Syntheses and biological evaluation of alkanediamines as antioxidant and hypolipidemic agents

Article abstract of DOI:10.1016/S0968-0896(01)00185-7

A new series of compounds belonging to N,N′- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2-5a-f) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for hypolipidemic activity.

Full text of DOI:10.1016/S0968-0896(01)00185-7

Bioorganic & Medicinal Chemistry 9 (2001) 3093–3099
Syntheses and Biological Evaluation of Alkanediamines
as Antioxidant and Hypolipidemic Agents§
Sanjay Batra,a,* Amiya P. Bhaduri,a Bhawani S. Joshi,b Raja Roy,b
Ashok K. Khannac and Ramesh Chanderc
aMedicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bRSIC Division, Central Drug Research Institute, Lucknow 226 001, India
cBiochemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 18October 2000; accepted 10 February 2001
Abstract—A new series of compounds belonging to N,N0- [bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2–5a–f)
have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven
compounds namely 2c, 2e, 4c, 5b, 5c, 5e and 5f exhibit potent antioxidant activity. These compounds have also been evaluated for
hypolipidemic activity. # 2001 Elsevier Science Ltd. All rights reserved.
Atherosclerosis and its thrombotic complications, which
has been the major cause of coronary artery disease, is
associated with elevated levels of serum cholesterol and
low density lipoproteins along with free radical oxida-
tive stress. It is now well documented that the low den-
sity lipoprotein (LDL) cholesterol, which has undergone
ities. The details of their synthesis and biological activ-
ity are reported herein.
Chemistry
.
oxidative damage due to the hydroxyl radicals ( OH)
The synthesis of various diamines is outlined in Scheme
1. The starting substrates 1 a–f were obtained as repor-
ted earlier.4 These compounds, on reaction with various
1,n-diamines (where n=2, 3, 4 and 8) in the presence of
boron trifluoride etherate, furnished the diamino deri-
vatives 2–5a–f. The structure of these products was
established on the basis of Hetero multiple bond corre-
lation (HMBC) and Heteromultiple Quantum COSY
experiments. These compounds could also be obtained
by reacting the bromo derivatives 6a–f with appropriate
diamines as described earlier.3
generated by the alterations in the oxidation states of
metal ions, mainly iron and copper, is relatively more
atherogenic than the native LDL.2 Therefore, it is envi-
saged that, beside a cholesterol lowering property, a
hypolipedimic agent that incorporates antioxidant
activity will be able to protect endothelial and myo-
cardial function and would be a better antiathero-
sclerotic agent. With an objective to explore newer
molecular structures for such activity, we have earlier
reported the synthesis and biological evaluation of 3-
amino and substituted amino-1-aryl-6-hydroxy-hex-2-
ene-1-ones.3 In our continued efforts to further modify
these molecules, it was envisaged that, instead of a pri-
mary amine, if a diamine is used it may result in 1-aryl-
6-hydroxy-hex-2-ene-1-one moiety on both the ends of
the amine, thereby resulting in a better activity profile.
Indeed, it was observed that some of the N,N0- [bis (1-aryl-
6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkanediamines (2–
5a–f) show potent antioxidant and hypolipidemic activ-
Antioxidant activity
Oxidation of low-density lipoprotein by Cu2+. Human
serum was separated from the blood of normolipidemic
donors who have been fasted overnight. LDL was iso-
lated by sequential ultracentrifugation using Beckman
ultra-centrifuge model LE-80K.5 LDL preparation (d,
1.063) was dialyzed against 0.15 M NaCl solution con-
taining EDTA (0.02% w/v) in cold and the purity was
checked by polyacrylamide gel electrophoresis. LDL
(0.71 mg) and CuCl2. 2H2O (10 mM) in the absence or
presence of test compounds (2.5 or 5 mmol/mL) listed in
§CDRI Communication No. 6102 (see ref. 1).
*Corresponding author. Tel.:+091-522-212411-18(EPBAX 436,8
4383); fax: +91-522-224305, 223938; e-mail: batra_san@yahoo.co.uk,
root@cscdri.ren.nic.in
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00185-7

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S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
Scheme 1. Reagents and conditions: (a) BF3. Et2O, 1,n-alkanediamine, dry diethylether/dichloromethane (50:50, v/v), 8–24 h; (b) 1,n-alkanediamine,
methanol, steel bomb, 2–3 h.
Table 1 in 0.05 M phosphate buffer (pH 7.4) to a final
volume of 1.5 mL, was incubated at 37 ꢀC for 90 min.
The lipid peroxidation products in oxidized LDL, oxi-
dized LDL with Cu2+ in the absence or presence of test
compounds was assayed as thiobarbituric acid reactive
substances (TBARS).6 Briefly, the incubation mixture
was added 0.5 mL SDS (8% w/v), 0.5 mL glacial acetic
acid and 1.5 mL TBA (0.8% w/v) in the above sequence
with stirring each time at room temperature. This reac-
tion mixture was heated in a boiling water bath in the
dark for 30 min. The tubes were cooled, pink coloured
chromogen was extracted with 8mL of mixture of n-
butanol/pyridine (7:1 v/v) and the optical density was
measured on a spectrophotometer at 532 nm against a
reagent blank. An appropriate standard of mal-
onaldehyde (MDA) was tested simultaneously.
contents in both sets were measured by TBA method.6
The influence of the test substances on the formation of
lipid peroxides was calculated after subtracting the
values of reference tubes from those of their respective
experimental values.
