was
converted to bromide 4 using carbon tetrabromide in
dichloromethane. The bromide 4 was coupled with various
amines in the presence of triethylamine in acetonitrile to
obtain derivatives of anacardic acid (5a-5s) as depicted in
Scheme 1.
Cashew nut shell liquid (CNSL) is a by-product of
cashew nut industry and anacardic acid mixture (Fig. 1)
isolated from CNSL which are salicylic acid derivatives with
a nonisoprenoid alk(en)yl side chain [14]. Anacardic acid
and its derivatives have been tested for various biological
activities viz., antimicrobial activity [15, 16] and soybean
lipoxygenase-1 inhibitory activity [17, 18]. Anacardic acid
(pentadecyl salicylic acid) is a phenolic constituent present
in cashew (Anacardium occidentale L) nut shells and is
reported to exhibit a variety of biological activities. The
biological activity of anacardic acid has stimulated many
researchers to derive drug analogs for different applications
[19-23]. As a part of our ongoing research activity,
2.2. Antibacterial Activity
Compounds 5a – 5s were tested against two Gram
positive strains viz., i) Escherichia coli (MTCC443), (ii)
Pseudomonas aeruginosa (MTCC424), and two Gram
negative strains viz. i). Streptococcus pyogenes (MTCC442),
and ii) Staphylococcus aureus (MTCC96) using agar well
diffusion method according to the literature protocol [27].
The anti-bacterial activity of the analogs (250 μg/mL
*Address correspondence to this author at the Medicinal chemistry
Laboratory, GVK Biosciences PVT Ltd, Plot No 5C, IDA, Uppal,
Hyderabad, 500 039, AP, India; Tel: +91-40-6712 6600; Fax: +91-40-2720
8866; E-mail: asrinivas@gvkbio.com
1570-1808/11 $58.00+.00
© 2011 Bentham Science Publishers

Synthesis and Antibacterial Activity of 6-Substituted
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 973
a
b
c
n=0
n=2
n=4
OH
O
OH
C15H31-n
d
1
Fig. (1). The anacardic acid mixture.
n=6
OH
O
R
O
O
O
O
OH
O
O
a
d
b, c
R
OH
3
2
1
R=
O
O
O
O
e
O
O
Br
R1
5a-5s
4
Scheme 1. Synthesis of anacardic acid derivatives 5a-5s.
Experimental conditions: a) Dimethyl sulfate, K2CO3, Acetonitrile, 65 °C, 5h; b) Ozonolysis, MeOH, CH2Cl2, -78 °C, 2h; c) MeOH,
NaBH4, -15 °C-rt; 18h d) CBr4, Pyridine, Triphenylphosphine, CH2Cl2, 0 °C - rt, 6h; e) Amines, K2CO3, acetonitrile, 85-90 °C, 3-6 h.
concentration) was compared with standard drug ampicillin
and the results of investigation have been presented in Table
1. Based on the test results it is evident that several of
synthesized anacardic acid analogs possess moderate to good
activity against the Gram +ve and Gram –ve bacteria. Of all
the compounds prepared entities 5a, 5b, 5c, 5e, 5f, 5j, 5k,
5m, 5n and 5q display good to excellent activity while the
remaining compounds showed moderate activity against
Staphylococcus aureus. In case of Streptococcus pyogenes
molecules 5a, 5f, 5k, 5o, 5p, 5r, 5s showed good to excellent
activity while the remaining compounds showed moderate
activity. In case of inhibition of Pseudomonas aeruginosa
compounds 5i and 5l showed excellent activity, while 5a, 5c,
5d, 5e, 5g, 5h, 5j, 5k, 5m, 5n, 5o, 5p, 5q, 5r and 5s showed
good to moderate activity and remaining compounds 5b, 5f
and 5s showed less activity. In case of inhibition of
Escherichia coli compounds 5d, 5e, 5m and 5o showed
excellent activity with a zone of inhibition 20, 20, 22, 19
mm, remaining compounds showed moderate and less
activity. The most active antibacterial agent against
Escherichia coli found to be compound 5m having N-benzyl
piperazine, compound 5d having thiomorpholine and
compound 5e having 5-amino-cyclohexane residue as R1,
while all the other compounds in the series exhibited
moderate to good activity. As all the compounds showed
antibacterial activity against the bacteria tested, it indicates
that this basic moiety can be a potential scaffold for anti
bacterial drugs. Therefore other functionalities in the
molecule will also contribute to the activity. It may be
suggested that the 6-substituted anacardic acid derivative
with a suitable R1 may lead to a good antibacterial agent for
all the Escherichia coli, Pseudomonas aeruginosa,
Streptococcus pyogenes and Staphylococcus aureus bacterial
strains. Compounds 5a-5s, showed moderate antibacterial
activity when tested at 25, 50, and 100 μg/mL concentration
against Escherichia coli, Pseudomonas aeruginosa,
Streptococcus pyogenes and Staphylococcus aureus bacterial
strains. Anti-bacterial activity for these compounds (5a-5s)
were not tested at higher concentrations (>250 μg/mL).
