Synthesis of azabicyclo[3.1.0]amine analogues of anacardic acid as potent antibacterial agents

Article abstract of DOI:10.14233/ajchem.2013.13338

Azabicyclo[3.1.0]amine analogues of anacardic acid (16a, 16b, 18a, 18b, 19 and 19b) were synthesized from anacardic acid and tested for their antibacterial activity against Gram positive and Gram negative bacteria. Most of the compounds are having potency at par with ampicillin and inferior with other standard drugs.

Full text of DOI:10.14233/ajchem.2013.13338

Asian Journal of Chemistry; Vol. 25, No. 2 (2013), 986-994
http://dx.doi.org/10.14233/ajchem.2013.13338
Synthesis of Azabicyclo[3.1.0]amine Analogues of
Anacardic Acid as Potent Antibacterial Agents
1
1
2
RAVI KUMAR VEMPATI , N.S. REDDY , SRINIVASA RAO ALAPATI1,* and P.K. DUBEY
1Medicinal Chemistry Division, GVKBIO Sciences Pvt. Ltd., IDA-Uppal, Hyderbad-500 039, India
2Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad-500 072, India
*Corresponding author: E-mail: asrinivas@gvkbio.com
(Received: 27 December 2011;
Accepted: 29 August 2012)
AJC-12027
Azabicyclo[3.1.0]amine analogues of anacardic acid (16a, 16b, 18a, 18b, 19 and 19b) were synthesized from anacardic acid and tested
for their antibacterial activity against Gram positive and Gram negative bacteria. Most of the compounds are having potency at par with
ampicillin and inferior with other standard drugs.
Key Words: Cashew nut shell liquid, Anacardic acid, Trovofloxacin, Azabicyclo[3.1.0]amine analogues, Antibacterial activity.
Colarado potato beetle10, modulation of nuclear factor Kappaβ
signalling pathway by inhibit acetyl transferase in suppression
INTRODUCTION
The emerging resistance of microorganisms to known
antibiotics is creating a situation to develop novel antibiotics.
of nuclear factorβ11, cytotoxic activity on BT-20 breast and
Hela epithelioid cervix carcinoma cells12, zoosporicidal activity
Therefore, designing and innovating drugs could be the choice
to meet the ongoing demand for novel antibiotics. These novel
against Aphanomyces cochlioides13, kinase activity of Aurora
kinase A14, benzamide derivatives for HAT activation15 and
antibiotics should be identified either from natural products
or synthetic compounds. Due to weak biological activity, some
inhibition of the acetyl histone transferase PCAF16.
of the natural products were remained useless. As part of this
developing novel antibiotics, the milder natural products could
OH
O
be converted as potential drug candidates by making necessary
structural modifications.
OH
Anacardic acid is a natural product that can be isolated
from cashew nut shell liquid (CNSL), usually available as an
ene-mixture (Fig. 1). Cashew nut shell liquid contains anacardic
acid ene-mixture along with salicylic acid and a non-isoprenoid
long alk(en)yl side chain moiety1,2. Anacardic acid is thought
to possess its antibacterial activity due to its long alkyl chain3.
The anacardic acid ene-mixture is composed of a long C15-
alkyl side chain with monoenoic, dienoic and trienoic at the
C-8, C-11 and C-14 positions respectively (Fig. 1). Anacardic
acid and its derivatives have been reported to possess a range
of bioactivities such as antibacterial action against Methicillin
resistant Staphylococcus aureus (MRSA)4.
1a (anacardic acid)
1b (mono-ene)
1c (di-ene)
Earlier several researchers have carried out their work
on anacardic acid and its derivatives for different therapeutic
purposes for inhibition of triglycerides5, ureil soybean lipoxy-
genase-1 inhibition6, Sildenafil analogues7, dihydropyridine
analogues as calcium channel blockers8, isonicotinoyl-
hydrazones for antimycobacterial activity9, bioactivity against
1d (tri-ene)
Fig. 1. Anacardic acid and its ene-mixture

Vol. 25, No. 2 (2013)
Synthesis of Azabicyclo[3.1.0]amine Analogues of Anacardic Acid as Potent Antibacterial Agents 987
In our previous communication16, we have reported the
synthesis of novel benzylamine analogues of anacardic acid
and tested for their antibacterial activity against S. aureus and
S. pyogens (Gram positive) and E. Coli and P. aeruginosa
(Gram negative) groups of bacteria. As part of this program,
this time we have chosen to utilize the azabicyclo[3.1.0]amine,
which is part of known antibiotic drug (i.e.) Trovafloxacin
(Trovan) (Fig. 2).
EXPERIMENTAL
The reagents and solvents used in this study were of analy-
tical grade and were used without further purification. Melting
points were determined in open capillaries and are uncorrected.
Thin-layer chromatography was used for reaction monitoring
using silica gel GF254 and spots were detected using iodine
chamber or UV lamp at 254 nm. IR were recorded on FTIR
Perkin elmer spectrometer and the 1H NMR spectra on aVarian
EM-360 spectrometer (400 MHz) using TMS as an internal
standard. The mass spectra were recorded on Agilent ion trap
MS. All the products were characterized by IR, 1H NMR (400
MHz), Mass analysis. All compounds were purified by either
column chromatography or recrystallization techniques. IUPAC
names were generated using Chemdraw 11.0 computer program.
Preparation of anacardic acid (1a-1d, ene-mix): To a
solution of MeOH (6 vol) and H2O (1 vol) containing commer-
cial grade CNSL (100 g), was added Ca(OH)2 (50 g) and the
contents were heated to 60 ºC for 3 h. The precipitated solid
was filtered and the wet cake was washed with MeOH (1 vol)
to remove the cardol and cardanol. The brown coloured preci-
pitate was then suspended in water, pH was adjusted to 2 range
using 6 N HCl solution under vigorous stirring and extracted
with ethyl acetate (3 × 200 mL). The combined organic layer
was washed with H2O, brine solution, dried over anhydrous
Na2SO4, concentrated to dryness to afford the anacardic acid
ene-mixture as dark-brown coloured viscous oil (60 g, crude).