Hypolipidemic activity
Adult male Charles Foster rats (200–225 g) bred in the
animal house of the institute were divided in control,
triton and triton plus drug treated groups containing six
rats in each. Triton WR-1339 (Sigma, USA) was admi-
nistered (200 mg/kg b.wt.) by intraperitoneal injection.
The compounds 2c, 2e, 4c, 5b, 5c, 5e and 5f and guggu-
lipid were macerated with 2% aqueous gum acacia sus-
pension and fed orally (100 mg/kg b.wt.) simultaneously
with triton. At the end of the experiment, rats were fas-
ted overnight and blood was withdrawn from retro-
orbital plexus. Serum was separated by centrifugation at
low speed and assayed for total cholesterol (TC), phos-
pholipid (PL) and triglycerides (Tg) by the standard
procedure reported earlier.3 The compounds 2c and 2e
showing significant lipid lowering activity were further
tested in the above test model for assay of post heparin
lipolytic activity (PHLA).8 At the end of the experiment
before withdrawal of blood, rats were given intrave-
nously heparin solution in normal saline (10 mg/kg
b.wt.) through the tail vein. After 15 min, blood was
Generation of hydroxyl radicals and degeneration of
ꢁ
deoxyribose. The OH were generated in a non-enzymic
ꢁ
system comprising of FeSO4 H2O (2 mM), EDTA
(2 mM), sodium ascorbate (2 mM), H2O2 (2.8mM),
deoxyribose (2.8mM) added with the test drugs (1, 2 or
5 mmol) and probucol in 0.05 M KH2PO4–KOH buffer
(pH 7.4) made up to the final volume of 2 mL.7 The
reaction mixture was incubated at 37 ꢀC for 90 min.
Similarly separate tubes containing the above reagents
ꢁ
for generation of OH and various concentrations of
test samples to serve as corresponding references. MDA

S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
3095
withdrawn and collected in a tube containing 0.1 mL
sodium citrate solution (380 mg/ml w/v) for 0.9 mL of
blood. After 20 min in cold, blood was centrifuged and
plasma was used for assay of PHLA. The reaction mix-
ture containing 0.2 mL plasma, 0.01 mL intralipid
emulsion (Vitram Chemico, Stockholm, Sweden),
1.0 mL BSA (2.5%) in 0.1 Tris–HCl buffer (pH 7.4) to a
final volume of 2.0 mL was incubated at 37 ꢀC for
90 min. The amount of fatty acid released was mea-
sured. Protein was estimated by the method of reported
in the literature.9
model in rats, which has also been reported simul-
taneously in Table 1.
Effect of compounds on generation of hydroxyl radical in
vitro
The most active compounds were further tested against
the generation of hydroxyl radicals in non-enzymic sys-
tem of Fe2+, sodium ascorbate and H2O2. Addition of
the above compounds at 1.0, 2.5 and 5.0 mmol/mL into
the above reaction mixture inhibited the formation of
hydroxyl radicals in concentration-dependent manner
and their antioxidant potential corresponded with that
of the LDL oxidation when compared individually.
However, only compounds 4c, 5b, 5e and 5f show com-
parable IC50 values to that of probucol, while all the
others had higher IC50 values as shown in Table 2.
Results
Primary screening of compounds for antioxidant and
lipid lowering activities
It has been already reported earlier3 that the oxidation
of LDL in the presence of Cu2+ caused a marked for-
mation of lipid peroxides. All the test compounds when
added to this reaction mixture at 2.5 and 5 mmol/mL
concentration protected the Cu2+ mediated oxidation
of lipids to varying extents as shown in Table 1. Of all
the test compounds, 2c, 2e, 4c, 5b, 5c, 5e and 5f sig-
nificantly inhibited this oxidation. These potent anti-
oxidants were further tested for their cholesterol
lowering activity at the dose of 100 mg/kg po in triton
Effect of compounds in Triton induced hyperlipidemia in
rats
The data in Table 3 showed that the administration of
Triton WR-1339 increased the animal plasma level of
TC, PL and Tg by 3.9-, 2.06- and 1.94-fold, respectively,
followed by a 42% reduction (inhibition) of PHLA
activity. Oral feeding of the abovementioned com-
pounds and guggulipid (a positive control) at the dose of
100 mg/kg simultaneously with Triton caused lowering
Table 1. Screening of compounds for antioxidant and lipid lowering activitya,b
Compound no.