3. EXPERIMENTAL
3.1. Material and Methods
Chemical and solvents used were purchased either from
Fluka or Merck. All the reagents were of analytical grade.
Thin-layer chromatography (TLC) was performed on
E.Merck AL silica gel 60 F254 plates and visualized under

974 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Nallamilli et al.
Table 1. Results of Antibacterial Bioassay of Compounds 5a-5s (Concentration Used 250 μg/mL of DMSO) Zones of Inhibition of
Compounds 5a-5s
Name of the Bacteria
Compound no.
R1
E.coli
P. aeruginosa
S.aureus
S.pyogenes
MTCC443
MTCC424
MTCC96
MTCC442
5a
5b
5c
5d
5e
15
17
16
20
20
18
15
17
18
17
17
17
17
16
17
18
16
17
17
17
N
N
N
O
N
S
HN
OH
O
5f
18
15
18
18
N
OH
5g
5h
17
16
16
17
16
16
16
17
N
O
O
N
NH
5i
5j
N
NH
18
16
17
20
17
16
16
17
17
16
17
18
N
N
OH
5k
N
N
O
O
N
N
5l
17
22
20
18
16
17
17
17
5m
N
N

Synthesis and Antibacterial Activity of 6-Substituted
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 975
(Table 1). Contd…..
Name of the Bacteria
E.coli
Compound no.
R1
P. aeruginosa
S.aureus
S.pyogenes
MTCC443
MTCC424
MTCC96
MTCC442
O
N
N
5n
17
16
17
17
O
N
5o
5p
5q
19
16
17
17
18
16
16
15
17
18
18
17
N
N
N
N
N
N
NH
O
Cl
5r
14
16
16
18
N
N
5s
17
20
15
20
16
18
19
19
OH
O
SD* ampicillin
SD* ampicillin
(Conc. 250 μg/mL)
UV light. The IR spectra were recorded on a Perkin Elmer
FT-IR spectrometer. The H NMR spectra were recorded in
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 37 oC in an inverted fashion.
Activity was determined by zones showing complete
inhibition (mm). Growth inhibition was calculated with
reference to positive control.
1
CDCl3 on a Varian EM-360 spectrometer (400MHz). The
13C NMR spectra recorded in CDCl3 on a Varian EM-360
spectrometer operating at 100MHz. All the chemical shifts
were reported in ꢀ (ppm) using TMS as an internal standard.
The mass spectra were recorded on Agilent ion trap MS. All
the reactions were carried out under argon atmosphere.
3.3. Experimental Section
3.2. Antibacterial Bioassay
Isolation of Anacardic Acid Ene Mixture (1)
Anacardic acid analogs (5a – 5s) 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. After 18 h
the exponentially growing cultures of the six bacteria in
Commercially available solvent extracted CNSL (200 g)
was dissolved in methanol: water mixture (8:2, 1 L). To the
above solution was added 30 g of activated charcoal and
0
heated at 50 C for 15 min, filtered over Celite to remove
insoluble materials and color impurities. The clear filtrate
was taken into a 3L round bottom flask fitted with reflux
condenser and mechanical stirrer. To this solution Calcium
hydroxide (100 g) was added portion wise over a period of
45 min at 50-55 0C and the reaction mixture was heated at 60
0C for 5 h. The precipitated calcium anacardate was filtered
and washed thoroughly with methanol (1 L) and ethyl
acetate (1 L) to afford off-white solid which was taken into
o
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 media to give a final
bacterial count of 1 x 106 cell/ml. The plates were set at
o
room temperature and later dried at 37 C for 20h. Paper
discs (6mm, punched from whatmann no 41 paper) were
ultraviolet sterilized and used for the assays. Discs were
soaked in different concentrations of the test solution and

976 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Nallamilli et al.
ice cold water, and adjusted to pH ~ 2 using 6N HCl and
stirred for 30 min. The aqueous solution was extracted with
ethyl acetate (2x500 mL), the combined organic layer was
washed with water (2x500 mL), brine solution (500 mL),
dried over anhydrous sodium sulfate and concentrated under
reduced pressure to yield an ene mixture of anacardic acid 1
(130 g, brown liquid).