Preparation of anacardic acid (2): To a solution of
ethanol (700 mL) containing the ene-mixture (1a-1d) (60 g,
crude) 10 % Pd/C (6 g) was slowly added under inert atmos-
phere into a hydrogenation flask. Hydrogenation was carried
out under 60 psi of hydrogen pressure for 2 h. Filtered the
contents through a pad of celite to remove the catalyst, collected
the clear filtrate, concentrated under reduced pressure to afford
the crude anacardic acid (2), which was recrystallized from
petroleum ether (40-60 ºC); Yield 36 g ; m.p. 85-86 ºC; IR
(KBr, νmax, cm-1): 3071, 3002, 2917, 1655, 1450, 1246, 1214,
O
O
F
OH
N
N
H
F
H2N
H
F
Fig.2. Trovafloxacin
Trovofloxacin is a new synthetic antibacerial fluoro
quinoline which exhibits high potency against a broad
spectrum of Gram (-ve) and Gram (+ve) bacteria. Among the
fluoroquinolines, trovafloxacin was found most active (MIC90,
1 µg/mL), followed by Sparfloxacin (MIC90, 8 µg/mL),
Levofloxacin (MIC90, 16 µg/mL), Ofloxacin (MIC90, 32 µg/
mL). Ciprofloxacin was the least active quinoline (MIC90, 64
µg/mL)17.
Hence, we have chosen to couple the azabicyclo[3.1.0]
amine with derivatives of anacardic acid and synthesized the
compounds as depicted in Figs. 3 and 4. The synthesized
targets were screened for their antibacterial activity against E.
coli, P. aeruginosa, S. aureus and S. pyogens, while using
ampicillin, chloramphenicol, ciprofloxacin and norfloxacin as
the standard drugs.
NH2
H
H
1
894, 815, 757; H NMR (400 MHz, CDCl3): δ 11.02 (br s,
1H), 7.36 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 6.78 (d,
J = 7.6 Hz, 1H), 2.98 (t, J = 8.0 Hz, 2H), 1.57-1.63 (m, 3H),
1.27 (br s, 23H), 0.88 (t, J = 6.8 Hz, 3H); Mass: m/z: 349
(M+H)+.
OR1
N
Preparation of methyl-2-methoxy-6-pentadecylben-
zoate (3a): To a stirred solution of compound 2 (26 g, 0.074
mmol) in acetonitrile (250 mL) was added powdered anhydrous
K2CO3 (41 g, 0.30 mol), followed by dimethyl sulfate (28 mL,
0.30 mmol) in portions for about 15 min at room temperature.
The contents were heated at 80 ºC for 3 h, cooled to room
temperature, filtered, and the clear filtrate was concentrated
under reduced pressure and the residue was diluted with water
(150 mL), extracted with EtOAc (2 × 100 mL). The combined
organic layer was washed with water, brine solution, dried
over anhydrous Na2SO4, concentrated to afford the compound
3a as a low-melting solid. m.p. 37-38 ºC, Yield: 22 g (78 %);
IR (KBr, νmax, cm-1): 3004, 2921, 2852, 1732, 1589, 1266,
1105; 1H NMR (400 MHz, CDCl3): δ 7.25 (t, J = 8.0 Hz, 1H),
6.82 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 3.90 (s, 3H),
3.81 (s, 3H), 2.53 (t, J = 8.0 Hz, 2H), 1.53-1.60 (m, 3H), 1.27
(brs, 23 H), 0.88 (t, J = 6.8 Hz, 3H); Mass: m/z: 377 (M+H)+.
16a
(R1 = Me)
16b (R1 = Et)
Fig. 3. Compounds 16a and 16b
OR1
O
OR2
H
N
NH2
H
18a (R1 & R2 = Me)
18b
(R1 & R2 = Et)
19a
(R1= Me, R2 = H)
19b (R1 = Et, R2 = H)
Fig. 4. Compounds 18a, 18b, 19a and 19b

988 Vempati et al.
Asian J. Chem.
Preparation of ethyl-2-ethoxy-6-pentadecylbenzoate
the crude compounds 5a or 5b as pale brown coloured solids.
The crude products were used as such in the step without fur-
ther purification.
(3b): To a stirred solution of compound 2 (26 g, 0.074 mmol)
in acetonitrile (250 mL) was added powdered anhydrous
K2CO3 (41 g, 0.30 mol), followed by diethyl sulfate (39 mL,
0.30 mmol) in portions for about 15 min at room temperature.
The contents were heated at 80 ºC for 3 h, cooled to room
temperature, filtered, collected the filtrate, concentrated under
reduced pressure and the residue was diluted with water
(150 mL), extracted with EtOAc (2 × 100 mL). The combined
organic layer was washed with water, brine solution, dried
over anhydrous Na2SO4, concentrated to afford the compound
3b as a low-melting solid. m.p. 57-59 ºC, Yield: 23 g (76 %);
IR (KBr, νmax, cm-1): 2982, 2926, 2854, 1729, 1585, 1462,
1395, 1268, 1196, 1111, 1069, 1007, 921, 825; 1H NMR (400
MHz, CDCl3): δ 7.22 (t, J = 8.2 Hz, 1H), 6.79 (d, J = 8.0 Hz,
1H), 6.73 (d, J = 8.0 Hz, 1H), 4.41-4.31 (m, 4H), 2.54 (t, J =
8.0 Hz, 2H), 1.59-1.55 (m, 3H), 1.45-1.35 (m, 6H), 1.27-1.24
(m, 23H), 0.88 (t, J = 6.4 Hz, 3H); Mass: m/z: 405.2 (M+H)+.
Preparation of 2-methoxy-6-pentadecylphenyl)methanol
(4a): To a stirred suspension of LiAlH4 (3.3 g, 88 mmol) in
dry THF (100 mL) was added the solution of compound 3a
(22 g, 58.5 mmol) in dry THF (50 mL) at -20 ºC and allowed
the contents to rt and stirred for 16 h. The reaction mixture
was quenched with saturated NH4Cl solution, filtered through
a pad of celite, collected the filtrate, concentrated to dryness.