Inhibition of oxidized-LDL
5 mM
Cholesterol lowering activity (% decrease) in
triton model in rats (dose 100 mg/kg)
2.5 mM
Probucol
Guggulipidc
58Æ3.80**b
NA
72Æ6.75***
NA
32Æ2.26**
35Æ1.90**
15Æ4.8
16Æ5.5
31Æ3.85
17Æ2.2
30Æ4.08
15Æ3.52
20Æ2.5
17Æ6.9
19Æ6.4
17Æ4.6
11Æ3.7
14Æ5.5
10.26Æ3.18
11Æ1.7
22Æ4.0
11Æ0.22
17Æ1.01
12Æ2.21
—
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
5a
5b
5c
5d
5e
5f
33Æ2.58*
17Æ3.88NS
46Æ1.85*
34Æ0.60NS
55Æ4.18**
53Æ4.95*
24Æ2.25NS
—
49Æ1.87**
22Æ1.25*
68Æ1.45***
52Æ0.42*
77Æ4.90***
68Æ2.87**
38Æ3.75*
—
2Æ0.98NS
15Æ1.71NS
23Æ4.08NS
11Æ1.51NS
21Æ1.53*
44Æ3.25*
51Æ1.31*
35Æ0.53NS
22Æ0.94*
50Æ2.26*
70Æ1.54***
3Æ0.27NS
10Æ0.60NS
8Æ0.48NS
—
NS
13Æ1.94
24Æ2.48NS
60Æ2.12***
2Æ0.32NS
3Æ0.36NS
2Æ0.21NS
—
62Æ3.69**
44Æ1.53**
—
74Æ1.66***
61Æ4.04***
—
24Æ1.85
25Æ4.20
—
53Æ0.94**
82Æ0.214.04***
19Æ2.55
52Æ2.95**
71Æ1.20***
22Æ3.05
aThe percent reversal and its significance against protection of LDL oxidation was deduced by comparing the values of n mol MDA formed/ mg
proteinÆS.D. of four separate observations with LDL in absence or presence of test compounds. Similarly cholesterol lowering activity and its
significance was deduced by comprising the levels of cholesterolÆS.D. of six hypolipidemic rats in both; with drug and without drug treatment
groups.
bP*<0.5; **<0.01; ***<0.001; NS, not significant.
c0.5 and 1.0 mg/mL.

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S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
Table 2. Inhibition of .OH generation by compounds
Compound no.
% inhibition by concn used (mM)
2.5
IC50
1.0
5.0
2c
2e
4c
5b
5c
5e
15Æ3.0
47Æ5.3
43Æ2.2
43Æ3.2
30Æ0.3
19Æ3.5
43Æ2.1
40Æ5.862
46Æ5.2
55Æ4.0
61Æ2.2
62Æ1.0
44Æ1.5
53Æ1.0
61Æ3.870
Æ5.9
68Æ7.83.4
77Æ9.5
70Æ1.5
74Æ2.1
61Æ7.4
82Æ1.0
Æ1.5
3.2
1.6
1.5
3.0
1.9
1.6
1.6
5f
Probucol
74Æ6.2
The percent inhibition and its significance against generation of .OH was deduced by comparing the values of n mol MDA formed/h Æ S.D. of four
separate observation with OH formed in the absence or presence of test compounds.
Table 3. Lipid lowering activity of test compounds in triton induced hyperlipidemic rats
Test compounds
Total cholesterola
Phospholipida
Triglyceridea
PHLA activityb
Control
Triton fed
87.30Æ7.85
80.55Æ9.00
92.18Æ11.52
253.05Æ20.7
278.73Æ29.39***
166.18Æ5.80***
179.30Æ9.75***
145.67Æ19.8***(R=-42%)
Triton+2c
Triton+2e
Triton+2f
Triton+4c
Triton+5b
Triton+5c
Triton+5e
Triton+5f
Triton+Guggulipid
165.49Æ12.77***(40.59)
167.21Æ11.66***(40.01)
196.58Æ14.90***(29.47)
234.83Æ21.91*(15.75)
221.99Æ24.12**(20.35)
220.28Æ21.71**(20.97)
239.03Æ24.35NS(14.24)
228.47Æ11.54*(18.03)
181.17Æ17.45***(35.00)
120.65Æ8.81**(27.39)
121.11Æ7.66**(27.12)
146.00Æ11.21NS(12.14)
124.15Æ9.66**(25.29)
107.99Æ5.33***(35.01)
109.53Æ10.09***(36.49)
134.33Æ11.78*(19.16)
120.45Æ7.68**(27.51)
114.66Æ10.42***(31.25)
126.66Æ10.00***(29.35)
123.88Æ7.96***(30.90)
158.44Æ8.77***(16.09)
129.71Æ8.97**(27.65)
131.32Æ13.39**(26.75)
131.23Æ9.10**(26.80)
136.85Æ8.38**(23.67)
129.04Æ8.60**(28.03)
116.00Æ19.30***(35.30)
210.05Æ8.76(R=60%)
203.00Æ10.29(R=53%)
—
—
—
—
—
—
218.51Æ7.09(R=68%)
Values are mean Æ S.D. of six rats. Triton fed group was compared with control and triton plus compound treated. P*<0.05; **<0.01; ***,0.001; NS
,
not significant.
amg/dl.
bmmol FFA/h/dl.
of plasma lipids to varying extents. Compounds 2c and
2e showed significant lowering of TC by 40%, PL by
27% and Tg by 29–31%. The plasma of the hyperlipi-
demic animals treated with compounds 2c and 2e and
guggulipid was further analyzed for PHLA activity and
it was found that these compounds potentially reacti-
vated the enzyme activity by 53 and 60%, respectively,
though these were lower than that observed by gugguli-
pid (68%).
possessing substituted amino octyl amino skeleton in
this series of compounds show better antioxidant activ-
ity than their corresponding amino ethyl amino analo-
gues, the lipid lowering activity is associated only with
compounds having an amino ethyl amino skeleton. This
further endorses our earlier findings that in this series of
compounds amino ethyl amino group elicit better bio-
logical response. To further investigate the possible
mode of action of these synthetic derivatives, we have
assayed the PHLA in experimental hyperlipidemia
induced by Triton. Triton caused lowering of PHLA by
42% that was shown to be reactivated by the test com-
pounds. It is remarkable that lowering of lipids was
directly related with stimulation of PHLA activity in
drug treated hyperlipidemic animals. Triton is known to
inhibit lipoprotein lipase activity by the modification of
the circulatory lipids such that the enzyme can no longer
act.10 It has also been reported that the main cause of
Triton hyperlipidemia is coating of the plasma lipopro-
teins by Triton, resulting in their faulty catabolism by
preventing the occurrence of the interaction between
lipid and lipoprotein lipases in the body.11 Thus, it is
presumed that these compounds may be acting both by
the modification of lipids as well as stimulation of lipa-
ses under experimental conditions.