The crude compound was purified by 100-200 silica column
chromatography (eluted with 10% ethyl acetate: pet ether) to
obtain 4 (Yield: 16.5 g, 90.8%; yellow viscous liquid); IR
(neat): 3071, 3002, 2931, 2854, 1732, 1588, 1464, 1437,
1268, 1109, 1072, 960, 749 cm-1; 1H NMR (400 MHz;
CDCl3): ꢀ 1.29-1.42 (m, 8H), 1.52-1.59 (m, 2H), 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); 13C NMR (100 MHz,
CDCl3): ꢀ 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; EI MS: m/z (rel.abund.%) 357 (M+, 100) &
359 (M+2, 100).
Methyl Anacardate Methyl Ethers Ene Mixture (2)
To a solution of 1 (65 g, 0.18 mol) in acetonitrile was
added K2CO3 (103.1 g, 0.74 mol) followed by dimethyl
sulfate (44.3 mL, 0.46 mol) and heated at 65 0C for 5 h. The
reaction mixture was cooled to room temperature, filtered
and washed with ethyl acetate. The filtrate was concentrated
and the residue was dissolved in ethyl acetate (300 mL). The
organic layer was washed with water, brine solution and
dried over anhydrous sodium sulphate and evaporated under
reduced pressure. The obtained crude compound was
purified by 60-120 silica-gel column chromatography (eluted
with 5% ethyl acetate: pet ether) to afford 2 (Yield: 58 g,
light yellow liquid).
General Experimental Procedure for the Synthesis of
Amines (5a-5s)
To an acetonitrile solution containing 4 (300 mg, 0.70
mmol) was added K2CO3 (293 mg, 2.11 mmol), and
appropriate amine (1.05 mmol). The contents were heated at
85-90 °C for 3-6 h under argon atmosphere, the reaction
medium was cooled to room temperature and poured into
water and extracted with ethyl acetate. The organic layer was
washed with brine solution, dried over anhydrous sodium
sulphate filtered and concentrated under reduced pressure, to
obtain the crude compounds. The crude compounds were
purified by column chromatography using silica gel (100-
200 mesh). Yields of the products varied between 35.5 and
99.5%.
2-(8-Hydroxy-octyl)-6-methoxy-benzoic acid methyl ester
(3)
A solution of 2 (15 g, 0.40 mol) in dichloromethane:
methanol (1:1, 500 mL) was cooled to -78 °C and treated
with a stream of O3 gas until the completion of starting
material. The reaction mixture was treated with the stream of
o
O2 at -78 C to remove excess amount of O3. To the reaction
mixture was added a solution of dimethyl sulfide (catalytic
o
Methyl 2-methoxy-6-(8-(pyrrolidin-1-yl)octyl)benzoate (5a)
qty) at -78 C, and the mixture was allowed to stir at room
temperature for 2 h. The reaction mixture was again cooled
to -15 °C, and was added sodium borohydride (9.97 g, 0.26
mol) portion wise over a period of 45 min; the reaction
mixture was allowed to reach room temperature and stirred
for 18 h. To the reaction mixture was added cold water (400
mL) and the aqueous layer was extracted with
dichloromethane (2x200 mL). The combined organic layer
was washed with brine solution (150 mL) dried over
anhydrous sodium sulphate and concentrated. The residue
was purified by neutral alumina column chromatography
(eluted with 20% ethyl acetate: pet ether) to afford 3 (Yield:
7.1 g, 59.5%, yellow viscous liquid); IR (neat): ꢀmax 3401,
2930, 1728, 1586, 1467, 1268, 1110, 1071, 954, 749 cm-1;
1H-NMR (400 MHz, CDCl3): ꢀ 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); 13C NMR (100 MHz, CDCl3), ꢀ:
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; EI MS: m/z (rel.abund.%) 295 (M+, 100).