The residue was dissolved in EtOAc, washed with H2O, brine
solution, dried and concentrated to afford the crude compound
4a as pale brown coloured solid (15 g, 73.6 %); m.p. 59-60 ºC;
IR (KBr, νmax, cm-1): 3386, 3072, 2916, 2846, 1705, 1461,
1265, 1118 and 1076; 1H NMR (400 MHz, CDCl3): δ 7.20 (t,
J = 8.0 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.0 Hz,
1H), 4.75 (d, J = 6.4 Hz, 2H), 3.87 (s, 3H), 2.67 (t, J = 6.4 Hz,
2H), 2.37 (t, J = 6.4 Hz, 2H), 1.53-1.58 (m, 3H), 1.27 (br s,
23H), 0.89 (t, J = 7.2 Hz, 3H); Mass: m/z: 349 (M+H)+.
Preparation of 2-ethoxy-6-pentadecylphenyl)methanol
(4b): To a stirred suspension of LiAlH4 (3.3 g, 88 mmol) in
dry THF (100 mL) was added the solution of compound 3b
(23.6 g, 58.5 mmol) in dry THF (50 mL) at -20 ºC and al-
lowed the contents to rt and stirred for 16 h. The reaction mix-
ture was quenched with saturated NH4Cl solution, filtered
through a pad of celite, collected the filtrate, concentrated to
dryness. The residue was dissolved in EtOAc, washed with
H2O, brine solution, dried and concentrated to afford the crude
compound 4b as pale brown coloured solid (16 g, 75.6 %);
m.p. 59-60 ºC; IR (KBr, νmax, cm-1): 3380, 3065, 2846, 1701,
1460, 1270, 1125, 1080 and 850; 1H NMR (400 MHz, CDCl3):
δ 7.22 (t, J = 8.2 Hz,1H), 6.86 (d, J = 7.6 Hz, 1H), 6.77 (d, J =
7.6 Hz,1H), 4.25-4.07 (m, 4H), 3.87 (s, 1H), 2.67 (t, J = 6.4
Hz, 2H), 1.53-1.58 (m, 3H), 1.27 (br s, 26H), 0.89 (t, J = 7.2
Hz, 3H); Mass: m/z: 363 (M+H)+.
Preparation of methyl 2-methoxy-6-((8E,11E)-
pentadeca-8,11,14-trienyl)benzoate (6a): To a solution of
1a-1d (65 g, 0.19 mmol) in acetonitrile was added K2CO3 (105
g, 0.76 mol) followed by dimethyl sulfate (44.5 mL, 0.47 mol)
and heated at 65 ºC 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 chromato-
graphy (eluted with 5 % ethyl acetate: pet ether) to afford 6a
(Yield: 59 g, pale yellow liquid) and the semi-pure product
was used as such in the next step.
Preparation of ethyl 2-ethoxy-6-[(8E, 11E)-pentadeca-
8,11,14-trienyl]benzoate (6b): To a solution of 1a-1d (65 g,
0.19 mol) in acetonitrile was added K2CO3 (105 g, 0.76 mol)
followed by diethyl sulfate (62 mL, 0.47 mol) and heated at
65 ºC 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 evapo-
rated 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 6b (Yield:
60 g, pale yellow liquid) and the semi-pure product was used
as such in the next step with out further purification.
Preparation of methyl-2-(8-hydroxyoctyl)-6-methoxy-
benzoate (7a): To a chilled solution of 6a (15 g, 0.40 mol) in
a mixture of dichloromethane: methanol (1:1, 500 mL) at -78
ºC, a stream of ozone gas was passed till the reaction was comp-
leted and excess ozone gas was expelled though a stream of
O2 at -78 ºC. To this mixture was added the solution of dimethyl
sulfide (catalytic qty) at -78 ºC and allowed to stir at room
temperature for 2 h. The reaction mixture was again cooled to
-30 ºC and sodium borohydride (10 g, 0.26 mol) was added
portion wise over a period of 1 h and allowed to stir at room
temperature for overnight. To the reaction mixture ice-cold
water (400 mL) was added slowly and separated the organic
layer. The aqueous layer was extracted with dichloromethane
(2 × 200 mL). The combined organic layer was washed with
brine solution (150 mL) dried over anhydrous sodium sulphate,
concentrated to dryness and the residue was purified by neutral
alumina column chromatography (eluted with 20 % ethyl
acetate: pet ether) to afford 7a (Yield: 6.6 g, 55.4 %, yellow
viscous liquid); IR (DCM film, cm-1): 3409, 2930, 2855, 1728,
1588, 1466, 1442, 1269, 1109, 1070, 958, 737; 1H NMR (400
MHz, CDCl3): δ 7.26-7.28 (m, 1H); 6.82 (d, 1H, J = 7.6 Hz),
6.75 (d, 1H, J = 8.4 Hz), 3.90 (s, 3H), 3.81 (s, 3H), 3.63(t, 2H,
J = 6.8 Hz), 2.53 (t, 2H, J = 8.0 Hz), 1.53-1.59 (m, 4H), 1.31
(bs, 8H); Mass: 295 (M+H)+.
