Synthesis and hypolipidemic activity of N-substituted phthalimides. Part V

Article abstract of DOI:10.1016/S0014-827X(03)00185-X

A series of N-aryl- or N-(1,2,4-triazol-yl)-phthalimides (4a-4i) have been synthesized starting from phthalic anhydride (1) and an appropriate amine (2a-2i). All compounds presented hypolipidemic activity, but compound 4d proved to be the most active and reduced plasma cholesterol and triglyceride levels in Swiss white mice significantly.

Full text of DOI:10.1016/S0014-827X(03)00185-X

Il Farmaco 58 (2003) 1283ꢀ1288
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Synthesis and hypolipidemic activity of N-substituted phthalimides.
Part Vꢀ
Vera L.M. Sena a, Rajendra M. Srivastava a,*, Ricardo O. Silva a, Vera L.M. Lima b
a Departamento de Qu´ımica Fundamental, Universidade Federal de Pernambuco (UFPE), Av. Luis Freire, S/N, Cidade Universita´ria, CEP 50.740-540
Recife, PE, Brazil
b Departamento de Bioqu´ımica, Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego, S/N, Cidade Universita´ria, CEP 50.670-420
Recife, PE, Brazil
Received 27 February 2003; accepted 9 June 2003
Abstract
A series of N-aryl- or N-(1,2,4-triazol-yl)-phthalimides (4aꢀ/4i) have been synthesized starting from phthalic anhydride (1) and an
appropriate amine (2aꢀ2i). All compounds presented hypolipidemic activity, but compound 4d proved to be the most active and
/
reduced plasma cholesterol and triglyceride levels in Swiss white mice significantly.
´
# 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: N-Arylphthalimides; Hypolipidemic activity; Triglycerides; Cholesterol
1. Introduction
CoA carboxylase activity. In 1983, another publication
appeared, where 10 N-arylphthalimides have been
examined and the most potent product, o-(N-phthali-
mido)acetophenone, was shown to lower both serum
cholesterol and triglyceride levels by 57 and 44% after 16
and 14 days of treatment, respectively [5]. It has also
been shown that replacement of one of the oxygen
atoms of the carbonyl groups by NH in phthalimide was
effective in reducing serum cholesterol (44%); however,
the hypotriglyceridemic activity of 3-iminophthalimi-
dine was 15% lower than that of phthalimide itself [6].
Phthalimide and N-substituted phthalimides are an
interesting class of compounds because they possess
important biological activities [1,2]. For the last two
decades, these compounds have also attracted more
attention due to their antihyperlipidemic activity, and
the research in this area continues. Although there are
several drugs, which reduce cholesterol and triglycerides
in blood, it is imperative to find still more effective and
nontoxic ones. With this idea in view, the present work
was undertaken. N-substituted phthalimide derivatives
were first examined by Chapman Jr et al. [3] in 1979 for
their hypolipidemic activity and it was found that N-
butyl- and N-pentylphthalimides were effective in redu-
cing serum cholesterol levels by 46 and 42%, respec-
tively. Two years later, Hall et al. [4] investigated 12
imide analogs and suggested that their ability to lower
serum cholesterol should be related to phthalimides’
effectiveness to suppress acetyl-CoA synthase activity.
In other words, phthalimides are able to inhibit acetyl-
Quantitative structureꢀactivity relationships (QSAR)
/
studies have also been carried out for phthalimide and
N-arylphthalimides, and enhanced hypolipidemic activ-
ity has been predicted for certain phthalimides [7,8]. In
1996, Antunes and Srivastava [9] reported the synthesis
and semi-empirical molecular orbital calculations of
three new phthalimide derivatives, and predicted that
these compounds might show antihyperlipidemic activ-
ity. Recently, the synthesis and hypolipidemic activity of
five N-phthalimidomethyl glycosides have been reported
from our laboratory [10].
Considering the growing importance of N-substituted
derivatives of phthalimides, we decided to synthesize
ꢀ For analgesic effect of N-phthalimide derivatives, see Ref. [25].
