Design, synthesis and hypolipidemic activity of novel 2-(naphthalen-2-yloxy)propionic acid derivatives as desmethyl fibrate analogs

Article abstract of DOI:10.1016/j.ejmech.2009.04.026

A series of 2-(naphthalen-2-yloxy)propionic acid derivatives were prepared. The hypolipidemic activity of the new compounds as well as the intermediate acid 2 was evaluated in the high cholesterol diet (HCD) fed hyperlipidemic rat model. Interestingly, the S-alkylated mercaptotriazole 8b and the 1,3,4-oxadiazole 9 produced striking reduction of serum levels of total cholesterol (TC), triglycerides (TGs) and low-density lipoproteins (LDLs) and elevation of serum high-density lipoproteins (HDLs) being more active than the reference gemfibrozil. In addition, the 1,2,4-triazole 7a, the hydroxypyrazoline 10 and the pyrazolone derivative 11 exhibited good hypolipidemic activity on different lipid parameters.

Full text of DOI:10.1016/j.ejmech.2009.04.026

European Journal of Medicinal Chemistry 44 (2009) 3973–3980
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and hypolipidemic activity of novel 2-(naphthalen-2-
yloxy)propionic acid derivatives as desmethyl fibrate analogs
*
Gamal A. Idrees, Omar M. Aly , Gamal El-Din A.A. Abuo-Rahma, M.F. Radwan
Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 2-(naphthalen-2-yloxy)propionic acid derivatives were prepared. The hypolipidemic activity
of the new compounds as well as the intermediate acid 2 was evaluated in the high cholesterol diet
(HCD) fed hyperlipidemic rat model. Interestingly, the S-alkylated mercaptotriazole 8b and the
1,3,4-oxadiazole 9 produced striking reduction of serum levels of total cholesterol (TC), triglycerides
(TGs) and low-density lipoproteins (LDLs) and elevation of serum high-density lipoproteins (HDLs) being
more active than the reference gemfibrozil. In addition, the 1,2,4-triazole 7a, the hydroxypyrazoline 10
and the pyrazolone derivative 11 exhibited good hypolipidemic activity on different lipid parameters.
Ó 2009 Elsevier Masson SAS. All rights reserved.
Received 11 November 2008
Received in revised form
12 April 2009
Accepted 16 April 2009
Available online 22 April 2009
Keywords:
Desmethylfibrates
Cholesterol
Triglycerides
Hypolipidemic
1. Introduction
[6]. The presence of the acidic functionality is critical for the hypo-
lipidemic action of fibrates [5]. Unfortunately, the free carboxylic
Hyperlipidemia is the major risk factor for atherosclerosis and
atherosclerosis-associated conditions such as coronary heart
diseases (CHD), ischaemic cerebrovascular diseases, and peripheral
vascular diseases. A 1% drop in serum cholesterol level was reported
to reduce the risk for CHD by 2% [1]. The search for effective and safe
hypolipidemic agents has engaged the interests of medicinal
chemists, biochemists, pharmacologists and clinicians. Fibric acid
derivatives (fibrates) represent an important class of lipid modifying
agents. The discovery of the biological target of fibrates, peroxisome
proliferator-activated receptors (PPARs) specifically the alpha iso-
type, enabled to explain the diverse lipid and non-lipid effects of
fibrates which contribute in their hypolipidemic and antiathero-
sclerotic benefits [2–4]. Literature references to SAR for this class of
drugs are sparse [5]. In order to define the structural requirements
for the maximal hypolipidemic properties related to fibrates, several
modifications of the fibrate moiety were reported and their biolog-
ical activities were investigated. From the literature, it is evident that
the high lipophilicity is required for the optimal antidyslipidemic
effects of fibrates. Although most active fibrates contain a phenox-
yisobutyrate moiety [5], it was proven that the desmethyl fibrate
analogs (2-phenoxypropionic acid derivatives) e.g. desmethylclofi-
bric acid retained the hypolipidemic activity with fewer side effects
group is responsible for the potential unwanted gastrointestinal
discomfort which is a frequent side effect associated with fibrate
therapy [7,8]. Modification of the carboxylic group to less acidic
functions as amides, hydrazides and cyclic derivatives may help to
minimize the gastrointestinal upset [9]. Moreover, several
compounds containing the 1,2,4-triazole and pyrazole moieties were
found to be of value in the management of hyperlipidemia [10,11].
Motivated by these findings, the present work aims at the design,
synthesis and hypolipidemic study of novel 2-(naphthalen-2-ylox-
y)propionic acid derivatives as desmethyl fibrate analogs. The new
analogs are designed to be prepared by replacement of the p-chlor-
ophenyl moiety in clofibric acid by the lipophilic 2-naphthyl moiety
and the carboxyl function by selected carboxylic acid derivatives like
amide, hydrazide and some cyclic derivatives (pyrazole, 1,2,4-tri-
azole and their isosteric 1,3,4-oxadiazole) with the aim of exploring
the impact of such modifications on the hypolipidemic profile.
O
O
O
O
OH
OH
Cl
Cl
* Corresponding author. Tel.: þ20165607771; fax: þ20862369075.
E-mail address: omarsokar@yahoo.com (O.M. Aly).
Clofibric acid
Desmethylclofibric acid
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.04.026

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G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
2. Results and discussion
explained by the strong intermolecular hydrogen bonding as
reported [18,19]. These findings in the IR and 1H NMR data clearly
provide the evidence for intramolecular cyclization of the thio-
semicarbazides into the corresponding 1,2,4-triazoline-5-thiones.
Furthermore, The IR spectra of compounds 7a,b indicate that they
predominantly exist in the thione form rather than the tautomeric
thiol form; there was no absorption of the SH at 2600–2500 cmꢁ1
[20], but bands due to NH (3122–3084 cmꢁ1) and N–C]S groups
(1356–1350, 1251, 1213–1210, 1177 cmꢁ1) were observed. The two
novel thioethers 8a,b were prepared by reacting the 1,2,4-triazo-
line-5-thiones 7a,b with ethyl iodide in the presence of either
anhydrous K2CO3 in refluxing acetone [21] or sodium methoxide in
methanol [20]. It was noticed that using a stronger base catalyst
(sodium methoxide) improved the yield and shortened the reaction
2.1. Chemistry
The syntheses of the designed compounds are outlined in
Schemes 1 and 2. The key intermediate, 2-(naphthalen-2-yloxy)
propionic acid ethyl ester 1 was prepared in excellent yield by
treating b-naphthol with ethyl 2-bromopropionate in boiling dry
acetone in the presence of anhydrous potassium carbonate [12–14].