Preparation of methane sulfonate esters (5a and 5b):
To a stirred solution of compound 4a (or) 4b (0.15 mol) in
CH2Cl2 (50 mL) was added Et3N (0.45 mol) and cooled to
0 ºC. To this mixture was added methanesulfonylchloride
(0.225 mol) at 0 ºC over a period of 15 min. The contents
were allowed to warm to rt and stirred for 4 h. The reaction
mixture was diluted with water and extracted with CH2Cl2 (2 ×
50 mL). The organic layer was washed with brine solution,
dried over anhydrous Na2SO4, concentrated to dryness to afford
Preparation of ethyl-2-ethoxy-6-(8-hydroxyoctyl)-
benzoate (7b): To a chilled solution of 6b (15 g, 0.37 mol) in
a mixture of dichloromethane: methanol (1:1, 500 mL) at
-78 ºC, a stream of Ozone gas was passed till the reaction was

Vol. 25, No. 2 (2013)
Synthesis of Azabicyclo[3.1.0]amine Analogues of Anacardic Acid as Potent Antibacterial Agents 989
completed and excess ozone gas was expelled though a stream
of O2 at -78 ºC. To this mixture was added dimethyl sulfide
(catalytic qty) at -78 ºC and allowed to stir at room temperature
for 2 h. The reaction mixture was again cooled to -30 ºC and
sodium borohydride (10 g, 0.26 mol) was added portion wise
over a period of 1 h and allowed to stir at room temperature
for overnight. To the reaction mixture ice-cold water (400 mL)
was added slowly and separated the organic layer. The aqueous
layer was extracted with dichloromethane (2 × 200 mL). The
combined organic layer was washed with brine solution
(150 mL) dried over anhydrous sodium sulphate, concentrated
to dryness and the residue was purified by neutral alumina
column chromatography (eluted with 20 % ethyl acetate: pet
ether) to afford 7b (Yield: 6.5 g, 53.7 %, yellow viscous liquid);
IR (DCM film, cm-1): 3423, 2929, 2858, 1725, 1587, 1462,
1389, 1266, 1109, 1066, 758; 1H NMR (400 MHz, CDCl3): δ
7.26-7.20 (m, 1H); 6.79 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0
Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H),
3.62 (t, J = 6.6 Hz, 2H), 2.54 (t, J = 8.0 Hz, 2H), 1.59-1.53 (m,
4H), 1.39 -1.32 (m, 14H); Mass: 323 (M+H)+.
Synthesis of (1R,5S,6r)-3-benzyl-6-nitro-3-azabicyclo-
[3.1.0]hexane-2,4-dione (10): To a solution of bromonitro-
methane (22.45 g, 160.42 mmol) in acetonitrile (600 mL) was
added potassium carbonate (22.14 g, 160.42 mmol), followed
by dropwise addition of N-benzylmaleimide (9) (20 g, 106.95
mmol) solution in acetonitrile (400 mL) over a period of 4 h
at room temperature and stirred for 0.5 h. After completion of
the reaction, filtered the reaction mass through celite bed and
washed with ethyl acetate (500 mL), collected the clear filtrate,
solvent was evaporated to afford the crude product as black
mass. The crude product was purified by silica-gel (100-200
mesh) packed column chromatography using 5 % to 10 %
ethyl acetate-pet ether as an eluent to afford the pure compound
10 (10.0 g, 38 %) as off-white solid. m.p. 112-114 ºC, IR (KBr,
ν
max, cm-1): 3086, 1788, 1710, 1560, 1397, 1359, 1173, 1017,
927, 883 and 721; 1H NMR (400 MHz, CDCl3): δ 7.33-7.25
(m, 5H), 4.53 (s, 2H), 4.48 (d, J = 1.6 Hz, 1H), 3.35 (d, J = 1.6
Hz, 1H), Mass: m/z : 245.1 (M+-1).
Synthesis of (1R,5S,6r)-3-benzyl-6-nitro-3-azabicyclo-
[3.1.0]hexane (11): To a solution of compound 10 (20 g,
81.3 mmol) in dry THF (200 mL) was added the solution of
Borane. THF complex (320 mL, 16 vol) and heated to reflux
temperature for 3 h. The reaction mass cooled to 10 ºC, added
methanol (120 mL) slowly and heated to reflux temperature
for 0.5 h.After completion of the reaction, solvent was distilled
out under reduced pressure and the residue was dissolved in
dichloromethane (300 mL), washed with water, brine solution,
dried over anhydrous sodium sulphate, concentrated to dryness
to afford the crude compound 11 (15.0 g, 84 %) as an oil. IR
(dichloromethane film, cm-1): 3440, 2977, 1726, 1643, 1434,
1203, 1158, 853 and 771; 1H NMR (400 MHz, DMSO-d6): δ
7.32-7.22 (m, 5H), 4.56 (s, 1H), 3.59 (s, 2H), 3.15-3.10 (m,
2H), 2.54-2.50 (m, 4H); Mass: m/z: 219.2 (M +1)+.
Preparation of methyl 2-(8-bromooctyl)-6-methoxy-
benzoate (8a): To a solution of 7a (15 g, 0.51 mol) in
dichloromethane (150 mL), cooled to 0 ºC was added dry
pyridine (42 mL, 0.51 mol) followed by triphenylphosphine
(22.7 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 room temperature for 6 h. The reaction
mixture was diluted with dichloromethane (100 mL), washed
with 2N HCl (2 × 150 mL), water (200 mL), brine solution
(175 mL), dried over anhydrous Na2SO4, filtered and evapo-
rated under vacuum. The crude compound was purified by
100-200 silica column chromatography (eluted with 10 % ethyl
acetate: pet ether) to obtain 8a (Yield: 16 g, 88 %; pale brown
viscous liquid); IR (DCM film, cm-1): 3003, 2930, 2856, 1733,
1584, 1470, 1437, 1267, 1111, 1074, 959, 748; 1H NMR (400
MHz; CDCl3): δ 7.26 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 7.2 Hz,
1H), 6.76 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.40
(t, J = 6.8 Hz, 2H), 2.53 (t, J = 8.0 Hz, 2H), 1.87-1.80 (m, 2H),
1.59-1.53 (m, 2H), 1.42-1.37 (m, 2H), 1.33-1.30 (m, 6H);
Mass: 357 (M+H)+ and 359 (M+2, 100).
Synthesis of (1R,5S,6s)-3-benzyl-3-azabicyclo[3.1.0]-
hexan-6-amine (12): To a solution of compound 11 (15 g,
68.8 mmol) in isopropanol (300 mL) was treated with 3N HCl
( 225 mL) and zinc dust (54 g, 825.68 mmol) was added slowly
portion wise over a period of 0.5 h and stirred at room tempe-
rature for 2 h. After completion of the reaction, the reaction
mass was slowly quenched with saturated NaHCO3 solution
(200 mL), stirred for 0.5 h, filtered the reaction mass through
celite pad, washed with dichloromethane (300 mL). Collected
the filtrate and the solvent was distilled out and the aqueous
layer was extracted with dichloromethane (2 × 100 mL). The
organic layer was washed with water, brine solution, dried
over anhydrous sodium sulphate, concentrated to dryness to
afford the compound 12 (10.0 g, semi pure) as an oil. The
crude compound was used as such in the next step without
any further purification.