* Corresponding author.
seven known N-arylphthalimides (4aꢀ
/
4g) and two new
E-mail address: rms@ufpe.br (R.M. Srivastava).
phthalimides (4h and 4i) The structures of latter two
´
0014-827X/03/$ - see front matter # 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
doi:10.1016/S0014-827X(03)00185-X

1284
V.L.M. Sena et al. / Il Farmaco 58 (2003) 1283ꢀ1288
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compounds are given in Fig. 1. All of them were tested
for their hypolipidemic properties because the literature
does not record such evaluation of these compounds.
2.2.2. 2-(2-Chlorophenyl)-isoindole-1,3-dione (4b)
73%, 143ꢀ143.6 8C (lit. [13]: 140 8C)*IR (KBr):
1745, 1711, 1588, 1526, 1486, 1469, 1440, 772, 748.
/
/
1
Interestingly, the intermediates (3aꢀ
demia and increase in animals’ body weight [11],
whereas phthalimides (4aꢀ4i) possess hypolipidemic
/3i) cause hyperlipi-
UV (MeOH): lmax 288 and 217 nm. H NMR (CDCl3):
d 8.00 (dd, 2H, Jꢂ
7.83 (dd, 2H, Jꢂ3.0 and Jꢂ
(m, 1H, H-3?), 7.42ꢀ7.48 (m, 2H, H-5? and H-6?), 7.38
(m, 1H, H-4?) ppm.
/
3.0 and Jꢂ
/
5.4 Hz, H-4 and H-7),
/
/
/5.4 Hz, H-5 and H-6), 7.58
property. This paper, therefore, reports the synthesis
and pharmacological tests of these N-substituted phtha-
limides. In fact, one of the compounds, 4d, presented an
excellent and quite promising hypolipidemic activity.
/
2.2.3. 2-(3-Chlorophenyl)-isoindole-1,3-dione (4c)
94%, 168.5ꢀ169 8C (lit. [14]: 166.8 8C)*IR (KBr):
1721, 1680, 1587, 1550, 1530, 1482, 1433, 774, 735, 684.
/
/
1
UV (MeOH): lmax 287 and 218 nm. H NMR (CDCl3):
2. Experimental procedures
d 7.98 (dd, 2H, Jꢂ
7.82 (dd, 2H, Jꢂ3.0 and Jꢂ
7.35ꢀ7.41 (m, 3H, H-2?, H-4? and H-6?), 7.43 (t, 1H, H-
/
3.0 and Jꢂ
/
5.4 Hz, H-4 and H-7),
/
/
5.4 Hz, H-5 and H-6),
2.1. General
/
5?) ppm.
All compounds were checked for their structures by
1
infrared (IR), UV, and H NMR spectroscopy. Melting
2.2.4. 2-(4-Chlorophenyl)-isoindole-1,3-dione (3d)
99%, 200.6ꢀ
(KBr): 1787, 1712, 1610, 1554, 1495, 1388, 1280, 885,
1
851, 825. UV (MeOH): lmax 288, 222, and 241 nm. H
NMR (CDCl3): d 7.97 (dd, 2H, Jꢂ
H-4 and H-7), 7.81 (dd, 2H, Jꢂ3.0 and Jꢂ
and H-6), 7.49 (d, 2H, Jꢂ9 Hz, H-3? and H-5?, AA?,
and BB? system), 7.42 (d, 2H, Jꢂ9.0 Hz, H-2? and H-6?,
AA?BB? system) ppm.
points were determined on a Tomas-Hoover capillary
melting point apparatus and are uncorrected. UV
spectra were registered with U-3200 Hitachi spectro-
photometer. IR spectra were measured with a Bruker
model IF S66 FTIR spectrophotometer using potassium
bromide discs. NMR spectra were recorded in CDCl3
/
201.2 8C (lit. [15]: 201ꢀ
/
202 8C)*IR
/
/
3.0 and Jꢂ
/
5.4 Hz,
/
/5.4 Hz, H-5
/
(for compounds 4aꢀ4g) or DMSO-d6 (for compounds
/
/
4h and 4i) using tetramethylsilane (TMS) as an internal
standard, on a Varian Unity Plus 300 MHz spectro-
photometer.
