Discovery of amide based fibrates as possible antidyslipidemic and antioxidant agents

Article abstract of DOI:10.1016/j.ejmech.2012.09.040

A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The results of the above studies shows that the compounds synthesized on fibrate based pharmacophores might result in identification of new lead for dyslipidemia.

Full text of DOI:10.1016/j.ejmech.2012.09.040

European Journal of Medicinal Chemistry 57 (2012) 302e310
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Original article
Discovery of amide based fibrates as possible antidyslipidemic and antioxidant
agentsq
,
a
a
b
b
Koneni V. Sashidhara a , Gopala Reddy Palnati , Ranga Prasad Dodda , Ravi Sonkar , A.K. Khanna ,
*
Gitika Bhatia b
a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Chattar Manzil Palace, Lucknow 226 001, Uttar Pradesh, India
b Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of amide based fibrates were synthesized and evaluated for antidyslipidemic activity in
triton induced hyperlipidemic rats. Interestingly, the compound 13 produced striking reduction in serum
levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG). In addition, it exhibited
improved lipoprotein lipase activity and found to possess moderate radical scavenging potential. The
results of the above studies shows that the compounds synthesized on fibrate based pharmacophores
might result in identification of new lead for dyslipidemia.
Received 30 June 2012
Received in revised form
18 September 2012
Accepted 21 September 2012
Available online 3 October 2012
Ó 2012 Elsevier Masson SAS. All rights reserved.
Keywords:
Amide based fibrates
Antidyslipidemic
Triton model
Antioxidant activity
1. Introduction
lowering serum triglycerides and raising HDL-cholesterol (HDL-C)
and remain the current treatment of choice for patients with severe
Elevated plasma triglycerides and low high density lipoprotein
cholesterol (HDL-C) are diagnostic markers for metabolic
syndrome, these abnormalities are among the key risk factors for
cardiovascular diseases [1,2]. Current therapies include both
increasing high density lipoprotein cholesterol (HDL-C) levels and
lowering LDL-C. HDL-C based approaches are much more complex
and sometimes disappointing. These negative results stimulated
interest on drugs that focus on lowering LDL-cholesterol, of these
therapeutics statins (HMG-CoA reductase inhibitors) are pretty
effective. However, statins can hardly normalize the high density
lipoprotein abnormality and most patients still experience adverse
coronary events despite statin therapy. In addition, recent reports
of undesirable side effects (myopathy) of some ‘super statins’
indicate that the scope of improving the potency of this class of
drugs may be modest [3]. The fibrate class of drugs (1e3, Fig. 1)
have been widely used for the clinical treatment of dyslipidemia by
hypertriglyceridemia [4,5]. Mechanistic studies reveals that the
hypolipidemic effect of the fibrate drugs is attributed to the acti-
vation of peroxisome proliferator-activated receptors (PPAR
a) [6e
8] which is one of the three isoforms ( and ) of PPARs [9].
a,
g
d
The elevation of HDL-cholesterol levels observed with fibrates
arises in part from the transcriptional induction of the major HDL
apolipoproteins, apoA-I and apoA-II [10]. Unfortunately a combi-
nation of fibrates and statins has met with serious safety concerns
as exemplified by the withdrawal of cerivastatin in 2001. Therefore,
there is a constant need for a different class of potent compounds to
treat dyslipidemia without severe side effects.
Additionally, oxidative stress is an important factor for the
development and progression of coronary heart diseases (CHD).
The involvement of hydroxyl free radicals has been found to be
a major causative factor for the peroxidative damage to lipoproteins
present in the blood, which are responsible for the initiation and
progression of atherosclerosis [11]. Furthermore, in hyperglycemic
patients, several non-enzymatic glycosylations occurs accompa-
q
nied by glucose oxidation catalyzed by Cuþ2 and Fe2þ resulting in the
Part XXII in the series, “Advances in drug design and discovery”. CSIR-CDRI
ꢀ
manuscript #8324.
formation of O2 and ꢀOH radicals which further accelerates the risk
of cardiac diseases in dyslipidemic subjects. As multiple mecha-
nisms are involved in the development of atherosclerosis
* Corresponding author. Tel.: þ91 9919317940; fax: þ91 522 2628493.
E-mail
addresses:
kv_sashidhara@cdri.res.in,
sashidhar123@gmail.com
(K.V. Sashidhara).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.09.040