The hydrazide 4 was prepared by treating the ester 1 with hydra-
zine hydrate in refluxing ethanol for 4 h. Base-catalyzed hydrolysis
of the ester 1 using sodium hydroxide afforded the acid 2 that was
converted to the corresponding amide 3 by the mixed anhydride
method using ethyl chloroformate in the presence of triethylamine
as a base at 0–5 ꢀC [15]. The synthesis of the target N-alkylidene/
arylidene hydrazides 5a–d was accomplished via the condensation
of equimolar amounts of the hydrazide 4 and the appropriate
carbonyl compounds in refluxing ethanol. It is noteworthy that the
two methyl groups of the hydrazone 5c appeared as two separate
time. The disappearance of NH absorption (3122–3084 cmꢁ1
)
characteristic for the IR spectra of the triazoles 7a,b supported the
etherification process. In the 1H NMR spectra of compounds 8a,b,
the lack of signals arising from the triazoline CS–NH function at
13.80 and 13.30 ppm, observed with compounds 7a,b, respectively,
also provided the evidence for the formation of thioether function.
Another support for elucidating the structures of these compounds
was the presence of absorptions arising from the ethyl protons at
singlets at d
2.04 and 2.06 ppm resembling those observed in the 1H
NMR spectrum of dimethylformamide [16]. In such cases of
restricted rotation due to C]N of the hydrazone moiety, the two
methyl groups are magnetically non-equivalent and appear as two
separate singlets [17]. Heating equimolar amounts of the hydrazide
4 and alkyl/aryl isothiocyanate in ethanol at reflux afforded the
1,4-disubstituted thiosemicarbazides 6a–c. Intramolecular cycliza-
tion of the 1,4-disubstituted thiosemicarbazides 6a,c in the pres-
ence of aqueous 2 N NaOH afforded the 1,2,4-triazoline-5-thiones
7a,b. The IR spectra of compounds 6a,b lacked the amidic C]O
(1687–1667 cmꢁ1) characteristic for the thiosemicarbazides 6a,c.
The 1H NMR spectra of compounds 7a,b lacked the three amidic NH
protons characteristic for the thiosemicarbazides 6a,c, but showed
a downfield broad singlet resonating at 13.30–13.80 ppm for the
triazoline CS–NH. This strong deshielding of CS–NH is probably
d
1.55 ppm for CH3 and d 4.60 ppm for CH2. The oxadiazole-2-thi-
one derivative 9 was prepared, according to the reported procedure
for the synthesis of analogous compounds [22–24], via cyclization
of the hydrazide 4 with carbon disulphide in the presence of
potassium hydroxide in refluxing ethanol. In the IR spectrum, the
absence of C]O band (characteristic for the hydrazide) together
with the appearance of vibrational bands at 3297 cmꢁ1 (NH), 1625–
1597 cmꢁ1 (C]N) and 1509, 1361–1331, 1250–1177 cmꢁ1 (N–C]S)
supports the conversion of the hydrazide 4 to the corresponding
1,3,4-oxadiazole-2-thione 9. Additionally, the absence of SH
absorption at 2600–2500 cmꢁ1 and the presence of bands due to
NH and N–C]S suggest the existence of compound 9 in the thione
OH
Br
K2CO3 anhyd.
dry acetone
H3C C COOC2H5
H
CH3
O C COOC2H5
H
1
i. NaOH
ii. HCl
NH2NH2.H2O
EtOH,
Reflux
CH3
CH3
OC CONHNH2
H
O C COOH
H
4
2
O
i. ClCOOEt,
ii. p-anisidine
R1 C R2
(Et)3N, 0-5°c
CH3
R1
O
C
H
CONHN
C
H
C
OCH3
O
CONH
R2
CH3
5a-d
3
;
5a R1 =p-(OCH3)C6H4 , R2 = H
;
5b
R
1 = p-(NO2)C6H4 , R2 = H
;
5c R1 = CH3, R2 = CH3
;
5d R1 = p -(Br)C6H4 , R2 = CH3
Scheme 1.

G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
3975
CH
3 N
NH
O
C
H
S
O
9
CS2, KOH
CH3
C CONHNHC
S
CH3
O C C
O
N
NHR
CH3
H
N
RNCS
Ethylacetoacetate
4
H
O
O
6a-c
11
6a;
6b;
6c;
R = CH3CH2
R = CH2=CH-CH2
R = C6H5
O BrBr
C C
H H
(Et)3N
EtOH
C
2N NaOH
CH3
N
NH
O C
H
N
R
S
CH3
N
7a; R = CH3CH2
7b; R = C6H5
O
7a,b
C
N
C
O
H
HO
C2H5I,
base
10
CH3 N
C
N
O
H
N
SCH2CH3
R
8a,b
8a; R = CH3CH2
8b; R = C6H5
Scheme 2.
rather than the thiol form. In the 1H NMR spectrum of compound 9,
the absence of NH and NH2 absorptions characteristic for the
hydrazide moiety and the appearance of a downfield broad singlet
control. The results were compared with that obtained by the
reference hypolipidemic agent gemfibrozil.
resonating at
d
12.80 ppm characteristic for the oxadiazoline CS–
2.2.1. Effect of high cholesterol diet feeding on the lipid profile
of adult male rats
NH supports the formation of compound 9. Clasien–Schmidt
condensation of benzaldehyde and acetophenone in the presence
of NaOH afforded the corresponding chalcone that was readily
brominated to the corresponding dibromo derivative [25]. Reaction
of the dibromo derivative with the hydrazide 4 in the presence of
triethylamine in refluxing ethanol for 24 h afforded the desired
hydroxypyrazoline 10. The 1H NMR spectrum of compound 10
showed a singlet at 4.99 ppm for the hydroxyl group. In addition,
the methylene protons of hydroxypyrazoline ring appeared as two
separate doublets centered at 3.47 ppm and 3.73 ppm with
a geminal coupling constant (J ¼ 18.6 Hz). The appearance of the
two doublets clearly reveals the magnetic non-equivalence of the
two protons of CH2 group adjacent to a chiral centre [25]. Heating
equimolar amounts of the hydrazide 4 and ethyl acetoacetate in
absolute ethanol at reflux afforded the methylpyrazolone 11. The
appearance of two separate doublets for the pyrazolone–CH2
protons with a strong coupling constant (J ¼ 16 Hz) reflects the
magnetic non-equivalence of the two protons.
The results revealed that feeding rats with high cholesterol diet
for 14 days significantly elevated the serum level of total choles-
terol, triglycerides and LDL by 59.58%, 71.76% and 102.36% respec-
tively, when compared with normal control rats. Moreover,
induction of hyperlipidemia significantly decreased serum HDL
level by 34.77% from that of normal control rats.