Light yellow liquid; Yield: 210 mg, 71.8%; IR (neat):
ꢀmax 3061, 2931, 2858, 1730, 1634, 1587, 1462, 1440, 1268,
1
1111, 1072, 736 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.28
(bs, 8H), 1.42-1.59 (m, 4H), 1.78-1.81 (m, 4H), 2.38-2.55
(m, 8H), 3.81 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 8.8 Hz),
6.82 (d, 1H, J = 7.6 Hz), 7.24-7.28 (m, 1H); EI MS: m/z
(rel.abund.%) 348 (M+, 100).
Methyl 2-methoxy-6-(8-(piperidin-1-yl)octyl)benzoate (5b)
Brown liquid; Yield: 270 mg, 88.7%; IR (neat): ꢀmax
3069, 2929, 2854, 1733, 1587, 1466, 1267, 1111, 1072, 959,
746 cm-1; 1H-NMR (400 MHz, CDCl3): ꢀ 1.21-1.29 (m, 8H),
1.41-1.49 (m, 4H), 1.55-1.61 (m, 6H), 1.75 (bs, 2H), 2.26 (t,
2H, J = 8.0 Hz), 2.36 (bs, 2H), 2.53 (t, 2H, J = 8.0 Hz), 3.82
(s, 3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 7.6 Hz), 6.81 (d, 1H, J
= 8.0 Hz), 7.24-7.28 (m, 1H); 13C NMR (100 MHz, CDCl3):
24.36, 25.78, 26.70, 27.65, 29.26, 29.35, 29.40, 31.04, 33.39,
52.04, 54.48, 55.78, 59.49, 108.28,121.40, 123.40, 130.16,
141.25, 156.17, 168.86; EI MS: m/z (rel.abund.%) 362 (M+,
100).
2-(8-bromo-octyl)-6-methoxy-benzoic acid methyl ester (4)
2-Methoxy-6-(8-morpholinooctyl)benzoate (5c)
To a solution of 2 (15 g, 0.51 mol) in dichloromethane
(150 mL), cooled to 0 °C was added dry pyridine (42 mL,
0.51 mol) followed by triphenylphosphine (22.73 g, 0.86
mol). To the reaction mixture was added carbon tetrabromide
(25.4 g, 0.76 mol), portion wise over a period of 15 min and
stirred at rt for 6 h. The reaction mixture was diluted with
dichloromethane (100 mL) washed with 2N HCl (2x150
mL), water (200 mL), brine solution (175 mL), dried over
anhydrous Na2SO4, filtered and evaporated under vacuum.
Yellow liquid; Yield: 270 mg, 88.3%; IR (neat): ꢀmax
2931, 2855, 1731, 1587, 1462, 1268, 1115, 1072, 964, 914,
1
865 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.28 (bs, 8H),
1.41-1.59 (m, 4H), 2.30 (t, 2H, J = 7.6 Hz), 2.43 (bs, 4H),
2.53 (t, 2H, J = 8.0 Hz), 3.72 (t, 4H, J = 4.8 Hz), 3.82 (s,
3H), 3.91 (s, 3H), 6.75 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J =
8.0 Hz), 7.24-7.28 (m,1H); 13C NMR (100 MHz, CDCl3):
26.41, 27.41, 29.26, 29.35, 31.02, 33.39, 52.04, 55.78, 59.12,

Synthesis and Antibacterial Activity of 6-Substituted
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 977
66.88, 108.30, 121.39, 123.40, 130.17, 141.22, 156.17,
168.86; EI MS: m/z (rel.abund.%) 364 (M+, 100).
Methyl 2-methoxy-6-(8-(piperazin-1-yl)octyl)benzoate (5i)
Yellow liquid; Yield: 120 mg, 39.3%; IR(neat): ꢀmax
Methyl 2-methoxy-6-(8-thiomorpholinooctyl)benzoate (5d)
3537, 3061, 2930, 2853, 1730, 1585, 1465, 1268, 1112,
1
1073, 736 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.25 (m,
Brown liquid; Yield: 185 mg, 58%; IR (neat): ꢀmax 3067,
8H), 1.41-1.56 (m, 4H), 2.29-2.54 (m, 9H), 2.92-2.94 (m,
3H), 3.81 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H, J = 8.4 Hz), 6.81
(d, 1H, J = 8.0 Hz), 7.24-7.28 (m, 1H); EI MS: m/z
(rel.abund.%) 363 (M+, 100).