Preparation of ethyl 2-(8-bromooctyl)-6-ethoxybenzoate
(8b): To a solution of 7b (15 g, 0.51 mol) in dichloromethane
(150 mL), cooled to 0 ºC 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
room temperature for 6 h. The reaction mixture was diluted
with dichloromethane (100 mL), washed with 2N HCl (2 ×
150 mL), water (200 mL), brine solution (175 mL), dried over
anhydrous Na2SO4, filtered and evaporated under vacuum. The
crude compound was purified by 100-200 silica column
chromatography (eluted with 10 % ethyl acetate: pet ether) to
obtain 8b (Yield: 14 g, 78 %; pale brown viscous liquid); IR
(DCM film, cm-1): 2979, 2930, 2857, 1728, 1584, 1462, 1268,
1110, 1070, 852, 763; 1H NMR (400 MHz; CDCl3): δ 7.22 (t,
J = 7.8 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.4 Hz,
1H), 4.39 (q, J = 7.2 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.52 (t,
J = 6.6 Hz, 1H), 3.39 (t, J = 6.8 Hz, 1H), 2.55 (t, J = 8.0 Hz,
2H), 1.87-1.71 (m, 2H), 1.60-1.54 (m, 2H), 1.42-1.25 (m, 14
H), Mass: 385 (M+H)+ and 387 (M+2, 100).
Synthesis of (1R,5S,6s)-3-benzyl-3-azabicyclo[3.1.0]-
hexan-6-ylcarbamate (13): To a solution of compound 12
(10 g, 53.19 mmol) in dry dichloromethane (100 mL) was
added (BOC)2O (14.86 g, 69.14 mmol) drop wise, followed
by addition of triethylamine (8.05 g, 79.78 mmol) at 0 ºC. The
contents were allowed to room temperature and stirred for
2 h. After completion of the reaction, solvent was distilled and
the residue was purified by silica gel column chromatography
using 15 % ethyl acetate-pet ether as an eluent to afford the
pure compound 13 (9.6 g, 72 %) as yellow colour solid. m.p.

990 Vempati et al.
Asian J. Chem.
129-132 ºC, IR (KBr, νmax, cm-1): 3369, 2796, 1688, 1518,
azabicyclo amine (compound 14) (5 mmol) at room temperature
and heated at 80 ºC for 4 h. Upon completion, the reaction
mixture filtered, concentrated and the residue was extracted
with EtOAc. The combined organic layer was washed with
water, brine solution, dried over anhydrous sodium sulfate,
concentrated to afford the crude amino compounds (17a and
17b). The crude compounds were taken to next step as such
without further purification.
1
1284, 1250, 1167, 850, 753 and 698; H NMR (400 MHz,
DMSO-d6): δ 7.29-7.20 (m, 5H), 4.59 (brs, 1H), 3.55 (s, 2H),
3.06 (d, J = 8.8Hz, 2H), 2.89 (m, 1H), 2.39 (d, J = 8.8 Hz,
2H), 1.39 (s, 9H), Mass: m/z: 289.2 (M+H)+.
Synthesis of tert-butyl (1R, 5S, 6s)-3-azabicyclo[3.1.0]-
hexan-6-ylcarbamate (14): To a solution of compound 13
(10 g, 34.72 mmol), in methanol (100 mL) was added Pd(OH)2
(1 g) and the reaction mixture was hydrogenated at 30 psi for
3 h. After completion of reaction, filtered the reaction mass
through celite bed and washed with methanol (100 mL). The
solvent was distilled under vaccum and isolated the crude
compound and thick mass. The crude mass was purified by
column chromatography using 3 % methanol/chloroform as
an eluent to get pure compound 14 (5.8 g, 84 %) as off-white
solid. m.p. 109-112 ºC; IR (KBr, νmax, cm-1): 3365, 2935, 1719,
Preparation of amino compounds (18a and 18b): To a
stirred solution of compound 17a or 17b in methanol was
added methanolic HCl solution and stirred at room temperature
for 6 h. Upon completion, the reaction mixture was concen-
trated and the residue was diluted with water, basified with
NaHCO3 solution, extracted with EtOAc (2 × 100 mL). The
combined organic layer was washed with water, brine solution,
dried over anhydrous sodium sulfate, concentrated to afford
the crude amino compounds methyl-2-(8-[(1R,5S,6s)-6-
amino-3-azabicyclo[3.1.0]hexan-3-yl]octyl-6-methoxyben-
zoate (18a) and ethyl-2-(8-((1R, 5S, 6s)-6-amino-3-azabicyclo
[3.1.0]hexan-3-yl)octyl-6-ethoxybenzoate (18b) as brown
colour viscous oils. Compound 18a: IR (DCM film, cm-1):
3368, 2929, 2855, 2789, 1730, 1588, 1462, 1267, 1109, 1072,
1
1690, 1529, 1249, 1164, 1050, 850 and 598; H NMR (400
MHz, DMSO-d6): δ 6.83 (brs, 1H), 3.07-2.82 (m, 4H), 2.23
(s, 2H), 1.58-1.55 (m, 2H), 1.42 (s, 9H); Mass: m/z: 199.1
(M+H)+.
Preparation of amino compounds (15a and 15b): To a
stirred solution of compound 5a (or) 5b (5 mmol) in acetonitrile
(10 vol) was added K2CO3 (15 mmol) and the solution of
azabicyclo amine (compound 14) (5 mmol) at room temperature
and heated at 80 ºC for 4 h. Upon completion, the reaction
mixture filtered, concentrated and the residue was extracted
with EtOAc. The combined organic layer was washed with
water, brine solution, dried over anhydrous sodium sulfate,
concentrated to afford the title compounds tert-butyl(1R,5S,6s)-
3-(2-methoxy-6-pentadecyl)-3-azabicyclo [3.1.0]hexan-6-
ylcarbamate (15a) and tert-butyl(1R, 5S, 6s)-3-(2-ethoxy-6-
pentadecyl)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate (15b) as
brown coloured oils. The crude compounds were taken to next
step as such without further purification.