2.2.2. Effect of the tested compounds and gemfibrozil on serum TC
of hyperlipidemic rats
High blood total cholesterol (TC) has been known as the most
important risk factor of atherosclerosis [28]. In any population, the
incidence of coronary heart diseases (CHD) is directly related to the
level of TC [29]. The obtained data showed that the tested
compounds produced variable effects on the serum level of TC as
compared to the hyperlipidemic control group. The S-alkylated
mercaptotriazole 8b, the 1,3,4-oxadiazole 9 and the pyrazolone
derivative 11 significantly reduced the serum level of TC of hyper-
lipidemic rats by 19.44%, 16.18% and 15.89%, respectively and were
more active than the reference gemfibrozil which afforded only
4.68% reduction. Moreover, the 1,2,4-triazoline-5-thiones 7a,b and
the amide 3 produced mild hypocholesterolemic activity. No
significant reduction of serum TC was observed in the groups
treated with the hydrazones 5a–d or the 1,4-disubstituted thio-
semicarbazides 6a–c (Fig. 1).
2.2. Antihyperlipidemic activity
The hypolipidemic activity of the synthesized compounds was
studied in the high cholesterol diet (HCD) fed hyperlipidemic rat
model against hyperlipidemic control [i.e., rats fed with HCD and
given drug vehicle (0.5% carboxymethylcellulose)], by oral admin-
istration of 20 mg/kg of the tested compounds. Hyperlipidemia was
induced by feeding rats with high cholesterol diet (enriched with
2% cholesterol and 1% cholic acid) [26,27]. Rats receiving normal
rodent chow and the drug vehicle (0.5% CMC) served as normal
2.2.3. Effect of the tested compounds and gemfibrozil on serum TG
of hyperlipidemic rats
Elevated serum triglyceride level has been found to increase the
risk of developing hypertension and insulin resistance. It may also

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G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
125
100
75
50
25
0
16.18%
16.36%
19.44%
**
**
**
2
3
9
5c
6c
5a
5b
5d
6a
6b
7a
7b
8a
8b
10
11
gemfibrozil
Normal Control
Hyperlipidemic control
Fig. 1. Effect of the new compounds and intermediate acid 2 on serum TC of hyperlipidemic rats. Significantly different from hyperlipidemic control group at *P < 0.05, **P < 0.01.
Reduction in the level of serum TC is calculated for groups as percentage from the hyperlipidemic control group.
promote atherogenesis by inducing a prothrombic state (i.e.,
increased platelet agreeability, elevated fibrinogen concentrations,
increased plasminogen activator inhibitors [PAI], increased factor
VII, and increased factor X clotting activity) [30]. Patients with very
high triglyceride concentrations (500 mg/dL or greater) are
susceptible to develop acute pancreatitis [30,31]. Therefore, both
pharmacological and non-pharmacological measures should be
considered in patients with high triglyceride concentrations
[30–32]. Results of the present study revealed that the tested
compounds produced variable effects on serum TG level of hyper-
lipidemic rats. Among the tested compounds, the 1,3,4-oxadiazole
9, the 1,2,4-triazoline-5-thione 7a and the S-alkylated mercapto-
triazole 8b afforded significant hypotriglyceridemic activity
ranging from 19.07 to 26.78% reduction in serum level of TG of
hyperlipidemic rats being nearly equipotent to gemfibrozil which
reduced the serum level of TG by 22.23%. Moreover, the hydrazone
5b, the 1,2,4-triazoline-5-thione 7b and the hydroxypyrazoline 10
produced mild activity (Fig. 2).
2.2.4. Effect of the tested compounds and gemfibrozil on serum HDL
of hyperlipidemic rats
One of the risk factors for atherosclerotic cardiovascular
diseases comprises low levels of the good high-density lipopro-
tein (HDL) cholesterol [33]. Increasing serum concentrations of
HDL has been shown to prevent or delay the progression of CHD
[34]. One of the reported mechanisms for the protective action of
HDL from coronary heart disease may be that HDL collects
cholesterol particles from the cells and other circulating lipo-
proteins which in turn counteract the role of LDL thus preventing
the formation of atherosclerotic lesions [35]. Results of the
present investigation indicated that significant elevation of serum
level of HDL of hyperlipidemic rats ranging from 47.78% to 55.42%
110
100
19.07%
22.23%
90
26.78%
20.88%
*
80
**
70
**
**
60
50
40
30
20
10
0
2
3
9
5c
6c
5a
5b
5d
6a
6b
7a
7b
8a
8b
10
11
gemfibrozil
Normal Control
Hyperlipidemic control
Fig. 2. Effect of the new compounds and intermediate acid 2 on serum TG of hyperlipidemic rats. Significantly different from hyperlipidemic control group at *P < 0.05, **P < 0.01.
Reduction in the level of serum TG is calculated for groups as percentage from the hyperlipidemic control group (HCD fed).

G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
3977
25
20
15
10
5
55.42%
51.21%
47.78%
48.25%
49.73%
**
*
*
*
*
0
2
3
9
5c
6c
5a
5b
5d
6a
6b
7a
7b
8a
8b
10
11
gemfibrozil
Normal Control
Hyperlipidemic control
Fig. 3. Effect of the new compounds and intermediate acid 2 on serum HDL of hyperlipidemic rats. Significantly different from hyperlipidemic control group at *P < 0.05, **P < 0.01.
Elevation in the level of serum HDL is calculated for groups as percentage from the hyperlipidemic control group (HCD fed).
was achieved by the 1,3,4-oxadiazole 9, the 1,2,4-triazoline-5-
thiones 7a,b, the S-alkylated mercaptotriazole 8b and the
hydroxypyrazoline 10. The reference gemfibrozil was less active
affording only 25.18% elevation of serum HDL. Most of the other
compounds afforded moderate improvement of serum HDL
(Fig. 3).
products are potential causes for oxidative modifications of low-
density lipoprotein, which is the key point in the initiation and
progression of atherosclerosis [37,38]. The dietary and pharmaco-
logical lowering of elevated plasma LDL cholesterol appears to be
one of the methods to reduce the development of atherosclerosis. It
has been estimated that each 1% reduction in LDL concentration
may result in a 1% decrease in the incidence of CHD [1]. Interest-
ingly, results of our study revealed that the pyrazolone derivative
11, the 1,3,4-oxadiazole 9 and the S-alkylated mercaptotriazole 8b
significantly reduced the serum level of LDL of hyperlipidemic rats
by percentages ranging from 19.15% to 21.74% being more active
than gemfibrozil. In addition, the acid 2, the 1,2,4-triazoline-5-
thiones 7a,b and the S-alkylated mercaptotriazole 8a exhibited
moderate activity (Fig. 4).