3001, 2929, 2854, 2807, 1731, 1587, 1462, 1268, 1112,
1
1071, 957, 740 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.27
(bs, 8H), 1.41-1.60 (m, 4H), 2.32-2.36 (m,2H), 2.53 (t, 2H, J
= 8.0 Hz), 2.70 (bs, 8H), 3.82 (s, 3H), 3.91 (s, 3H), 6.76 (d,
1H, J = 8.4 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.25-7.29 (m,1H);
13C NMR (100 MHz, CDCl3): ꢀ 26.31, 27.48, 27.84, 29.31,
29.39, 31.11, 33.44, 52.17, 54.96, 55.84, 59.44, 108.30,
121.44, 123.36, 130.25, 141.25, 156.18, 168.97; EI MS: m/z
(rel.abund.%) 380 (M+, 100).
Methyl 2-methoxy-6-(8-(4-methylpiperazin-1-yl)octyl)ben-
zoate (5j)
Yellow liquid; Yield: 210 mg, 66.2%; IR (neat): ꢀmax
2931, 2852, 2801, 1731, 1588, 1462, 1270, 1111, 1072, 737
1
cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.28 (bs, 8H), 1.40-
Methyl 2-(8-(cyclohexylamino)octyl)-6-methoxybenzoate
(5e)
1.60 (m, 4H), 2.28-2.54 (m, 15H), 3.82 (s, 3H), 3.90 (s, 3H),
6.75 (d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 7.2 Hz), 7.24-7.28
(m, 1H); EI MS: m/z (rel.abund.%) 376 (M+, 100).
Yellow liquid; Yield: 150 mg, 47.5%; IR (neat): ꢀmax
2927, 2853, 1731, 1587, 1465, 1268, 1111, 1073, 737 cm-1;
1H-NMR (400 MHz, CDCl3): ꢀ 1.0-1.32 (m, 13H), 1.40-1.47
(m, 2H), 1.53-1.63 (m, 3H), 1.70-1.73 (m, 2H), 1.86-1.88
(m, 2H), 2.36-2.40 (m, 1H), 2.53 (t, 2H, J = 8.0 Hz), 2.59 (t,
2H, J = 7.6Hz), 3.82 (s, 3H), 3.90 (s, 3H), 6.75 (d, 1H, J =
8.4 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.24-7.28 (m, 1H); EI MS:
m/z (rel.abund.%) 376 (M+, 100).
Methyl 2-(8-(4-(2-hydroxyethyl)piperazin-1-yl)octyl)-6-
methoxybenzoate (5k)
Brown liquid; Yield: 200 mg, 58.4%; IR (neat): ꢀmax
3378, 3052, 2930, 2854, 1728, 1586, 1465, 1268,1154, 1112,
1
1071, 1012, 936, 737 cm-1; H-NMR (400 MHz, CDCl3): ꢀ
1.26-1.35 (m, 8H), 1.53-1.60 (m, 4H), 2.41 (t, 2H, J = 7.6
Hz), 2.52-2.67 (m, 12H), 3.66 (t, 2H, J = 5.2 Hz), 3.83 (s,
3H), 3.91 (s, 3H), 6.77 (d, 1H, J = 8.4 Hz), 6.82 (d, 1H, J =
8.0 Hz), 7.26-7.28 (m, 1H); EI MS: m/z (rel.abund.%) 407
(M+, 100).
1-(8-(3-methoxycarbonyl)phenyl)octyl)piperidine-2-
carboxylic acid (5f)
Yellow liquid; Yield: 110 mg, 32.3%; IR (neat): ꢀmax
3440, 3054, 2932, 2855, 1731, 1588, 1464, 1268, 1111,
tert-butyl 4-(8-(3-methoxy-2-(methoxycarbonyl)phenyl)
octyl)piperazine-1-carboxylate (5l)
1
1071, 737 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.29 (bs,
8H), 1.40-1.82 (m, 7H), 2.08-2.28 (m, 1H), 2.40-2.58 (m,
3H), 3.03-3.10 (m, 1H), 3.81 (s, 3H), 3.90 (s, 3H), 4.11 (t,
2H, J = 6.4 Hz), 6.75(d, 1H, J = 8.4 Hz), 6.81 (d, 1H, J = 7.6
Hz), 7.24-7.28 (m, 1H); EI MS: m/z (rel.abund.%) 404 (M-,
100).