1
838, 740; H NMR (400 MHz, CDCl3): 7.26 (t, J = 8.2 Hz,
1H), 6.81 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 3.90 (s,
3H), 3.81 (s, 3H), 3.05-3.00 (m, 1H), 2.52 (t, J = 7.6 Hz, 2H),
2.34-2.01 (m, 3H), 1.86-1.56 (m, 3H), 1.39-1.24 (m, 14H);
Mass: m/z 375 (M+H)+; 18b: IR (DCM film, cm-1): 3386, 2981,
2928, 2858, 2788, 1726, 1588, 1461, 1265, 1109, 1067, 851,
1
753; H NMR (400 MHz, CDCl3): 7.22 (t, J = 8.2 Hz, 1H),
6.79 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.39 (q, J1 =
7.2 Hz, J2 = 14.4 Hz, 2H), 4.03 (q, J1 = 6.8 Hz, J2 = 14.0 Hz,
2H), 3.15-3.03 (m, 1H), 2.54 (t, J = 7.6 Hz, 2H), 2.35-2.31
(m, 3H), 1.56-1.41 (m, 3H),1.39-1.25 (m, 17H); Mass: m/z
403 (M+H)+.
Preparation of amino compounds (16a and 16b): To a
stirred solution of compound 15a or 15b in methanol was
added methanolic HCl solution and stirred at room temperature
for 6 h. Upon completion, the reaction mixture was concen-
trated and the residue was diluted with water, basified with
NaHCO3 solution, extracted with EtOAc (2 × 100 mL). The
combined organic layer was washed with water, brine solution,
dried over anhydrous sodium sulfate, concentrated to afford
the pure amino compounds (1R,5S,6s)-3-(2-methoxy-6-
pentadecylbenzyl)-3-azabicyclo[3.1.0]hexan-6-amine
(16a) and (1R,5S,6s)-3-(2-ethoxy-6-pentadecylbenzyl)-3-
azabicyclo[3.1.0]hexan-6-amine (16b) as brown colour viscous
oils. Compound 16a: IR (dichloromethane film, cm-1): 3366,
Preparation of amino compounds (19a and 19b): To a
stirred solution of compound 18a or 18b (1.0 mmol) in a
mixture of THF and water (3:1) was added LiOH (1.0 mmol)
and heated to reflux temperature for 6 h. The THF was distilled
out and the aqueous layer pH was adjusted to 4 range and
extracted with EtOAc (2 × 100 mL). The combined organic
layer was washed with water, brine, dried over anhydrous
sodium sulfate, concentrated to dryness and the crude product
was purified by silica gel (100-200 mesh) column chromato-
graphy using ethyl acetate/pet ether as an eluent to afford the
pure compounds 2-(8-((1R, 5S, 6s)-6-amino-3-azabicyclo
[3.1.0]hexan-3-yl)octyl)-6-methoxybenzoic acid (19a) or
2-(8-[(1R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-
yl]octyl)-6-ethoxybenzoic acid 19b as thick brown coloured
oily mass. Compound 19a: IR (DCM film, cm-1): 3340, 2929,
2855, 1656, 1464, 1266, 1085, 840, 749; 1H NMR (400 MHz,
CDCl3): 11.10 (br s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 6.83 (d, J =
8.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 3.10-3.02
(m, 1H), 2.54 (t, J = 8.0 Hz, 2H), 2.38-1.99 (m, 3H), 1.84-
1.51 (m, 3H), 1.38-1.25 (m, 14H); Mass: m/z 361 (M+H)+;
19b: IR (DCM film, cm-1): 3344, 2926, 2851, 1655, 1462,
1267, 1089, 842, 750; 1H NMR (400 MHz, CDCl3): 11.2 (br
s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.72
(d, J = 8.4 Hz, 1H), 4.05 (q, J1 = 6.6 Hz, J2 = 13.8 Hz, 2H),
3.12-3.01 (m, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.34-2.29 (m,
1
2923, 2853, 1674, 1587, 1461, 1260, 1085, 754; H NMR
(400 MHz, CDCl3): δ 7.22-7.12 (m, 1H), 6.80-6.70 (m, 2H),
4.01-3.40 (m, 5H), 3.1-2.80 (m, 2H), 2.90-2.60 (m, 3H), 2.28-
1.25 (m, 28H), 0.87 (m, 5H); Mass: m/z 429.4 (M+H)+.; 16b:
IR (dichloromethane film, cm-1): 3455, 2923, 2855, 1670,
1
1587, 1458, 1389, 1255, 1095, 750; H NMR (400 MHz,
CDCl3): δ 7.23-7.07 (m, 1H), 6.81-6.67 (m, 2H), 4.01-3.40
(m, 4H), 2.90-2.60 (m, 6H), 2.28-1.25 (m, 30H), 0.87 (m, 5H);
Mass: m/z 443 (M+H)+.
Preparation of amino compounds (17a and 17b): To a
stirred solution of compound 8a (or) 8b (5 mmol) in acetonitrile
(10 vol) was added K2CO3 (15 mmol) and the solution of

Vol. 25, No. 2 (2013)
Synthesis of Azabicyclo[3.1.0]amine Analogues of Anacardic Acid as Potent Antibacterial Agents 991
OH
O
OR
O
O H
O
1
3H), 1.53-1.42 (m, 3H),1.36-1.24 (m, 17H); Mass: m/z 375
(M+H)+.
ii
iii
ia
ib
OH
OR
H
OH
2
The synthesis of the azabicyclo amine analogues of
anacardic acid (16a and 16b) was achieved by (i) Isolation
and subsequent saturation of the ene-mixture of anacardic acid
from commercially available CNSL (ii) Alkylation of the
phenolic hydroxyl group and esterfication of carboxylic acid
group (iii) Reduction of the ester to alcohol (iv) Transformation
of the alcohol to its mesylate (v) Coupling of mesylate
compound with azabicyclo[3.1.0]amine to afford the novel
azabicyclo analogues of anacardic acid (vi) cleavage of boc
protection to afford the free amine and screening for their
antibacterial activity as depicted Scheme-I.