2.2.5. Effect of the tested compounds and gemfibrozil on serum LDL
of hyperlipidemic rats
Elevated serum LDL cholesterol is one of the most powerful and
independent risk factors for CHD. The LDL fraction is generally
thought to carry cholesterol to the tissues and is responsible for the
atherogenesis process [36]. Hypercholesterolemia increases
oxidative stress and leads to lipid peroxidation. Lipid peroxidation
19.15%
21.74%
19.58%
75
50
25
0
*
*
**
2
3
9
5c
6c
5a
5b
5d
6a
6b
7a
7b
8a
8b
10
11
gemfibrozil
Normal Control
Hyperlipidemic control
Fig. 4. Effect of the new compounds and intermediate acid 2 on serum LDL of hyperlipidemic rats. Significantly different from hyperlipidemic control group at *P < 0.05, **P < 0.01.
Reduction in the level of serum LDL is calculated for groups as percentage from the hyperlipidemic control group (HCD fed).

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G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
2.2.6. Ratios of LDL/HDL for tested compounds and gemfibrozil
in hyperlipidemic rats
spectrometer (60 MHz) using TMS as internal standard. Elemental
analyses were performed on a Heraeus Vario EL apparatus.
The HDL fraction leads cholesterol out of the tissue and protects
against atherosclerosis [35], whereas the LDL fraction carries
cholesterol to the tissues and is responsible for the atherogenesis
process [38]. Thus, decreasing the ratio of the plasma level of LDL to
that of HDL seems to play an important role in reducing the risk of
atherosclerosis. Results (Table 1) illustrate that the oxadiazole 9
recorded the lowest LDL/HDL ratio (3.29). Likewise, the S-alkylated
mercaptotriazole 8b and the 1,2,4-triazoline-5-thiones 7a,b afforded
low LDL/HDL ratios expressed as 3.40, 3.61, and 3.75, respectively.
This valuable finding reflects the role of the mentioned compounds
in improving the lipid profile and preventing the progression of
atherosclerosis and subsequent cardiovascular complications.
The analysis of the lipid profile data (TC, TG, HDL and LDL) of
different groups clearly suggests that some of the synthesized
compounds exerted good hypolipidemic activity. The 1,3,4-oxa-
diazole 9 and the S-alkylated mercaptotriazole 8b appear to be
ideal hypolipidemic agents acting via several mechanisms. They
produced striking reduction of serum levels of TC, TG and LDL and
elevation of serum HDL. In addition, the 1,2,4-triazoline-5-thione
7a afforded pronounced reduction of serum TG levels and increase
in HDL. The pyrazolone derivative 11 reduced serum TC and LDL
levels. Moreover, the hydroxypyrazoline 10 was effective in
elevating HDL levels. From the obtained data, it’s obvious that the
presence of the carboxylic group or its amide prodrugs is not
essential for the hypolipidemic activity. This was evidenced by the
good antihyperlipidemic activity of the 1,3,4-oxadiazole 9, the
S-alkylated mercaptotriazole 8b and the pyrazolone derivative 11
which generally exhibited better hypolipidemic activity relative to
gemfibrozil. Comparing the effects of the free acid 2 with gemfi-
brozil, it could be concluded that variation of the aryl moiety
produced remarkable changes in the hypolipidemic activity.
3.1.1. Synthesis of N-(4-methoxyphenyl)-2-(naphthalen-2-
yloxy)propionamide (3)
To a stirred solution of the acid 2 (2.16 g, 10 mmol) in 30 mL dry
chloroform at 0–5 ꢀC, triethylamine (1.01 g, 10 mmol) was added,
followed by ethyl chloroformate (1.08 g, 10 mmol) in a dropwise
manner. The mixture was stirred in the ice bath for 30 min, and
then p-anisidine (1.23 g, 10 mmol) in dry chloroform was added
dropwise. The reaction mixture was stirred for additional 12 h at
room temperature. The solvent was evaporated under reduced
pressure and the crude product was dissolved in 30 mL chloroform,
washed with water (2 ꢂ 30 mL), 5% NaHCO3 solution (2 ꢂ 20 mL),
1 N HCl (2 ꢂ 20 mL), water (2 ꢂ 30 mL) and finally with brine
(2 ꢂ 30 mL). The organic layer was dried over anhydrous sodium
sulfate and evaporated under reduced pressure. The product was
collected and recrystallized from aqueous ethanol to give (2.1 g,
65%) compound 3 as a white powder, mp 154–155 ꢀC. 1H NMR
(270 MHz, CDCl3):
d
1.71 (d, 3H, J ¼ 8.1 Hz, CHCH3), 3.76 (s, 3H,
OCH3), 4.93 (q, 1H, J ¼ 8.1 Hz, CHCH3), 6.82–7.81 (m, 11H, Ar–H),
8.12 (br s, 1H, NH); Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N,
4.36. Found: C, 74.80; H, 6.00; N, 4.36.
3.1.2. General procedure for the synthesis N-(alkylidene or
arylidene)-2-(naphthalen-2-yloxy)propionic acid hydrazides (5a–d)
A mixture of the hydrazide 4 (2.30 g, 10 mmol) and the appro-
priate carbonyl compound (10 mmol) in absolute ethanol (20 mL)
was heated at reflux for 3 h. The reaction mixture was cooled and
the precipitated solid was filtered off, dried and recrystallized from
ethanol to give the target compounds 5a–d.
3.1.2.1. N-(4-Methoxybenzylidene)-2-(naphthalen-2-yloxy)propionic
acid hydrazide (5a). White powder, 74% yield, mp 187–188 ꢀC; 1H
NMR (300 MHz, CDCl3):
d
1.75 (d, 3H, J ¼ 6.6 Hz, CHCH3), 3.83 (s, 3H,
3. Experimental
OCH3), 5.00 (q,1H, J ¼ 6.6 Hz, CHCH3), 6.91–7.83 (m,11H, Ar–H), 8.06 (s,
1H, azomethine proton), 9.30 (bs,1H, NH); Anal. Calcd for C21H20N2O3:
C, 72.40; H, 5.79; N, 8.04. Found: C, 72.32; H, 5.56; N, 8.23.