2.2.5. 2-(2-Fluorophenyl)-isoindole-1,3-dione (4e)
67%, 194ꢀ195 8C (lit. [16]: 192ꢀ193 8C)*IR (KBr):
1760, 1712, 1680, 1526, 1460, 1423, 1350, 1296, 1260,
/
/
/
2.2. General procedure for the preparation of N-aryl- or
N-heterocyclic phthalimides
1
988, 754, 727. UV (MeOH): lmax 280 and 222 nm. H
NMR (CDCl3): d 7.97 (dd, 2H, Jꢂ
H-4 and H-7), 7.80 (dd, 2H, Jꢂ3.0 and Jꢂ
and H-6), 7.20ꢀ7.50 (m, 4H, H-3?, H-4?, H-5?, and H-6?)
ppm.
/
3.0 and Jꢂ
/
5.4 Hz,
Compounds 4aꢀ
equimolar quantities of phthalic anhydride (1; 3.4
mmol) and a suitable substituted amine (2bꢀ2g; 3.4
mmol), followed by refluxing in nitrobenzene for 45
min. After cooling, the compounds 4bꢀ4g were pre-
cipitated by the addition of excess n-hexane. Filtration
and washing the solid with a small quantity of hexane
provided the crude solid, which was crystallized from
ethanol to provide pure compound in excellent yield.
The compounds 4a, 4h, and 4i in glacial acetic acid were
stirred under reflux for 1 h and the solvent in each case
was evaporated under reduced pressure to yield the
crude product, which was recrystallized from acetone or
acetic acid.
/
4i have been synthesized by mixing
/
/5.4 Hz, H-5
/
/
/
2.2.6. 2-(3-Fluorophenyl)-isoindole-1,3-dione (4f)
89%, 206ꢀ207 8C (lit. [16]: 200ꢀ201 8C)*IR (KBr):
1768, 1710, 1612, 1590, 1500, 1460, 1409, 1335, 1296,
/
/
/
1172, 981, 774, 728. UV (MeOH): lmax 285 and 222 nm.
1H NMR (CDCl3): d 7.96 (dd, 2H, Jꢂ
/
3.0 and Jꢂ
3.0 and Jꢂ5.7 Hz,
H-5 and H-6), 7.47 (ddd, 1H, J5?, 4?ꢂ8.1, J5?, 6?ꢂ8.1,
and J5?, F 6.0 Hz, H-5?), 7.30 (ddd, 1H, J6?, 5?ꢂ8.1, J6?,
4?ꢂ0.9, and J6?, 2?ꢂ2.1 Hz, H-6?), 7.24 (dt, 1H, J2?, F
9.0, J2?, 4?ꢂ2.4, and J2?, 6?ꢂ2.4 Hz, H-2?), 7.11 (dddd,
1H, J4?, F 8.4, J4?, 5?ꢂ8.1, J4?, 2?ꢂ2.4, and J4?, 6?ꢂ0.9
Hz, H-4?) ppm.
/
5.7
Hz, H-4 and H-7), 7.80 (dd, 2H, Jꢂ
/
/
/
/
ꢂ
/
/
/
/
ꢂ
/
/
/
ꢂ
/
/
/
/
2.2.1. 2-Phenylisoindole-1,3-dione (4a)
99%, 210 8C (lit. [12]: 205.5ꢀ
/
206 8C)*IR (KBr):
/
3031, 1770, 1711, 1594, 1466, 1452 cmꢁ1
.
UV
(MeOH): lmax 294 and 244 nm. H NMR (CDCl3): d
2.2.7. 2-(4-Fluorophenyl)-isoindole-1,3-dione (4g)
98%, 180.6ꢀ181.2 8C (lit. [17]: 180ꢀ181.5 8C)*IR
(KBr): 1770, 1680, 1603, 1514, 1467, 1409, 1393, 886,
1
/
/
/
7.95 (dd, 2H, Jꢂ
/
3.0 and Jꢂ
/
5.4 Hz, H-4 and H-7), 7.79
1
(dd, 2H, Jꢂ3.0 and Jꢂ
/
/5.4 Hz, H-5 and H-6), 7.52 (m,
864, 725. UV (MeOH): lmax 281 and 221 nm. H NMR
2H, H-5? and H-3?), 7.47 (m, 2H, H-2? and H-6?), 7.40
(m, 1H, H-4?) ppm.