Discussion
Since the major aim of the present study was to further
optimize the lead obtained from earlier reported 1,3-
hexanedione derivatives, in the first instance all the
compounds were screened for in vitro antioxidant
activity against Cu2+-induced LDL oxidation as
described earlier. Of all the test compounds, 2c, 2e, 4c,
5b, 5c, 5e and 5f exhibited potent prevention against the
Cu2+-induced LDL oxidation. However, the IC50 of
compounds 4c, 5b, 5e and 5f were only comparable to
that of the standard, namely probucol, but as we were
interested in compounds with antioxidant as well as
hypolipidemic activity, all potent antioxidants were
evaluated for their cholesterol lowering property in Tri-
ton-induced hyperlipidemia. Out of all the test com-
pounds only compounds 2c and 2e showed promising
activity while no other compound elicited significant
biological response. The analysis of the structure–activ-
ity relationship indicates that, although compounds
Conclusion
The synthesis and biological evaluation of various N,N0-
[bis (1-aryl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,n-alkane-

S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
3097
diamines included in the present study represent the
extension of our earlier work on 1,3-hexanedione
derivatives. The preliminary biological screening data of
these compounds endorse our earlier findings that the
amino ethyl amino moiety is an optimum requirement
to generate both antioxidant and hypolipidemic activity
in this series of compounds.
C28H36N2O4 C, 72.37, H, 7.80, N, 6.02. Found C, 72.44,
H, 7.64, N, 6.12%.
N,N0- [bis (1-(4-Methoxylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 2-ethanediamine (2c). (54%, 148–149 ꢀC):
1
IR (KBr) 3410, 1588 cmÀ1; H NMR (CDCl3) d 1.78
(m, 4H, 2ÂCH2), 2.48(t, 4H, J=8Hz, 2 ÂCH2), 3.60
(m, 4H, J=6 Hz, 2ÂCH2OH), 3.68(m, 4H, 2 ÂNH–
CH2), 3.82 (s, 6H, 2Ar–OCH3), 5.68(s, 2H, 2 Â=CH),
7.26, 7.31 (d, 4H, J=8 Hz, Ar–H), 7.78, 7.82 (d, 4H,
J=8Hz, Ar–H); Mass (FAB) 496 (M +). Anal. calcd for
C28H36N2O6 C, 67.72, H, 7.30, N, 5.64. Found C, 67.41,
H, 7.39, N, 5.39%.
Experimental
Melting points are uncorrected and were determined in
capillary tubes on a hot stage apparatus containing sili-
con oil. IR spectra were recorded using a Shimadzu
FTIR-8201PC spectrophotometer. 1H NMR spectra
were recorded on a Bruker Avance DRX-300 or Bruker
DPX-200 FT spectrometers, using TMS as an internal
standard (chemical shifts in d values, J in Hz). The
FABMS were recorded on JEOL/SX-102 spectrometer.
Elemental analyses were performed by a Carlo Erba
1108microanalyzer. Basic aluminum oxide (100 mesh,
pH 9.5) was used for column chromatography of var-
ious amines.
N,N0 - [bis (1- (4-Fluorophenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 2-ethanediamine (2d). (77%, 150–151 ꢀC):
;
IR (KBr) 3408, 1572 cmÀ1 1H NMR (CDCl3) d
1.80 (m, 4H, 2ÂCH2), 2.51 (t, 4H, J=8Hz,
2ÂCH2), 3.62 (m, 4H, J=6 Hz, 2ÂCH2OH), 3.73
(m, 4H, 2ÂNH–CH2), 5.67 (s, 2H, 2Â=CH), 7.01
(t, 4H, J=10 Hz, Ar–H), 7.82 (dd, 4H, J=6 Hz, Ar–
H); Mass (FAB) 472 (M+). Anal. calcd for
C26H30F2N2O4 C, 64.99, H, 6.29, N, 5.83. Found C,
65.26, H, 6.36, N, 5.70%.
General method for preparation of N,N0- [bis (1-aryl-6-
hydroxy-hex-2-ene-1-one-3-yl) 1, n-alkanediamines
N,N0- [bis (1-(4-Chlorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 2-ethanediamine (2e). (58%, 180–181 ꢀC): IR
1
Method A. To a stirred solution of appropriate com-
pound from 1a–e (5 mmol) in 25 mL of dry ether was
added boron trifluoride etherate (0.13 mL, 10 mmol) at
room temperature. After 15–25 min, solid separates out
to which was added dropwise a solution of suitable
diaminoalkane (10 mmol) in 20 mL of dichloromethane
with stirring at 0 ꢀC (maintained by ice–salt mixture).