Yellow liquid; Yield: 300 mg, 77.1%; IR (neat): 3071,
2931, 2857, 2810, 1731, 1693, 1589, 1426, 1268, 1172,
1
1118, 1070, 1003, 865, 758 cm-1; H NMR (400 MHz,
CDCl3): ꢀ 1.28 (s, 8H), 1.46 (s, 11H), 1.52-1.60 (m, 2H),
2.31-2.39 (m,6H), 2.53 (t, 2H, J = 8.0 Hz), 3.40-3.44(m,
4H), 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); EI MS: m/z
(rel.abund.%) 463 (M+, 100).
Methyl 2-(8-(3-hydroxypyrrolidin-1-yl)octyl)-6-methoxy-
benzoate (5g)
Yellow liquid; Yield: 250 mg, 81.7%; IR (neat): ꢀmax
3535, 3054, 2928, 2855, 1728, 1586, 1466, 1267, 1111,
Methyl2-(8-(4-benzylpiperazin-1-yl)octyl)-6-methoxyben-
zoate (5m)
1
1074, 739 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.28 (bs,
8H), 1.43-1.60 (m, 4H), 1.65-1.70 (m, 1H), 2.15-2.28 (m,
3H), 2.39-2.55 (m, 5H), 2.66-2.69 (m, 1H), 2.82-2.91 (m,
1H), 3.82 (s, 3H), 3.90 (s, 3H), 6.76 (d, 1H, J = 8.8 Hz), 6.82
(d, 1H, J = 7.6 Hz), 7.24-7.26 (m, 1H); EI MS: m/z
(rel.abund.%) 364 (M+, 100).
Brown liquid; Yield: 200 mg, 52.5%; IR (neat): ꢀmax
3077, 2933, 2855, 1732, 1677, 1589, 1461, 1442, 1268,
1
1112, 1071 cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.27 (bs,
8H), 1.45-1.48 (m, 2H), 1.55 (t, 2H, J =7.2 Hz), 2.28-2.54
(m, 10H), 3.51(s, 2H), 3.81 (s, 3H), 3.90 (s, 3H), 6.75(d, 1H,
J = 8.4 Hz), 6.81 (d, 1H, J = 7.6 Hz), 7.24-7.31 (m, 6H); EI
MS: m/z (rel.abund.%) 453 (M+, 100).
Methyl 2-(8-(4-(tert-butoxycarbonylamino)piperidin-1-yl)
octyl)-6-methoxybenzoate (5h)
Yellow liquid; Yield: 400 mg, 99.5%; IR (neat): ꢀmax
3366, 2930, 2855, 1722, 1587, 1508, 1464, 1368, 1269,
1171, 1111, 1071, 1042, 889, 738 cm-1; 1H-NMR (400 MHz,
CDCl3): ꢀ 1.25-1.29 (m, 8H), 1.44 (s, 11H), 1.52-1.60 (m,
2H), 1.89-2.04 (m, 5H), 2.28 (t, 2H, J = 7.6 Hz), 2.52 (t, 2H,
J =7.6 Hz), 2.82-2.84 (bs, 2H), 3.42 (bs, 1H), 3.82 (s, 3H),
3.90 (s, 3H), 4.40 (bs, 1H), 6.75 (d, 1H, J = 8.4 Hz), 6.81 (d,
1H, J = 8.0 Hz), 7.24-7.28 (m, 1H); 13C NMR (100 MHz,
CDCl3): 27.04, 27.56, 28.36, 29.26, 29.35, 29.63, 31.04,
32.51, 33.39, 52.06, 52.41, 55.80, 58.72, 108.31, 121.42,
123.40, 130.17, 141.24, 155.16, 156.18, 168.88; EI MS: m/z
(rel.abund.%) 477 (M+, 100).
tert-butyl 4-(8-(3-methoxy-2-(methoxycarbonyl)phenyl)
octyl)-1,4-diazepane-1—carboxylate (5n)
Yellow liquid; Yield: 420 mg, 97.2%; IR (neat): ꢀmax
3053, 2976, 2930, 2857, 1691, 1586, 1418, 1266, 1169,
1
1117, 737 cm-1; H-NMR (CDCl3, 400 MHz): ꢀ 1.28 (bs,
8H), 1.46 (s, 9H), 1.53-1.64 (m, 4H), 1.78-1.83 (m, 2H),
2.43 (t, 2H, J = 7.6 Hz), 2.53 (t, 2H, J = 8.0 Hz), 2.56-2.65
(m, 3H), 3.38-3.50 (m, 5H), 3.82 (s, 3H), 3.90 (s, 3H), 6.76
(d, 1H, J = 8.0 Hz), 6.81 (d, 1H, J = 8.0 Hz), 7.24-7.28 (m,
1H); EI MS: m/z (rel.abund.%) 477 (M+, 100).