(CDCl3): d 7.95 (dd, 2H, Jꢂ
/
3.0 and Jꢂ
/
5.4 Hz, H-4
and H-7), 7.80 (dd, 2H, Jꢂ3.0 and Jꢂ
/
/5.4 Hz, H-5 and

V.L.M. Sena et al. / Il Farmaco 58 (2003) 1283ꢀ
/1288
1285
H-6), 7.43 (m, 2H, H-2? and H-6?), 7.19 (m, 2H, H-3?
and H-5?) ppm.
3. Results and discussion
3.1. Chemistry
N-Aryl- or N-(1,2,4-triazol-yl)-phthalimides (4aꢀ
Scheme 1) were obtained by the reaction of phthalic
anhydride (1) and an appropriate amine (2aꢀ2i) follow-
ing the procedure described earlier [20,21].
The ring opening took place by nucleophilic attack of
the amine nitrogen atom on carbonyl carbon of phthalic
anhydride with the formation of N-substituted phtha-
/
4i;
2.2.8. 2-[1H-(1,2,4)Triazole-3-yl]-isoindole-1,3-dione
(4h)
/
69%, 305ꢀ
/
306 8C*
/
IR (KBr): 3392 (ꢀNH), 3063,
/
2855, 1792, 1770, 1744, 1526, 1492, 1466, 1374, 1353,
1118, 874, 719 cmꢁ1. UV (MeOH): lmax 273, 223, and
205 nm. 1H NMR (DMSO-d6): d 8.68 (s, 1H, H-5?), 8.01
(m, 4H, H-6, H-5, H-4, and H-3) ppm, the NH proton
was not visible in the spectrum. It is assumed that the
same was present at d 3.6 ppm along with the protons of
the water molecule present in the solvent. Anal. Calc. for
C10H6N4O2: C, 56.08; H, 2.82; N, 26.16. Found: C,
56.60; H, 3.00; N, 26.08%.
lamic acids (3aꢀ
under heating conditions to give products 4aꢀ
(Scheme 1). The yields were between 69 and 99%.
IR spectra of compounds 4aꢀ4g and 4i did not absorb
in the region 3100ꢀ
3600 cmꢁ1 indicating the absence of
OH or ꢀNH groups. The spectra of all compounds
/3i) as an intermediate which lose water
/4i
/
/
ꢀ
/
/
showed two strong absorptions around 1777 and 1711
cmꢁ1, the former and the latter absorptions are due to
the asymmetric and symmetric stretching vibrations of
the carbonyl groups present in the phthalimide ring.
Similar absorptions have been reported for N-substi-
tuted phthalimides [22]. Compound 4h (Fig. 1) exhibited
2.2.9. 2-([1,2,4]Triazole-4-yl)-isoindole-1,3-dione (4i)
75.4%, 269.7ꢀ
/
270.4 8C*IR (KBr): 3107, 1730, 1686,
/
1560, 1444, 1368, 1346, 1287, 1200, 1173, 1116, 1079,
1052, 879, 704 cmꢁ1. UV (MeOH): lmax 275, 257, and
1
an absorption characteristic to ꢀ
cmꢁ1, and the absorptions between 1606 and 1527
C groups.
/
NH group at 3392
206 nm. H NMR (DMSO-d6): d 8.72 (s, 2H, H-3?, H-
5?), 7.78ꢀ7.71 (m, 4H, H-7, H-6, H-5, and H-4) ppm.
/
cmꢁ1 which are due Cꢁ
/
N and Cꢁ
/
Anal. Calc. for C10H6N4O2: C, 56.08; H, 2.82; N, 26.16.
Found: C, 56.39; H, 2.70; N, 26.25%.
UV spectra of these compounds exhibited absorptions
in two main regions: the low-energy band between 274
and 288 nm (n0
/
p*) and the high-energy band between
p* transitions.