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
303
Fig. 1. Chemical structures of some biologically important fibrates and our prototype.
(hyperlipidemia, oxidative stress, and inflammation), agents with
at least two mechanisms of action may offer a therapeutic benefit
compared to those only targeting a single mechanism [12].
Carboxamides represent an important class of compounds found
in versatile building blocks for the preparation of pharmaceuticals
[13]. Moreover, this class of compounds has been clinically used as
therapeutic options [14] such as, lidoderm (5, Fig. 1) and benzafi-
brate (3, Fig. 1) [15]. Furthermore, the natural product amide,
aegeline (4, Fig. 1) was reported to exhibit antidyslipidemic activity
[16]. In continuation of our drug discovery programme on new
antidyslipidemic agents [17e21], and our laboratory experiences on
molecular hybridization approach [22e25], we herein report the
synthesis and biological evaluation of amide based fibrate hybrids as
possible antidyslipidemic agents. In this context a series of novel
amide based fibrates were synthesized (our prototype 6 in Fig. 1)
and evaluated for their lipid lowering and anti-oxidant potential.
Fig. 1 showed chemical structures of some important fibrates and
our synthesized prototype. The frequently prescribed hypolipi-
demic agent, gemfibrozil (2, Fig. 1) having a 5-phenoxypentanoic
moiety instead of the fibric acid moiety is also considered a fibrate
because of having almost similar pharmacological properties as the
other classical fibrates like clofibrate (1, Fig. 1).
is shown in Scheme 1. All the synthesized compounds were char-
acterized using 1H NMR, 13C NMR, IR spectroscopy and mass
spectrometry (Supporting information).
3. Pharmacology
3.1. Animals used
Rats (Charles Foster strain, male, adult, body weight 200e225 g)
were kept in a room with controlled temperature (25e26 ꢁC),
humidity (60e80%) and12/12 h light/dark cycle (light on from
8.00 A.M. to 8.00 P.M.) under hygienic conditions. Animals, which
were acclimatized for one week before starting the experiment, had
free access to the normal diet and water.
3.2. Lipid lowering and post heparin lipolytic activity
Rats were divided into twelve groups, control, triton induced,
triton plus 8e14 & 18e28, and gemfibrozil (100 mg/kg) treated
groups, containing six rats in each group. In this experiment of
18 h, hyperlipidemia was developed by administration of triton
WR-1339 (Sigma chemical company, St. Louis, MO, USA) at a dose
of 400 mg/kg body weight intraperitoneally to animals of all the
groups except the control. These derivatives were macerated with
gum acacia (0.2% w/v), suspended in water and fed simulta-
neously with triton with a dose of 100 mg/kg p.o. to the animals of
treated group and the diet being withdrawn. Animals of control
and triton group without treatment with amide based fibrate
compounds were given same amount of gum acacia suspension
(vehicle). After 18 h of treatment the animals were anaesthetized
with thiopentone solution (50 mg/kg b.w.) prepared in normal
saline and then 1.0 ml blood was withdrawn from retro-orbital
sinus using glass capillary in EDTA coated eppendorf tube
(3.0 mg/ml blood). The blood was centrifuged (at 2500 g) at 4 ꢁC
for 10 min and plasma was separated. Plasma was diluted with
normal saline (ratio of 1:3) and used for analysis of total choles-
terol (TC), triglycerides (TG) and phospholipids (PL) by standard
enzymatic methods [26] and post heparin lipolytic activity (PHLA)
2. Chemistry
The detailed synthetic route of the target compounds (8e14 &
18e28) is outlined in Scheme 1. Following reported procedures,
treating phenol/thiophenol (6e7 & 15e17) with ethyl bromoacetate
in the presence of K2CO3 afforded the corresponding esters deriv-
atives (6ae7a & 15ae17a) which were then subjected to basic
hydrolysis with potassium hydroxide furnished their respective
acids (6be7b & 15be17b), further these were transformed to the
corresponding acid chlorides by using thionyl chloride. Condensa-
tion of the acid chlorides with 4-hydroxy aniline furnished their
corresponding amide derivatives (6ce7c & 15ce17c). The desired
amide based fibrate hybrids (8e14 & 18e28), were obtained in
excellent yield by treating the amides with appropriate substituted
2-bromoesters in the presence of K2CO3. General synthetic scheme