C
H
C
C
H
15 29
15 29
15 29
1a-1d
6a
6b
(R & R ) = Me)
1
2
(R & R ) = Et)
1
2
OR
O
OR
O
1
1
iv
O R
2
OR
2
Br
OH
8a
8b
(R & R ) = Me)
1
2
7a
7b
(R & R ) = Me)
1
2
(R & R ) = Et)
1
2
(R & R ) = Et)
1
2
Reagents: (ia) Ca(OH)2, MeOH:H2O(5:1), 60 ºC, 3 h, (ib) 6 N HCl, (ii) Dim-
ethyl sulfate (or) Diethyl sulfate, K2CO3, Acetonitrile, 90 ºC, 24 h; (iii) a)
O3, MeOH:DCM (1:1), -78 ºC, 4 h (b) NaBH4, rt, 16 h ; (iv) CBr4, PPh3,
Pyridine, DCM, rt, 16 h
OH
O
OH
O
OH
O
ia
ib
ii
iii
Scheme-II
OH
OH
OH
C
H
15 29
C
H
15 29
C
H
15 31
with Borane. THF solution (iii) reduction of nitro group using
zinc dust and conc. HCl (iv) Protection of amine using Boc
anhydride (v) N-debenzylation using Pd(OH)2 and H2(g)
(Scheme-III).
1a-1d
2
OR
O
C
OR
1
1
OR
1
v
iv
O R
H
OH
2
OMs
The synthesis of the azabicyclo[3.1.0]amine analogues
of anacardic acid were achieved by (i) coupling of mesylate
compounds (5a and 5b) with compound 14 to afford the novel
azabicyclo analogues of anacardic acid (15a and 15b) (ii)
cleavage of boc protection to afford the free amines (16a and
16b) (Scheme-IV).
C
H
15 31
15 31
C
H
15 31
4a
3a
(R = Me)
1
(R & R = Me)
1
2
5a
(R = Me)
1
4b (R = Et)
3b (R & R = Et)
1
1
2
5b (R = Et)
1
Reagents: (ia) Ca(OH)2, MeOH:H2O(5:1), 60 ºC, 3 h, (ib) 6 N HCl, (ii) 10 %
Pd/C, H2, EtOH, 60 psi, rt, 2 h; (iii) (CH3)2SO4/(C2H5)2SO4, K2CO3, CH3CN,
80 ºC, 3 h (iv) LiAlH4, THF, 0 ºC-rt, 16 h (v) CH3SO2Cl, (C2H5)3N, CH2Cl2,
0 ºC-rt, 3 h
The synthesis of the azabicyclo[3.1.0]amine analogues
of anacardic acid (18a and 18b) were achieved by (i) coupling
of bromo derivatives of anacardic acid (8a and 8b) with comp-
ound 14 to afford the novel azabicycloamine analogues of
anacardic acid (17a and 17b) (ii) cleavage of boc protection
of 17a and 17b to afford the free amines 18a and 18b respec-
tively (iii) Hydrolysis of 18a and 18b to afford the carboxylic
acids (19a and 19b) (Scheme-V).
Scheme-I
Isolation of the anacardic acid ene-mixture (Fig. 1, 1a-d)
from commercially available cashew nut shell liquid was
carried out by treating with Ca(OH)2 in a MeOH-H2O mixture
at 50 ºC for 3 h followed by filtration of calcium anacardate as
a brown coloured solid. This solid was treated with 6 N HCl
to obtain the anacardic acid ene-mixture as a dark brown
coloured oily liquid. The ene-mixture was the saturated by
hydrogenolysis using Pd/C-H2 in EtOH under 60 psi of hydrogen
pressure at room temperature to afford the anacardic acid (2)
as a pale brown coloured solid which was then alkylated with
dimethylsulphate (or) diethylsulphate and K2CO3 in acetonitrile
at reflux temperature. The 2-methoxy methyl ester (or) ethoxy
ethyl ester of anacardic acid (3a or 3b) was reduced with
LiAlH4 in THF at room temperature for 16 h to afford the
corresponding benzyl alcohol (4a or 4b), which was then trans-
formed to its methane sulfonate esters (5a or 5b) by treatment
with methane sulfonyl chloride and triethylamine in dichloro-
methane at 0 ºC (Scheme-I).
RESULTS AND DISCUSSION
To generate the lead molecules compounds 5a, 5b, 8a
and 8b compounds were coupled with azabicyclo[3.1.0]amine
(14) to afford novel azabicyclo[3.1.0]amine analogues of
anacardic acid to afford compounds 16a, 16b, 18a and 18b.
Compounds 18a and 18b were hydrolyzed to afford compounds
19a and 19b.
In order to evaluate the antibacterial activity, compounds
16a, 16b, 18a, 18b, 19a and 19b were screened for in vitro
activity against S. aureus and S. pyogens (Gram positive (G
+ve)) and E. coli and P. aeruginosa (Gram negative (G -ve))
groups of bacteria.
The synthesis of bromo derivatives of anacardic acid (8a
and 8b) were achieved by i) Isolation of ene-mixture of anacardic
acid from commercially available CNSL; ii) Alkylation of the
phenolic hydroxyl group and esterfication of carboxylic acid
group; (iii) a) Ozonolysis of alkene (ene-mixture) to afford
the C-8 aldehyde b) reduction of aldehyde to alcohol (in situ)
(iv) Transformation of the alcohol to its bromo derivative
(Scheme-II).
The compounds 16a, 16b, 18a, 18b, 19a and 19b 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 was 7.4.After
18 h the exponentially growing cultures of the bacteria in
nutrient broth at 37 ºC were diluted in sterile broth. From each
of these diluted cultures, 1 mL was added to 100 mL of steri-
lized and cooled nutrient agar media to give the final bacterial
count of 1 × 106 cell/ml. Paper discs (6 mm, punched from
Whatmann no. 41 paper) were ultraviolet and used for assays.