3.1. Chemistry
Melting points were determined on Stuart electrothermal
melting point apparatus and are uncorrected. IR spectra were
recordedas KBrdisks onaNexusFT-IR spectrometer.1HNMR spectra
were run on a Mercury 300BB NMR spectrometer (300 MHz), on
a JEOL EX-270NMR spectrometer (270 MHz), on a GEMINI-200 NMR
3.1.2.2. N-(4-Nitrobenzylidene)-2-(naphthalen-2-yloxy)propionic acid
1
hydrazide (5b). Yellow crystals, yield 83%, mp 188–190 ꢀC; H NMR
(60 MHz, CDCl3):
d
1.80 (d, 3H, J ¼ 7.2 Hz, CHCH3), 5.30 (q, 1H,
J ¼ 7.2 Hz, CHCH3), 7.60–9.00 (m, 11H, Ar–H), 10.70 (s, 1H, azome-
thine proton), 11.50 (bs, 1H, NH); Anal. Calcd for C20H17N3O4: C,
66.11; H, 4.72; N, 11.56. Found: C, 66.09; H, 4.51; N, 11.52.
spectrometer (200 MHz) and on
a Varian EM-360L NMR
Table 1
3.1.2.3. N-Isopropylidene-2-(naphthalen-2-yloxy)propionic
hydrazide (5c). White powder, yield 65%, mp 128–129 ꢀC; 1H NMR
(270 MHz,CDCl3):
CH3), 2.06 (s, 3H,N]C–CH3), 4.99(q,1H,J ¼ 8.1 Hz, CHCH3), 7.06–7.77
(m, 7H, Ar–H), 9.03 (bs,1H, NH); Anal. Calcd for C16H18N2O2: C, 71.09;
H, 6.71; N, 10.36. Found: C, 71.12; H, 6.64; N, 10.42.
acid
Ratios of LDL/HDL for tested compounds and gemfibrozil in hyperlipidemic rats.
Group
LDL/HDLa
d
11.73(d, 3H,J ¼ 8.1 Hz, CHCH3), 2.04(s, 3H, N]C–
Normal control
Hyperlipidemic control
Gemfibrozil
3
2.05
6.36
4.81
5.19
5.40
4.74
6.10
6.04
6.71
8.16
5.70
3.61
3.75
4.50
3.40
3.29
3.99
4.54
5a
5b
5c
5d
6a
6b
6c
7a
7b
8a
8b
9
3.1.2.4. N-[1-(4-Bromophenyl)ethylidene]-2-(naphthalen-2-yloxy)
propionic acid hydrazide (5d). White powder, yield 67%, mp 162–
163 ꢀC; 1H NMR (270 MHz, CDCl3):
d
1.75 (d, 3H, J ¼ 8.1 Hz,
CHCH3), 2.08 (s, 3H, N]C–CH3), 5.04 (q, 1H, J ¼ 7.2 Hz, CHCH3),
7.05–8.12 (m, 11H, Ar–H), 9.35 (bs, 1H, NH); Anal. Calcd for
C21H19BrN2O2: C, 61.32; H, 4.66; N, 6.81. Found: C, 61.34; H, 4.59;
N, 6.80.
3.1.3. General procedure for the synthesis of 1-[2-(naphthalen-2-
yloxy)propionyl]-4-substituted thiosemicarbazides (6a–c)
A mixture of the hydrazide 4 (2.30 g, 10 mmol) and the appro-
priate alkyl or aryl isothiocyanate (10 mmol) in absolute ethanol
10
11
a
LDL/HDL ratios are calculated from the mean values of LDL and HDL.

G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
3979
was heated at reflux for 3 h. The mixture was cooled and the
precipitated solid was filtered, dried and recrystallized from
ethanol to give compounds 6a–c.
carbonate (0.5 g) in dry acetone (20 mL) was heated at reflux for
8 h. The reaction mixture was cooled, poured on ice cooled water
and stirred well. The precipitated solid was filtered, washed with
water, dried and recrystallized from ethanol to give compounds
8a,b.
Method B: To a mixture of the 1,2,4-triazole-5-thiones 7a or 7b
(10 mmol) and sodium methoxide [prepared from sodium (0.46 g,
20 mmol) and MeOH (15 mL)], ethyl iodide (1.56 g, 10 mmol) was
added dropwise. The reaction mixture was heated at reflux for 1 h,
then cooled to room temperature, poured on ice cooled water and
stirred well. The solid obtained was filtered, washed with water,
dried and recrystallized from ethanol to give the target compounds
8a,b.
3.1.3.1. 1-[2-(Naphthalen-2-yloxy)propionyl]-4-ethyl thiosemicarbazide
(6a). White powder, yield 75%, mp 161–163 ꢀC; IR (cmꢁ1): 3376,
3289 (NH), 3094 (Arom-CH), 2974–2932 (Aliph-CH), 1687 (C]O),
1540, 1251, 1211, 1178 (N–C]S), 1626, 1506, 1460 (CjC), 1060, 1094
(C–O–C); 1H NMR (60 MHz, CDCl3):
d
0.90 (t, 3H, J ¼ 8 Hz, CH2CH3),
1.80 (d, 3H, J ¼ 6.6 Hz, CHCH3), 3.60 (q, 2H, J ¼ 8 Hz, CH2CH3), 5.40 (q,
1H, J ¼ 6.6 Hz, CHCH3), 6.80 (bs, 1H, CSNH), 7.70–8.50 (m, 7H, Ar–H),
9.20 (bs, 1H, NHCS), 9.80 (bs, 1H, CONH); Anal. Calcd for C16H19N3O2S:
C, 60.54; H, 6.03; N, 13.24. Found: C, 60.67; H, 6.00; N, 13.29.
3.1.3.2. 1-[2-(Naphthalen-2-yloxy)propionyl]-4-allyl thiosemicarbazide
3.1.5.1. 3-Ethylthio-5-[1-(naphthalen-2-yloxy)ethyl]-4-ethyl-4H-1,2,4-
triazole (8a). White powder, yield 64% (method A), 77% (method
B); mp 111–112 ꢀC; IR data (cmꢁ1): 3032 (Arom-CH), 2986–2922
(Aliph-CH), 1623, 1596, 1512, 1487, 1465 (C]N, CjC), 1081 (C–O–C),
(6b). White powder, yield 59%, mp 165–166 ꢀC; 1H NMR (270 MHz,
CDCl3):
d
1.68 (d, 3H, J ¼ 8.1 Hz, CHCH3), 3.94 (m, 2H, CSNHCH2),
5.01 (m, 3H, CHCH3 þ NHCH2CH]CH2), 5.57 (m, 1H,
NHCH2CH]CH2), 6.39 (bs, 1H, CSNH), 7.19–7.81 (m, 7H, Ar–H), 8.48
(bs, 1H, NHCS), 8.99 (bs, 1H, CONH); Anal. Calcd for C17H19N3O2S: C,
61.98; H, 5.81; N, 12.76. Found: C, 62.00; H, 5.79; N, 12.72.