The reaction was allowed to stir at room temperature
for 8–10 h. On completion the excess solvent was eva-
porated and the reaction mixture was extracted with
ethyl acetate (2Â50mL). The organic layers were com-
bined, dried over sodium sulphate and evaporated to yield
a residue, which upon trituration with cold dry diethyl-
ether or purification using column chromatography over
basic alumina using chloroform/methanol (249:1,v/v) as
eluent yielded the diaminoalkane derivatives.
(KBr) 3434, 1592 cmÀ1; H NMR (CDCl3) d 1.79 (m,
4H, 2ÂCH2), 2.51 (t, 4H, J=8Hz, 2 ÂCH2), 3.62 (m,
4H, J= 6 Hz, 2ÂCH2OH), 3.72 (m, 4H, 2 NH–CH2),
5.68(s, 2H, 2 Â=CH), 7.37, 7.41(d, 4H, J=8Hz, Ar–
H), 7.74, 7.78(d, 4H, J=8Hz, Ar–H); Mass (FAB) 504,
506 (M+). Anal. calcd for C26H30Cl2N2O4 C, 61.78, H,
5.98, N, 5.54. Found C, 62.05, H, 5.69, N, 5.72%.
N,N0-[bis (1- (4-Bromophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 2-ethanediamine (2f). (62%, 183–184 ꢀC): IR
1
(KBr) 3434, 1592 cmÀ1; H NMR (CDCl3) d 1.78(m,
4H, 2ÂCH2), 2.55 (t, 4H, J=8Hz, 2 ÂCH2), 3.61 (m,
4H, J=6 Hz, 2ÂCH2OH), 3.74 (m, 4H, 2ÂNH–CH2),
5.68(s, 2H, 2 ¼CH), 7.50, 7.54 (d, 4H, J=8Hz, Ar–
H), 7.67, 7.71 (d, 4H, J= 8Hz, Ar–H); Mass (FAB)
592, 596 (M+). Anal. calcd for C26H30Br2N2O4 C,
52.54, H, 5.09, N, 4.71. Found C, 52.33, H, 5.07, N,
4.57%.
Method B. As described in method A of ref 3.
N,N-[bis(1-Phenyl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,2-
ethanediamine (2a). (85%, 133–134 ꢀC): IR (KBr) 3432,
N,N0-[bis(1-Phenyl-6-hydroxy-hex-2-ene-1-one-3-yl)-1,3-
propanediamine (3a). (72%, 143–144 ꢀC): IR (KBr)
1
1654 cmÀ1; H NMR (CDCl3) d 1.79 (m, 4H, 2ÂCH2),
3406, 1594 cmÀ1 1H NMR (CDCl3) d 1.77 (m, 4H,
;
2.52 (t, 4H, J= 8Hz, 2 ÂCH2), 3.62 (m, 8H, 2ÂNH–
CH2 and 2ÂCH2OH), 5.73 (s, 2H, 2Â=CH), 7.38(m,
6H, Ar–H), 7.81 (m, 4H, Ar–H); Mass (FAB) 436
(M+). Anal. calcd for C26H32N2O4 C, 71.53, H, 7.38, N,
6.41. Found C, 71.51, H, 7.56, N, 6.39%.
2ÂCH2), 2.04 (m, 2H, CH2), 2.52 (t, 4H, J=8Hz,
2ÂCH2), 3.65 (m, 8H, 2ÂNH–CH2 and 2ÂCH2OH),
5.74 (s, 2H, 2¼CH), 7.39 (m, 6H, Ar–H), 7.82 (m, 4H,
Ar–H); Mass (FAB) 450 (M+). Anal. calcd for
C27H34N2O4 C, 71.97, H, 7.60, N, 6.21. Found C, 72.21,
H, 7.51, N, 5.95%).
N,N0 - [bis (1-(4-Methylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 2-ethanediamine (2b). (65%, 160–161 ꢀC):
IR (KBr) 3384, 1566 cmÀ1; 1H NMR (CDCl3) d 1.77 (m,
4H, 2ÂCH2), 2.42 (s, 6H, 2ÂAr-CH3), 2.50 (t, 4H,
J=8ÂHz, 2ÂCH2), 3.57 (m, 4H, J=6 Hz, 2ÂCH2OH),
3.70 (m, 4H, 2ÂNH-CH2), 5.61 (s, 2H, 2¼CH), 7.17,
7.21 (d, 4H, J=8Hz, Ar–H), 7.70, 7.74 (d, 4H, J=8Hz,
Ar–H); Mass (FAB) 464 (M+). Anal. calcd for
N,N0 - [bis (1-(4-Methylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 3-propanediamine (3b). (70%, oil): IR (neat)
3376, 1606 cmÀ1 1H NMR (CDCl3) d 1.79 (m, 4H,
;
2ÂCH2), 2.06 (m, 2H, CH2), 2.37(s, 6H, 2ÂAr–CH3),
2.44 (t, 4H, J=8Hz, 2 ÂCH2), 3.67 (m, 8H, 2ÂNH–CH2
and 2ÂCH2OH), 5.72 (s, 2H, 2Â=CH), 7.18, 7.22 (d,
4H, J=8Hz, Ar-H), 7.72, 7.76 (d, 4H, J=8Hz, Ar–H);

3098
S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
Mass (FAB) 478(M +). Anal. calcd for C29H38N2O4 C,
72.77, H, 7.80, N, 6.02. Found C, 72.44, H, 7.64, N,
6.12%.