978 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Nallamilli et al.
Methyl 2-(8-(1H-pyrazol-1-yl)octyl)-6-methoxybenzoate
(5o)
yields. Their antibacterial activity has been performed, as all
the compounds showed antibacterial activity against the
bacteria tested, it indicates that the basic moiety can be a
potential scaffold for antibacterial drugs. Thus, further lead
optimization is required to get a wide spectrum of activity.
Light yellow liquid; Yield: 150 mg, 51.7 %; IR (neat):
ꢀmax 3002, 2931, 2856, 1730, 1587, 1465, 1441, 1395, 1269,
1
1107, 1073, 961, 749 cm-1; H-NMR (CDCl3, 400 MHz): ꢀ
1.25-1.28 (m, 8H), 1.53-1.57 (m, 2H), 1.82-1.86 (m, 2H),
2.52 (t, 2H, J = 8.0 Hz), 3.81 (s, 3H), 3.89 (s, 3H), 4.11 (t,
2H, J = 7.6 Hz), 6.22(t, 1H, J = 2.0 Hz), 6.75 (d, 1H, J = 8.0
Hz), 6.81 (d, 1H, J = 7.2 Hz), 7.24-7.28 (m, 1H), 7.36 (d,
1H, J = 2.4 Hz), 7.49 (d, 1H, J = 1.6 Hz); EI MS: m/z
(rel.abund.%) 345 (M+, 100).
ACKNOWLEDGEMENTS
We thank GVK Biosciences Private Limited for the
financial support and encouragement. Help from the
analytical department for the analytical data is appreciated.
We also thank Dr. Balaram Patro for his helpful suggestions.
Methyl 2-(8-(1H-imidazol-1-yl)octyl)-6-methoxybenzoate
(5p)
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Light yellow liquid; Yield: 110 mg, 37.9 %; IR (neat):
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1
cm-1; H-NMR (400 MHz; CDCl3): ꢀ 1.28 (bs, 8H), 1.53-
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1
1073, 738 cm-1; H-NMR (400 MHz; CDCl3): ꢀ 1.22-1.39
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Yellow liquid; Yield: 130 mg, 35.5%; IR (neat): ꢀmax
3538, 3418, 3056, 3003, 2929, 2854, 1729, 1588, 1468,
1397, 1312, 1268, 1209, 1109, 1073, 1036, 956, 835, 737
1
cm-1; H-NMR (400 MHz, CDCl3): ꢀ 1.27-1.43 (m, 8H),
1.55-1.68 (m, 4H), 2.55 (t, 2H, J = 7.6 Hz), 3.09-3.14 (q,
2H), 3.83 (s, 3H), 3.84 (s, 3H), 3.92 (s, 3H), 4.29 (s, 1H),
6.44 (d, 1H, J = 2.4 Hz), 6.77 (d, 1H, J = 8.0 Hz), 6.83 (d,
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2-(8-(3-methoxy-2-(methoxycarbonyl)phenyl)octyl)-1,1,3,3-
tetramethylisoindoline-5-carboxylic acid (5s)
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Yellow liquid; Yield: 315 mg, 75.5 %; IR (neat): ꢀmax
3069, 2928, 2856, 1722, 1588, 1464, 1429, 1369, 1273,
1
1247, 1108, 1073, 959, 835, 740 cm-1; H-NMR (400 MHz,
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CDCl3): ꢀ 1.29-1.48 (m, 20H), 1.53-1.60 (m, 2H), 1.72-1.79
(m, 2H), 2.53 (t, 2H, J = 7.6Hz), 3.81 (s, 3H), 3.90 (s, 3H),
4.31 (t, 2H, J = 6.8 Hz), 6.75 (d, 1H, J = 8.4 Hz), 6.81 (d,
1H, J = 8 Hz), 7.16 (d, 1H, J = 7.6 Hz), 7.24-7.28 (m, 1H),
7.79 (s, 1H), 7.94 (d, 1H, J = 8.0 Hz); EI MS: m/z
(rel.abund.%) 496(M+, 100).
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4. CONCLUSION
In conclusion, we have synthesized 6-substituted
anacardic acid derivatives (5a-5s) with good to excellent

Synthesis and Antibacterial Activity of 6-Substituted
Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10 979
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