Such absorptions have been observed for N-substituted
205 and 241 nm corresponding to p0
/
2.3. Hypolipidemic activity
alkylphthalimides [23].
The chemical shifts of N-(o-, m-, and p-chlorophe-
A suspension of 4aꢀ4i in 1% carboxymethylcellulose
/
(CMC) was administered orally by an intubation needle
to Swiss white mice for 16 days at a 20 mg/kg per day
dose. This dose was chosen based on the previous
experiments with the animals. Blood samples were
collected after fasting the animals for 13 h and
puncturing their retro-orbital plexus and withdrawing
the blood directly into tubes containing a solution (1
mg/ml) of ethylenediaminetetraacetic acid disodium salt
(EDTA) before and after 16 days of treatment, and the
nyl)phthalimides (4bꢀ
any problem. However, it was initially difficult to locate
the chemical shifts of the phenyl protons of 4eꢀ4g
/
4d) have been assigned without
/
containing a fluorine atom. We had to carry out several
NMR experiments to determine the chemical shifts of
the protons in order to make the correct assignments
except for the compound 4e which is still being analyzed.
Section 2 provides only the chemical shifts. The detailed
NMR studies including J-resolved, irradiation, and C-13
experiments of 4eꢀ
future.
/
4g will be reported elsewhere in the
plasma was separated by centrifugation at 2500ꢃg for
/
10 min. The animals were weighed everyday during the
treatment. Samples of plasma were used in duplicate to
determine the plasma cholesterol and triglyceride levels
by using enzymatic assay CHOD-PAP [18], using
cholesterol esterase, cholesterol oxidase, and peroxidase
contained in Merck test 1.14830.0001 Ecoline 25
reagents (diagnostica-Merck KGaA, Darmstadt, Ger-
many), and GPO-PAP [19], using the enzymes lipase,
glycerokinase, glycerol phosphate oxidase, and perox-
idase as described in Merck test 1.19706.0001 System
Multi-Test, respectively.
4. Pharmacological evaluations
Although several N-arylphthalimides have been eval-
uated for pharmacological activity [3], none of the
present compounds 4aꢀ4i were evaluated for biological
activity tests before. The literature [3] reports that N-p-
carboxyphenylphthalimide is quite effective as a hypo-
lipidemic agent causing the reduction of cholesterol and
TG by 47 and 42%, respectively.
/

1286
V.L.M. Sena et al. / Il Farmaco 58 (2003) 1283ꢀ1288
/
Scheme 1.
Compounds 4aꢀ
/
4i, when tested for activity in Swiss
similar in decreasing cholesterol concentration (22 and
20%, respectively). When a comparison of the biological
activity of p-chloro and p-fluoro substituents in phenyl
ring of compounds 4d and 4g was made, the p-chloro
substituent proved to be approximately twice as effective
as p-fluoro substituent. In fact, N-o-chloro- and N-o-
fluorophenylphthalimides presented only little effects in
terms of diminishing the cholesterol levels. When N-aryl
groups of phthalimide was replaced by triazoles, the
activity of compound 4g was found to lower the serum
cholesterol content by 40%, whereas 4i was 50% less
effective as hypocholesterolemic agent.
white mice using 20 mg/kg per day, presented the
reduction of plasma cholesterol and TG levels (Table
1). According to the literature [5], compound 4a
decreased cholesterol level by 43% after 16 days,
whereas the triglycerides presented a reduction of 39%
after 14 days. Our experiments show a lower diminution
of cholesterol, but higher decrease in triglyceride levels
(see Table 1). Among compounds tested, only N-(4-
chlorophenyl)phthalimide (4d) presented significant hy-
polipidemic activity (P B0.05), characterized by 63 and
47% decrease in cholesterol and TG levels, respectively
(Table 1).