695, 751 (C–S); 1H NMR (60 MHz, CDCl3):
d
1.35 (t, 3H, J ¼ 7 Hz,
SCH2CH3), 1.55 (t, 3H, J ¼ 7 Hz, NCH2CH3), 2.00 (d, 3H, J ¼ 7.2 Hz,
CHCH3), 3.55 (q, 2H, J ¼ 7 Hz, SCH2CH3), 4.40 (q, 2H, J ¼ 7 Hz,
NCH2CH3), 6.35 (q, 1H, J ¼ 7.2 Hz, CHCH3), 7.70–8.60 (m, 7H, Ar–H);
Anal. Calcd for C18H21N3OS: C, 66.02; H, 6.46; N, 21.83. Found: C,
66.00; H, 6.46; N, 21.78.
3.1.3.3. 1-[2-(Naphthalen-2-yloxy)propionyl]-4-phenyl thiosemicar-
bazide (6c). White powder, yield 77%, mp 191–192 ꢀC; IR (cmꢁ1):
3315, 3171 (NH), 3024 (Arom-CH), 2937 (Aliph-CH), 1667 (C]O),
1546, 1215, 1211, 1178 (N–C]S), 1595, 1497, 1468 (CjC), 1122, 1050
3.1.5.2. 3-Ethylthio-5-[1-(naphthalen-2-yloxy)ethyl]-4-phenyl-4H-
1,2,4-triazole (8b). White powder, yield 59% (method A), 71%
(method B); mp 101–103 ꢀC; IR data (cmꢁ1): 3060 (Arom-CH),
2929–2857 (Aliph-CH), 1627, 1597, 1525, 1498 (C]N, CjC), 1180,
(C–O–C); 1H NMR (60 MHz, CDCl3):
d
1.70 (d, 3H, J ¼ 6.4 Hz, CHCH3),
5.00 (q, 1H, J ¼ 6.6 Hz, CHCH3), 7.22–7.77 (m, 12H, Ar–H), 8.32 (bs,
1H, CSNH), 9.05 (bs, 1H, NHCS), 9.66 (bs, 1H, CONH); Anal. Calcd for
C20H19N3O2S: C, 65.73; H, 5.24; N, 11.50. Found: C, 65.80; H, 5.24; N,
11.48.
1055 (C–O–C), 694, 755 (C–S); 1H NMR (60 MHz, CDCl3):
d 1.35
(t, 3H, J ¼ 7 Hz, SCH2CH3), 1.80 (d, 3H, J ¼ 7.2 Hz, CHCH3), 3.55 (q,
2H, J ¼ 7 Hz, SCH2CH3), 6.00 (q, 1H, J ¼ 7.2 Hz, CHCH3), 7.30–8.50
(m, 12H, Ar–H); Anal. Calcd for C22H21N3OS: C, 70.37; H, 5.64; N,
11.19. Found: C, 70.41; H, 5.72; N, 11.20.
3.1.4. General procedure for the synthesis of 3-[1-(naphthalen-2-
yloxy)ethyl]-4-ethyl/phenyl-1,4-dihydro-1,2,4-triazole-5-thione (7a,b)
A solution of the thiosemicarbazide derivatives 6a or 6c
(10 mmol) in aqueous 2 N sodium hydroxide (15 mL) was heated at
reflux for 3 h. The solution was cooled and acidified with hydro-
chloric acid to pH 4.5. The precipitated solid was then filtered,
washed with water, dried and recrystallized from aqueous ethanol
to give the target compounds 7a,b.
3.1.6. Synthesis of 5-[1-(naphthalen-2-yloxy)ethyl]-3H-1,3,4-
oxadiazole-2-thione (9)
To a solution of the hydrazide 4 (2.30 g, 10 mmol) in ethanol
(100 mL) was added a solution of KOH (0.84 g, 15 mmol) in ethanol
(20 mL), followed by CS2 (8 mL). The reaction mixture was heated
at reflux for 8 h. The solution was concentrated under reduced
pressure and acidified with hydrochloric acid. The precipitated
solid was filtered off, washed with water, dried and recrystallized
from methanol/H2O to give (1.88 g, 69%) compound 9 as yellowish
white crystals, mp 121–122 ꢀC; IR (cmꢁ1): 3297 (NH), 3048 (Arom-
CH), 1625, 1597, 1572 (C]N, CjC), 1509, 1361–1331, 1250–1177,
3.1.4.1. 3-[1-(Naphthalen-2-yloxy)ethyl]-4-ethyl-1,4-dihydro-1,2,4-
triazole-5-thione (7a). White powder, yield 47%, mp 150–152 ꢀC;
IR data (cmꢁ1): 3122 (NH), 3048 (Arom-CH), 2982–2948 (Aliph-
CH), 1596, 1572, 1485 (C]N, CjC), 1356, 1251, 1210, 1176 (N–
C]S), 1088 (C–O–C); 1H NMR (60 MHz, CDCl3):
d 1.55 (t, 3H,
J ¼ 8 Hz, CH2CH3), 2.00 (d, 3H, J ¼ 7.2 Hz, CHCH3), 4.60 (q, 2H,
J ¼ 8 Hz, CH2CH3), 6.15 (q, 1H, J ¼ 7.2 Hz, CHCH3), 7.70–8.60 (m,
7H, Ar–H), 13.80 (bs, 1H, NH); Anal. Calcd for C16H17N3OS: C,
64.19; H, 5.72; N, 14.04. Found: C, 64.22; H, 5.72; N, 14.00.
(N–C]S), 1088 (C–O–C). 1H NMR (60 MHz, CDCl3):
d 1.80 (d, 3H,
J ¼ 7.2 Hz, CHCH3), 5.80 (q, 1H, J ¼ 7.2 Hz, CHCH3), 7.40–8.50 (m, 7H,
Ar–H), 12.80 (bs, 1H, NH). Anal. Calcd for C14H12N2O2S: C, 61.75; H,
4.44; N, 10.29. Found: C, 62.00; H, 4.48; N, 10.25.