C30H40N2O4 C, 73.14, H, 8.18, N, 5.68. Found C, 73.44,
H, 7.94, N, 5.62%.
N,N0-[bis (1-(4-Methoxylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 3-butanediamine (4c). (59%, 148–149 ꢀC):
IR (KBr) 3430, 1584 cmÀ1; 1H NMR (CDCl3) d 1.84 (m,
8H, 2ÂCH2), 2.35 (t, 4H, J=8Hz, 2 ÂCH2), 3.43 (m,
4H, 2ÂNH–CH2), 3.67 (t, 4H, J=6 Hz, 2ÂCH2OH),
3.83 (s, 6H, 2ÂAr–OCH3), 5.64 (s, 2H, 2¼CH), 6.87,
6.91 (d, 4H, J=8Hz, Ar–H), 7.79, 7.83 (d, 4H, J=8Hz,
Ar–H); Mass (FAB) 524 (M+). Anal. calcd for
C30H40N2O6 C, 68.67, H, 7.68, N, 5.33. Found C, 69.44,
H, 7.57, N, 5.49%.
N,N0- [bis (1-(4-Methoxylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 3-propanediamine (3d). (50%, 121–122 ꢀC):
IR (KBr) 3390, 1582 cmÀ1; 1H NMR (CDCl3) d 1.78(m,
4H, 2ÂCH2), 2.04 (m, 2H, CH2), 2.49 (t, 4H, J=8Hz,
2ÂCH2), 3.60 (m, 8H, 2ÂNH–CH2 and 2ÂCH2OH),
3.83 (s, 6H, 2ÂAr–OCH3), 5.69 (s, 2H, 2¼CH), 6.88,
6.92 (d, 4H, J=8 Hz, Ar–H), 7.80, 7.84 (d, 4H, J=8Hz,
Ar–H); Mass (FAB) 510 (M+). Anal. calcd for
C29H38N2O6 C, 68.23, H, 7.45, N, 5.49. Found C, 68.34,
H, 7.57, N, 5.49%.
N,N0- [bis (1-(4-Fluorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 4-butanediamine (4d). (85%, 128–129 ꢀC): IR
N,N0- [bis (1-(4-Fluorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 3-propanediamine (3d). (50%, 82–83 ꢀC): IR
1
(KBr) 3474, 1594 cmÀ1; H NMR (CDCl3) d 1.84 (m,
1
(KBr) 3438, 1580 cmÀ1; H NMR (CDCl3) d 1.81 (m,
8H, 4ÂCH2), 2.47 (t, 4H, J=8Hz, 2 ÂCH2), 3.46 (m,
4H, 2ÂNH–CH2), 3.69 (t, 4H, J=6 Hz, 2ÂCH2OH),
5.63 (s, 2H, 2¼CH), 7.05 (m, 4H, Ar–H), 7.84 (dd,
4H, J=6 Hz, Ar–H); Mass (FAB) 528(M +). Anal.
calcd for C28H34F2N2O4 C, 66.13, H, 6.74, N, 5.51.
Found C, 66.38, H, 6.68, N, 5.41%.
4H, 2ÂCH2), 2.07 (m, 2H, CH2), 2.52 (t, 4H, J=8Hz,
2ÂCH2), 3.63 (m, 8H, 2ÂNH–CH2 and 2ÂCH2OH),
5.69 (s, 2H, 2Â=CH), 7.07 (t, 4H, J=10 Hz, Ar–H),
7.85 (dd, 4H, J=6 Hz, Ar–H); Mass (FAB) 486 (M+).
Anal. calcd for C27H32F2N2O4 C, 65.57, H, 6.52, N,
5.66. Found C, 65.78, H, 6.59, N, 5.98%.
N,N0- [bis (1-(4-Chlorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 4-butanediamine (4e). (64%, 154–156 ꢀC): IR
N,N0- [bis (1-(4-Chlorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 3-propanediamine (3e). (73%, 118–119 ꢀC): IR
1
(KBr) 3440, 1590 cmÀ1; H NMR (CDCl3) d 1.83 (m,
1
(KBr) 3374, 1588 cmÀ1; H NMR (CDCl3) d 1.87 (m,
8H, 4ÂCH2), 2.47 (t, 4H, J=8Hz, 2 CH 2), 3.44 (m, 4H,
2ÂNH–CH2), 3.68(t, 4H, J=6 Hz, 2ÂCH2OH), 5.63 (s,
2H, 2¼CH), 7.33, 7.37(d, 4H, J=8Hz, Ar–H), 7.73,
7.77 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 532, 534
(M+). Anal. calcd for C28H34Cl2N2O4 C, 63.04, H, 6.42,
N, 4.50. Found C, 63.05, H, 6.19, N, 4.42%.
4H, 2ÂCH2), 2.09 (m, 2H, CH2), 2.54 (t, 4H, J=8Hz,
2ÂCH2), 3.66 (m, 8H, 2ÂNH–CH2 and 2ÂCH2OH),
5.72 (s, 2H, 2¼CH), 7.38, 7.42(d, 4H, J=8Hz, Ar–H),
7.76, 7.80 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 518, 519
(M+). Anal. calcd for C27H32Cl2N2O4 C, 62.43, H, 6.21,
N, 5.39. Found C, 62.05, H, 6.19, N, 5.42%.