Although compounds 4b and 4c are less effective in
diminishing plasma cholesterol levels (11 and 22%,
respectively), they are much better in reducing TG (39
and 21%, respectively). Compounds containing fluorine
/
Under similar conditions as used for our compounds,
we tested pravastatin (drug used commercially) and
observed a 36% reduction in the cholesterol levels (3.39
0.1 mmol/l before the treatment and 2.190.05 mmol/l
after the treatment, significant for P B0.001). The
animals also presented a reduction of 42% (0.8990.2
mmol/l before the treatment and 0.5290.09 mmol/l after
the treatment) in TG levels being significant for P B
0.001. This is interesting because two of our compounds,
/
/
/
atom in the phenyl ring, 4eꢀ
/4g, have also been found to
/
reduce TG levels in plasma by 37, 38, and 50%,
respectively. Phthalimides N-[3-chlorophenyl]phthali-
mide (4c) and N-[3-fluorophenyl]phthalimide (4f) are
/
/
Fig. 1. Structures of compounds 4h and 4i.

V.L.M. Sena et al. / Il Farmaco 58 (2003) 1283ꢀ
/1288
1287
Table 1
Effects of N-substituted phthalimides on mice plasma cholesterol and triglycerides levels
Cholesterol (mmol/l)
Before After
Triglycerides (mmol/l)
Before After
Comp.
Reduction (%)
Reduction (%)
4a
4b
2.739
2.109
2.499
3.189
2.569
2.019
2.859
3.139
2.779
2.049
/
0.61
0.55
0.53
1.32
0.63
0.63
0.31
0.56
0.28
0.31
1.839
1.869
1.949
1.199
2.419
1.609
2.139
1.879
2.249
2.099
/
0.23 a
0.50
33
11
22
63
6
1.529
1.149
1.709
1.549
1.459
0.789
1.539
1.889
1.809
1.019
/
0.41
0.43
0.44
0.46
0.51
0.33
0.42
0.10
0.14
0.31
0.759
0.699
1.359
0.819
0.919
0.489
0.779
1.609
1.599
0.989
/
0.12 a
0.18 a
0.57 a
0.37 b
0.21
51
40
21
47
37
39
50
15
12
2
/
/
/
/
4c
/
/0.52
/
/
4d
/
/0.65
/
/
4e
/
/0.34
/
/
4f
4g
/
/
0.30 a
0.23
24
25
40
19
3 d
/
/
0.14 a
0.23 a
0.03 a
0.12
/
/
/
/
4h
4i
CMC c
/
/0.37
/
/
/
/
0.21 a
0.23
/
/
/
/
/
/0.15
Values represent the mean9
/
S.D. for six animals in each group.
a
b
c
Significant difference P B
/0.05.
Significant difference P B
/0.005.
Neither cholesterol nor triglycerides showed any significant reduction in their blood plasma.
In fact, the cholesterol level increased slightly.
d
viz. 4a and 4h, produced similar results as that of
pravastatin. The literature also reports that N-phthali-
midobutan-3-one reduces serum cholesterol level by
37% in 16 days [3]. There are other phthalimides which
decrease this level still higher [5]. When we compare the
results of compound 4d with the results of pravastatin,
we verified that compound 4d presented antihypercho-
lesterolemic activity (reduction of 63% in the cholesterol
level) superior to pravastatin (36% reduction). However,
this same compound presented hypotriglyceridemic
activity (47% of reduction) similar to pravastatin
(42%). Thus, it is clear that para-substituted N-phenyl-
and N-(1,2,4)-triazole-3-yl-phthalimides are better in
lowering the plasma cholesterol and TG levels. Our
results clearly indicate the superiority of 4d over the
commercially available drug. Although it has not been
proven experimentally, it is possible that the alterations
found in the plasmatic TG levels can be due to the
interference of those drugs in the enzymes that regulate
the synthesis de novo of TG. Lamb et al. [24] demon-
strated that a positive correlation exists among the
inhibition in the activity of the enzyme regulators
(glycerol-3-phosphate acyltransferase and phosphati-
dase phosphohydrolase) and the decrease in the levels
of TG in the serum. Similar observation was found by
Chapman and coworkers [4] for saccharin and phthali-
mide. It is interesting to note that changes in phenyl
substitution of N-phenylphthalimide affect hypolipi-
demic activity.
Acknowledgements
We thank Brazilian National Research Council
(CNPq) and Pernambuco State Foundation for Science
and Technology (FACEPE) for financial support.
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