3.1.4.2. 3-[1-(Naphthalen-2-yloxy)ethyl]-4-phenyl-1,4-dihydro-1,2,4-
triazole-5-thione (7b). White powder, yield 58%, mp 214–215 ꢀC; IR
data (cmꢁ1): 3084 (NH), 3022 (Arom-CH), 2924–2772 (Aliph-CH),
1596, 1561 (C]N, CjC), 1499, 1350, 1251, 1213, 1177 (N–C]S), 1124,
3.1.7. Synthesis of 1-(5-hydroxy-3,5-diphenyl-4,5-dihydropyrazol-
1-yl)-2-(naphthalen-2-yloxy)propan-1-one (10)
To a solution of the dibromo derivative (3.67 g, 10 mmol) in
absolute ethanol (75 mL) were added the hydrazide 4 (2.30 g,
10 mmol) and triethylamine (10 mL). The reaction mixture was
heated at reflux for 24 h on a water bath. The volume of the solution
was reduced, cooled, poured on crushed ice and kept overnight. The
precipitated solid was collected by filtration and recrystallized from
methanol to give (2.5 g, 57%) compound 10 as white powder, mp
1079 (C–O–C); 1H NMR (60 MHz, CDCl3):
d
1.80 (d, 3H, J ¼ 7.2 Hz,
CHCH3), 5.80 (q, 1H, J ¼ 7.2 Hz, CHCH3), 7.40–8.50 (m, 12H, Ar–H),
13.30 (bs, 1H, NH). Anal. Calcd for C20H19N3OS: C, 69.14; H, 4.93; N,
12.09. Found: C, 69.22; H, 5.00; N, 12.12.
3.1.5. General procedure for the synthesis of 3-ethylthio-5-[1-
(naphthalen-2-yloxy)ethyl]-4-ethyl/phenyl-4H-1,2,4-triazoles
(8a,b)
Method A: A mixture of the 1,2,4-triazole-5-thiones 7a or 7b
(10 mmol), ethyl iodide (1.56 g,10 mmol) and anhydrous potassium
124–126 ꢀC; 1H NMR (200 MHz, CDCl3):
d
1.76 (d, 3H, J ¼ 6.4 Hz,
CHCH3), 3.47 (d, 1H, J ¼ 18.6 Hz, pyrazoline–CH2), 3.73 (d, 1H,
J ¼ 18.6 Hz, pyrazoline–CH2), 4.99 (s, 1H, OH), 5.87 (q, 1H, J ¼ 6.4 Hz,
CHCH3), 7.15–7.78 (m, 17H, Ar–H); Anal. Calcd for C28H24N2O3: C,
77.04; H, 5.54; N, 6.42. Found: C, 77.10; H, 5.42; N, 6.44.

3980
G.A. Idrees et al. / European Journal of Medicinal Chemistry 44 (2009) 3973–3980
3.1.8. Synthesis of 3-methyl-1-[2-(naphthalen-2-yloxy)propionyl]-
1,4-dihydropyrazol-5-one (11)
pyrazolone derivative 11 which generally exhibited better
hypolipidemic activity relative to gemfibrozil. Comparing the
effects of the free acid 2 with gemfibrozil, it could be concluded
that variation of the aryl moiety produced remarkable changes
in the hypolipidemic activity.
A mixture of the hydrazide 4 (2.30 g, 10 mmol) and ethyl ace-
toacetate (1.30 g, 10 mmol) in absolute ethanol was heated at reflux
for 3 h. The reaction mixture was cooled and the formed precipitate
was filtered off, dried and recrystallized from acetic acid/H2O to
give (2 g, 67%) compound 11 as white solid, mp 162–163 ꢀC; 1H
References
NMR (300 MHz, CDCl3):
d
1.72 (d, 3H, J ¼ 8 Hz, CHCH3), 2.14 (s, 3H,
CH3 at C-3 of pyrazoline), 3.37 (d, 1H, J ¼ 16 Hz, pyrazoline–CH2),
3.43 (d, 1H, J ¼ 16 Hz, pyrazoline–CH2), 5.00 (q, 1H, J ¼ 8 Hz,
CHCH3), 7.17–7.81 (m, 7H, Ar–H); Anal. Calcd for C17H16N2O3: C,
68.91; H, 5.44; N, 9.45. Found: C, 69.00; H, 5.42; N, 9.52.
[1] K.S. Jain, M.K. Kathiravan, R.S. Somani, C.J. Shishoo, Bioorg. Med. Chem. 15
(2007) 4674–4699.
[2] S. Kersten, B. Desvergne, W. Wahli, Nature 405 (2000) 421–442.
[3] T.M. Willson, P.J. Brown, D.D. Sternbach, B.R. Henke, J. Med. Chem. 43 (2000)
527–550.
[4] J.C. Fruchart, B. Staels, P. Duriez, Curr. Atheroscler. Rep. 3 (2001) 83–92.
[5] D.A. Williams, T.L. Lemke, Foye’s Principles of Medicinal Chemistry, fifth ed.
Lippincott Williams and Wilkins, Philadelphia, Baltimore, 2002, pp. 595–97.
[6] D.R. Feller, V.S. Kamanna, H.A. Newman, K.J. Romstedt, D.T. Witiak, G. Bettoni,
S.H. Bryant, D. Conte-Camerino, F. Loiodice, V. Tortorella, J. Med. Chem. 30
(1987) 1265–1267.
3.2. Antihyperlipidemic activities
Male albino rats of Wistar strain weighing 160–180 g were used
in this study. Rats were obtained from the animal house of National
Research Centre, Dokki, Cairo. The animals were kept for one week
in the laboratory under 12 h day and night cycle for accommoda-
tion with free access to food and water ad libitum. Rats were divided
into control (fed normal rodent chow), hyperlipidemic control and
hyperlipidemic plus compound treated groups. Each group con-
sisted of six animals. Hyperlipidemia was induced by feeding rats
with high cholesterol diet (HCD) for 14 days. The high cholesterol
diet was prepared by mixing normal rodent chow with 2%
cholesterol (Sigma, USA) and 1% cholic acid (Sigma, USA) [37,38].
Hyperlipidemic rats had a free access to the HCD and water ad
libitum during the entire period of the experiment. The tested
compounds as well as the standard drug gemfibrozil were given
orally at a dose of 20 mg/kg using 0.5% CMC as a drug vehicle from
day 8 to day 14 (7 days) in the HCD fed rats. Control and hyper-
lipidemic control rats (fed with HCD) received only the drug vehicle
from day 8 to day 14 of the experiment. At the end of experiment,
that is, on the 14th day, the animals were fasted for 12 h and the tail
blood was collected under mild ether anesthesia. Serum was
separated by centrifugation at 3000 rpm for 10 min for measure-
ment of TC, TG and HDL using Randox kits (UK) on a Jenway UV–vis
spectrophotometer. Serum levels of LDL in mg/dL were calculated
using Friedewald’s formula [39].
[7] A. Korolkovas, Essentials of Medicinal Chemistry, second ed. John Wiley &
Sons, New York, 1988, pp. 513.
[8] R.W. Mahley, T.P. Bersot, in: J.G. Hardman, L.E. Limbird, A.G. Gilman (Eds.),
Goodman and Gilman’s the Pharmacological Basis of Therapeutics, tenth ed.