Discs were soaked in different concentrations of the test
The azabicyclo[3.1.0]amine was synthesized as per the
reported procedures17 as depicted in Scheme-III. The synthesis
of azabicyclo amine was achieved by (i) treatment of N-benzyl
maleimide with bromonitromethane (ii) reduction of Imide

992 Vempati et al.
Asian J. Chem.
O
O
H
H
H
H
(iii)
O
O
O
O
(ii)
(i)
Ph
N
N
N
N
N
Ph
Ph
O
O
9
11
10
H
H
H
H
H
H
(v)
(iv)
N
NH2
HN
NH
O
N
NH
Ph
Ph
O
O
O
14
13
12
Reagents: (i) Bromonitromethane, K2CO3, Acetonitrile, rt, 4 h; (ii) Borane THF complex, THF, 65 ºC, 3 h; (iii) Zn dust,
1N HCl, Isopropyl alcohol, rt, 2 h; (iv) (BOC)2O, TEA, DCM, 0 ºC-rt, 4 h; (v) Pd(OH)2, H2, EtOH, rt, 50 psi, 4 h
Scheme-III
O
O
H
H
HN
N
O
O
H
HN
NH
14
H
OR1
OR1
Triethylamine,
acetonitrile, 85 °C, 3h
OMs
5a
(R1 = Me)
5b (R1 = Et)
15a
(R1 = Me)
15b (R1 = Et)
NH2
H
H
OR1
N
HCl (g) in MeOH,
r.t, 12 h
16a
(R1 = Me)
16b (R1 = Et)
Scheme-IV
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 samples were taken in
triplicates. The plates were incubated at 37 ºC in an inverted
fashion. Activity was determined by measuring the zones
showing the inhibition (mm). Growth inhibition was calcu-
lated with reference to positive control.
and compounds 18a and 18b have shown inferior activity.
Similarly, when the compounds were screened against P.
aeruginosa, almost all the compounds displayed moderate
activity compared to ampicillin and other standard drugs.
On screening against S. aureus, 16a, 16b, 19a and 19b
have displayed at par activity with ampicillin and 18a and
18b displayed moderated activity. Similarly, when the
compounds were screened against P. aeruginosa, almost all
the compounds displayed moderate activity compared to ampi-
cillin and other standard drugs and the in vitro results are
summarized in Table-1.
When the compounds were screened against E. coli mole-
cules 16a and 16b displayed very good activities (15 mm zone
of inhibition) at par with ampicillin while other molecules 19a
and 19b exhibited moderate activity (14 mm zone of inhibition)

Vol. 25, No. 2 (2013)
Synthesis of Azabicyclo[3.1.0]amine Analogues of Anacardic Acid as Potent Antibacterial Agents 993
O
H
O
HN
NH
14
H
OR1
O
OR1
O
Triethylamine,
acetonitrile, 85 °C, 3h
OR2
OR2
H
O
Br
N
O
N
H
8a (R1 & R2 = Me)
8b
(R1 & R2 = Et)
17a (R1 & R2 = Me)
17b
(R1 & R2 = Et)
H
OR1
O
OR1
O
LiOH
OH
H+
OR2
H
H
N
N
NH2
NH2
19a (R1 = Me)
19b
(R1 = Et)
H
18a (R1 & R2 = Me)
18b
(R1 & R2 = Et)
H
Scheme-V
TABLE-1
ANTIMICROBIAL ACTIVITY OF COMPOUNDS ANTIMICROBIAL ACTIVITY (ZONE OF INHIBITION IN mm)
Zone of inhibition (mm)
Compd.
No.
Structure
Staphycoccous
aureus
Streptococcus
pyogens
Escherichia
coli
Pseudomonas
aeruginosa
NH2
H
H
16a
16b
13
13
12
12
15
15
12
12
O
N
NH2
H
H
O
N
O
O
O
H
18a
18b
11
11
13
13
12
12
11
11
N
NH2
H
O
O
O
H
N
NH2
H
O
O
OH
H
19a
19b
13
13
12
12
14
14
13
13
N
NH2
H
O
O
OH
H
N
NH2
H
Ampicillin
13
14
19
22
14
13
19
19
15
17
23
25
15
17
23
19
Chloramphenicol
Ciprofloxacin
Norfloxacin
Zone of inhibition (DMSO as solvent); standard drugs: Ampicillin, Chloramphenicol, Ciprofloxacin, Norfloxacin.

994 Vempati et al.
Asian J. Chem.
7. R. Paramshivappa, P.P. Kumar, P.V.S. Rao and A.S. Rao, J. Agric. Food
Chem., 50, 7709 (2002).
Conclusion
Novel azabicyclo[3.1.0]amine analogues of anacardic acid
8. (a) P.P. Kumar, R. Paramshivappa, P.V.S. Rao and A.S. Rao, PCT WO
105854 A2 (2003). (b) P.P. Kumar, R.Paramshivappa, P.V.S. Rao and
A.S. Rao, PCT WO 062201 A1 (2003).
were synthesized and screened for their antibacterial activity.
Few analogues displayed activities at par withAmpicillin and
all the analogues displayed moderate activity compared to other
standard drugs.
9. B.N. Swamy, T.K. Suma, C.V. Rao and G.C. Reddy, Eur. J. Med. Chem.,
42, 420 (2007).
10. D.J. Schultz, C. Olsen, G.A. Cobbs, N.J. Stolowich and M.M. Parrott,
J. Agric. Food Chem., 54, 7522 (2006).
ACKNOWLEDGEMENTS
11. B. Sung, K.P. Manoj, K.S. Ahn, T. Yi, M.M. Chaturvedi, M. Liu and
B.B. Agarawal, Blood, 111, 4880 (2008).
The author thank GVKBIO Sciences Pvt. Ltd. for financial
support. Thanks are also due to Dr. Balaram Patro, Dr. Joseph,
Dr. Ravi Kumar for their constant support and encouragement.
12. I. Kubo, M. Ochi, P.C. Viera and S. Komastu, J. Agric. Food Chem.,
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A. Reddy, S. Roy, K.S. Rangappa and T.K. Kundu, J. Med. Chem., 51,
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