N,N0 - [bis (1- (4-bromophenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 4-butanediamine (4f). (69%, 162–163 ꢀC):
IR (KBr) 3450, 1594 cmÀ1; 1H NMR (CDCl3) d 1.84 (m,
8H, 4ÂCH2), 2.47 (t, 4H, J=8Hz, 2 ÂCH2), 3.44 (m,
4H, 2ÂNH–CH2), 3.68(t, 4H, J=6 Hz, 2ÂCH2OH),
5.63 (s, 2H, 2¼CH), 7.50, 7.54 (d, 4H, J=8Hz, Ar–
H), 7.67, 7.71 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 618,
622 (M+). Anal. calcd for C28H34Br2N2O4 C, 54.03, H,
5.51, N, 4.50. Found C, 54.25, H, 5.44, N, 4.71%.
N,N0- [bis (1-(4-Bromophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 3-propanediamine (3f). (56%, 129–130 ꢀC): IR
1
(KBr) 3450, 1594 cmÀ1; H NMR (CDCl3) d 1.88 (m,
4H, 2ÂCH2), 2.06 (m, 2H, CH2), 2.51 (t, 4H, J=8Hz,
2ÂCH2), 3.62 (m, 8H, 2ÂNH–CH2 and 2ÂCH2OH),
5.67 (s, 2H, 2¼CH), 7.40, 7.44 (d, 4H, J=8ÂHz, Ar–
H), 7.67, 7.71 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 604,
608(M +). Anal. calcd for C26H30Br2N2O4 C, 53.30, H,
5.30, N, 4.60. Found C, 53.35, H, 5.04, N, 4.71%.
N,N0-[bis(1-Phenyl-6-hydroxy-hex-2-ene-1-one-3-yl)-1, 8-
octanediamine (5a). (88%, 134–135 ꢀC): IR (KBr) 3350,
N,N0-[bis(1-Phenyl-6-hydroxy-hex-2-ene-1-one-3-yl)-1, 4-
butanediamine (4a). (81%, 134–135 ꢀC): IR (KBr) 3350,
1
1594 cmÀ1; H NMR (CDCl3) d 1.75 (m, 8H, 4ÂCH2),
1
1594 cmÀ1; H NMR (CDCl3) d 1.75 (m, 8H, 4ÂCH2),
2.48(t, 4H, J= 8Hz, 2 Â CH2), 3.30 (m, 4H, 2ÂNH–
CH2), 3.68(t, 4H, J=6 Hz, 2ÂCH2OH), 5.68(s, 2H,
2¼CH), 7.57 (m, 6H, Ar–H), 7.81 (m, 4H, Ar–H); Mass
(FAB) 520 (M+). Anal. calcd for C28H36N2O4 C, 72.38, H,
7.81, N, 6.03. Found C, 72.31, H, 7.94, N, 6.26%.
2.48(t, 4H, J=8Hz, 2 ÂCH2), 3.30 (m, 4H, 2ÂNH–
CH2), 3.68(t, 4H, J=6 Hz, 2ÂCH2OH), 5.68(s, 2H,
2¼CH), 7.57 (m, 6H, Ar–H), 7.81 (m, 4H, Ar–H);
Mass (FAB) 464 (M+). Anal. calcd for C28H36N2O4 C,
72.38, H, 7.81, N, 6.03. Found C, 72.31, H, 7.94, N,
6.26%.
N, N0- [bis (1-(4-Methylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 8-octanediamine (5b). (84%, 118–119 ꢀC):
IR (KBr) 3428, 1592 cmÀ1; 1H NMR (CDCl3) d 1.65 (m,
16H, 8ÂCH2), 2.37 (s, 6H, 2ÂAr–CH3), 2.44 (t, 4H,
J=8ÂHz, 2ÂCH2), 3.36 (m, 4H, 2ÂNH–CH2), 3.72 (t,
4H, J=6 Hz, 2ÂCH2OH), 5.65 (s, 2H, 2¼CH), 7.17,
7.21 (d, 4H, J=8Hz, Ar–H), 7.72, 7.76 (d, 4H,
J=8ÂHz, Ar–H); Mass (FAB) 548(M +). Anal. calcd
for C34H48N2O4 C, 74.42, H, 8.81, N, 5.10. Found C,
74.44, H, 8.64, N, 5.02%.