McGraw-Hill, Medical Publishing Division, New York, 2001 pp. 995 (Chapter 36).
[9] A. Korolkovas, Essentials of Medicinal Chemistry, second ed. John Wiley and
Sons, New York, 1988, pp. 1091–103, 156, 341, 359, 396, 811.
[10] N.S. Habib, K.A. Ismail, A.A. El-Tombary, T. Abdel Aziem, Pharmazie 55 (2000)
495–499.
[11] V.L. Sena, R.M. Srivastava, R.O. Silva, V.L. Lima, Farmaco 58 (2003) 1283–1288.
[12] E. Palaska, G. Sahin, P. Kelicen, N.T. Durlu, G. Altinok, Farmaco 57 (2002) 101–107.
[13] S.A. Khanum, S. Shashikanth, S. Umesha, R. Kavitha, Eur. J. Med. Chem. 40
(2005) 1156–1162.
[14] G. Sahin, E. Palaska, P. Kelicen, R. Demirdamar, G. Altinok, Arzneimittelfor-
schung 51 (2001) 478–484.
[15] G. Kokotos, Synthesis (Stuttgart) 4 (1990) 299–301.
[16] W. Kemp, Organic Spectroscopy, third ed. The Macmillan Press Ltd, Inc.,
London, 1993, pp. 130.
[17] S.D. Joshi, H.M. Vagdevi, V.P. Vaidya, G.S. Gadaginamath, Eur. J. Med. Chem. 42
(2007) 1–8.
¨
[18] I. Ku¨ çu¨kgu¨ zel, S. Rollas, M. Ulgen, J. Pharm. Univ. Mar. 10 (1994) 17–25.
[19] S.G. Ku¨çu¨ kgu¨zel, S. Rollas, H. Erdeniz, M. Kiraz, Eur. J. Med. Chem. 34 (1999)
153–160.
[20] G. Mekuskiene, S. Tumkevicius, P. Vainilavicius, J. Chem. Res. (S) (2002) 213–215.
[21] L. Labanauskas, E. Udrenaite, P. Gaidelis, A. Brukstus, Farmaco 59 (2004)
255–259.
[22] D.H. Boschelli, D.T. Connor, D.A. Bornemeier, R.D. Dyer, J.A. Kennedy,
P.J. Kuipers, G.C. Okonkwo, D.J. Schrier, C.D. Wright, J. Med. Chem. 36 (1993)
1802–1810.
[23] K. Raman, H.K. Singh, S.K. Salzman, S.S. Parmar, J. Pharm. Sci. 82 (1993) 167–169.
[24] G. Sahin, E. Palaska, M. Ekizoglu, M. Ozalp, Farmaco 57 (2002) 539–542.
[25] M.S. Karthikeyan, B.S. Holla, N.S. Kumari, Eur. J. Med. Chem. 42 (2007) 30–36.
[26] V. Sudhahar, S.A. Kumar, P.T. Sudharsan, P. Varalakshmi, Vasc. Pharmacol. 46
(2007) 412–418.
[27] M. Minhajuddin, Z.H. Beg, J. Iqbal, Food Chem. Toxicol. 43 (2005) 747–753.
[28] Third Report of the National Cholesterol Education Program (NCEP) Expert
Panel on Detection, and Treatment of High Blood Cholesterol in Adults (Adult
Treatment Panel III), Final Report. National Institute of Health, NIH Publication
No. 02-5215, September 2002.
4. Statistical analysis
The results obtained were expressed as mean ꢃ SD. The differ-
ence between groups was evaluated by one-way ANOVA test. Mean,
standard deviation calculations and ANOVA test were performed
using ‘‘GraphPad Prism version 4.0’’ software. A P value < 0.05 was
considered significant.
[29] W.P. Castelli, Atherosclerosis 124 (Suppl.) (1996) S1–S9.
[30] S.M. Grundy, Am. J. Cardiol. 81 (1998) 1B–6B.
5. Conclusion
[31] Expert panel on detection, evaluation, and treatment of high blood cholesterol
in adults. Executive summary of the third report of the National Cholesterol
Education Program (NCEP) Expert Panel on detection, evaluation, and treat-
ment of high blood cholesterol in adults (Adult Treatment Panel III), J. Am.
Med. Assoc. 285 (2001) 2486–2497.
[32] S.C. Smith, et al., AHA/ACC scientific statement: AHA/ACC guidelines for pre-
venting heart attack and death in patients with atherosclerotic cardiovascular
disease: 2001 update: a statement for healthcare professionals from the
American Heart Association and the American College of Cardiology, Circu-
lation 104 (2001) 1577–1579.
The analysis of the lipid profile data (TC, TG, HDL and LDL) of
different groups clearly suggests that some of the synthesized
compounds exerted good hypolipidemic activity. The 1,3,4-oxa-
diazole 9 and the S-alkylated mercaptotriazole 8b appear to be
ideal hypolipidemic agents acting via several mechanisms. They
produced striking reduction of serum levels of TC, TG and LDL
and elevation of serum HDL. In addition, the 1,2,4-triazoline-5-
thione 7a afforded pronounced reduction of serum TG levels and
increase in HDL. The pyrazolone derivative 11 reduced serum TC
and LDL levels. Moreover, the hydroxypyrazoline 10 was effec-
tive in elevating HDL levels. From the obtained data, it’s obvious
that the presence of the carboxylic group or its amide prodrugs
is not essential for the hypolipidemic activity. This was evi-
denced by the good antihyperlipidemic activity of the 1,3,4-
oxadiazole 9, the S-alkylated mercaptotriazole 8b and the
[33] T. Gordon, W.P. Castelli, M.C. Hjortland, W.B. Kannel, T.R. Dawber, Am. J. Med
62 (1977) 707–714.
[34] Expert panel on detection, evaluation, and treatment of high blood cholesterol
in adults. Summary of the second report of the National Cholesterol Education
Program (NCEP) Expert Panel on detection, evaluation, and treatment of high
blood cholesterol in adults (Adult Treatment Panel II), J. Am. Med. Assoc. 269
(1993) 3015–3023.
[35] J.L. Marx, Science 205 (1979) 677–679.
[36] J.A. Berliner, J.W. Heinecke, Free Radical Biol. Med. 20 (1996) 707–727.
[37] S. Bedwell, R.T. Dean, W. Jessup, Biochem. J. 262 (1989) 707–712.
[38] D.A. Cox, M.L. Cohen, Pharmacol. Rev. 48 (1996) 3–19.
[39] W.T. Friedewald, R.I. Levy, D.S. Fredrickson, Clin. Chem. 18 (1972) 499–502.