N,N0 - [bis (1-(4-Methylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 4-butanediamine (4b). (78%, 128–129 ꢀC):
IR (KBr) 3352, 1572 cmÀ1; 1H NMR (CDCl3) d 1.76 (m,
8H, 4ÂCH2), 2.30(s, 6H, 2ÂAr–CH3), 2.40 (t, 4H,
J=8Hz, 2 ÂCH2), 3.36 (m, 4H, 2ÂNH–CH2), 3.63 (t,
4H, J=6 Hz, 2ÂCH2OH), 5.60 (s, 2H, 2¼CH), 7.10,
7.14 (d, 4H, J=8Hz, Ar–H), 7.74, 7.78(d, 4H, J=8Hz,
Ar–H); mass (FAB) 492 (M+). Anal. calcd for

S. Batra et al. / Bioorg. Med. Chem. 9 (2001) 3093–3099
3099
N,N0- [bis (1-(4-methoxylphenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 3-octanediamine (4c). (75%, 117–118 ꢀC):
IR (KBr) 3402, 1592 cmÀ1; 1H NMR (CDCl3) d 1.65 (m,
16H, 8ÂCH2), 2.42 (t, 4H, J=8Hz, 2 ÂCH2), 3.33 (m,
4H, 2ÂNH–CH2), 3.71 (t, 4H, J=6 Hz, 2ÂCH2OH),
3.83 (s, 6H, 2ÂAr–OCH3), 5.63 (s, 2H, 2¼CH), 6.87,
6.91 (d, 4H, J=8 Hz, Ar–H), 7.80, 7.84 (d, 4H, J=8Hz,
Ar–H); Mass (FAB) 580 (M+). Anal. calcd for
C34H48N2O6 C, 70.31, H, 8.33, N, 4.82. Found C, 70.34,
H, 8.57, N, 4.49%.
4H, 2ÂNH–CH2), 3.73 (t, 4H, J=6 Hz, 2ÂCH2OH),
5.61 (s, 2H, 2¼CH), 7.49, 7.53 (d, 4H, J=8Hz, Ar–
H), 7.69, 7.73 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 672,
676 (M+). Anal. calcd for C32H40Br2N2O4 C, 56.68, H,
5.96, N, 4.14. Found C, 56.35, H, 5.84, N, 4.17%.
Acknowledgements
One of the authors (B.S.J.) gratefully acknowledges the
financial support in the form of senior research fellow-
ship from CSIR, New Delhi.
N,N0- [bis (1-(4-Fluorophenyl-6-hydroxy-hex-2-ene-1-one
-3-yl)-1, 8-octanediamine (4d). (79%, 131–132 ꢀC): IR
1
(KBr) 3330, 1592 cmÀ1; H NMR (CDCl3) d 1.60 (m,
16H, 8ÂCH2), 2.45 (t, 4H, J=8Hz, 2 ÂCH2), 3.33 (m,
4H, 2ÂNH–CH2), 3.73 (t, 4H, J=6 Hz, 2ÂCH2OH),
5.62 (s, 2H, 2¼CH), 7.07 (t, 4H, J=10 Hz, Ar–H),
7.85 (dd, 4H, J=6 Hz, Ar–H); Mass (FAB) 554 (M+).
Anal. calcd for C27H32F2N2O4 C, 65.57, H, 6.52, N,
5.66. Found C, 65.78, H, 6.59, N, 5.98%.
References and Notes
1. Indian Patent filed on Sept 5, 2000.
2. (a) Bedwell, S.; Dean, R. I.; Jessup, W. Biochem. J. 1989,
262, 707. (b) Steinberg, D.; Parthasarthy, S.; Carew, T. E.;
Khoo, J. C.; Witzum, J. L. New Engl. J. Med. 1989, 320, 915.
3. Batra, S.; Srivastava, S.; Singh, K.; Khanna, A. K.;
Chander, R.; Bhaduri, A. P. Bioorg. Med. Chem. 2000, 8, 2195
and references cited therein.
4. De, D.; Seth, M.; Bhaduri, A. P. Ind. J. Chem. 1989, 28B,
503.
5. Sabesin, S. M.; Hasswins, H. L.; Ragland, J. B. Gaster-
oenterology 1977, 72, 510.
6. Ohkawa, H.; Ohishi, N. J. Lip. Res. 1978, 19, 1053.
7. Halliwell, B.; Gutteridge, J. M. C.; Arouma, O. I. Anal.
Biochem. 1987, 165, 215.
8. Mosinger, F. J. Lipid. Res. 1965, 6, 157.
9. Lowry, H.; Rosebrough, M. J.; Farr, A. L.; Randall, R. J.
J. Biol. Chem. 1951, 193, 265.
10. Schotz, M. C.; Scanu, A.; Page, T. H. Am. J. Physiol.
1957, 188, 399.
11. Friedman, M.; Byers, S. O. Am. J. Physiol. 1957, 190, 439.
N,N0 - [bis (1- (4-Chlorophenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 8-octanediamine (5e). (74%, 131–132 ꢀC):
IR (KBr) 3330, 1592 cmÀ1; 1H NMR (CDCl3) d 1.60 (m,
16H, 8ÂCH2), 2.45 (t, 4H, J=8Hz, 2 ÂCH2), 3.33 (m,
4H, 2ÂNH–CH2), 3.73 (t, 4H, J=6 Hz, 2ÂCH2OH),
5.62 (s, 2H, 2¼CH), 7.33, 7.37 (d, 4H, J=8Hz, Ar–
H), 7.75, 7.79 (d, 4H, J=8Hz, Ar–H); Mass (FAB) 586,
588 (M+). Anal. calcd for C32H40Cl2N2O4 C, 65.41, H,
6.86, N, 4.76. Found C, 65.19, H, 6.79, N, 4.42%.
N,N0 - [bis (1- (4-Bromophenyl-6-hydroxy-hex-2-ene-1-
one-3-yl)-1, 8-octanediamine (5f). (81%, 132–133 ꢀC):
IR (KBr) 3416, 1594 cmÀ1; 1H NMR (CDCl3) d 1.63 (m,
16H, 8ÂCH2), 2.45 (t, 4H, J=8Hz, 2 ÂCH2), 3.37 (m,