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K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
Scheme 1. Synthesis of novel amide based fibrates. Reagents and conditions: (i) K2CO3, CH3CN, 100 ꢁC, 4 h (ii) 20% aq. KOH, MeOH, rt, 30 min. (iii) (a) Benzene, SOCl2, reflux, 2 h, (b)
Benzene, 4-Hydroxy aniline, reflux, 2 h (iv) Different bromoesters, K2CO3, CH3CN, 100 ꢁC, 4 h.
were assayed (wing and Robinson, 1968) using spectrophotom-
eter, Beckmann auto-analyzer and standard kits purchased from
Beckmann Coulter International, USA.
37 ꢁC for 90 min in metabolic shaker (parallel to the reference con-
taining incubation mixture without enzyme source) [27].
3.4. Antioxidant activity (generation of free radicals)
3.3. Lipoprotein lipase activity
Superoxide anions (Oꢂ2) were generated enzymatically [28] by
xanthine (160 mM), xanthine oxidase (0.04 U) and nitroblue
The incubation mixture containing 0.2 ml plasma, 0.01 ml intra-
lipid emulsion, 0.1 ml heparin (0.1% w/v, in normal saline), 0.5 ml BSA
(2.5% inTriseHCl buffer), and 0.3 ml TriseHCl buffer was incubated at
tetrazolium (320
mM) in absence or presence of compounds
(100 g/ml) in 100 mM phosphate buffer (pH 8.2). Fractions were
m

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
305
Table 1
The lipid lowering activity of amide based fibrates (100 mg/kg) in triton treated hyperlipidemic rats. Triton treated group is compared with control and drug treated group is
compared with triton group.
Compound no.
Structure
Total cholesterol (TC)a
Phospholipids (PL)a
Triglyceride (TG)a
PHLAb
O
O
O
8
ꢂ23***
ꢂ25***
ꢂ26***
þ26***
O
O
HN
O
O
O
9
ꢂ12*
ꢂ9NS
ꢂ13*
þ12*
HN
O
O
O
O
O
O
10
ꢂ25***
ꢂ24***
ꢂ27***
þ23***
O
N
H
O
11
12
ꢂ14*
ꢂ14*
ꢂ19*
ꢂ11*
þ15*
þ17*
O
O
HN
O
O
O
O
O
O
ꢂ21**
ꢂ22**
HN
O
O
O
O
13
14
18
ꢂ26***
ꢂ24***
ꢂ28***
þ24***
S
S
HN
O
O
O
ꢂ6NS
ꢂ4NS
ꢂ5NS
þ7NS
HN
O
O
ꢂ24***
ꢂ23***
ꢂ24***
þ15*
O
O
HN
O
O
O
O
19
20
21
ꢂ10*
ꢂ7NS
ꢂ9NS
ꢂ9NS
ꢂ9NS
ꢂ6NS
ꢂ11*
þ5NS
þ14*
þ13*
HN
O
O
O
O
O
O
O
O
ꢂ10NS
O
N
H
ꢂ10NS
O
HN
O
O
O
(continued on next page)
O

306
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
Table 1 (continued )
Compound no.
Structure
Total cholesterol (TC)a
Phospholipids (PL)a
Triglyceride (TG)a
PHLAb
O
Cl
Cl
O
22
ꢂ25***
ꢂ26***
ꢂ25***
þ23***
O
O
HN
O
O
O
O
23
24
ꢂ6NS
ꢂ9NS
ꢂ6NS
þ9NS
þ12*
HN
O
O
Cl
O
ꢂ9NS
ꢂ6NS
ꢂ8NS
H
N
O
O
O
O
O
Cl
O
25
26
ꢂ8NS
ꢂ7NS
ꢂ10*
ꢂ13*
þ10*
þ9NS
Cl
O
HN
O
O
O
O
O
Cl
O
ꢂ8NS
ꢂ4NS
O
N
H
Cl
O
Cl
O
27
28
ꢂ2NS
ꢂ3NS
ꢂ5NS
þ4NS
Cl
Cl
O
HN
O
O
Cl
O
ꢂ9NS
ꢂ8NS
ꢂ7NS
þ12*
H
N
O
O
O
O
Gemfibrozil
ꢂ31***
ꢂ33***
ꢂ33***
þ31***
NS
Values are mean ꢄ SD of six rats, ***p < 0.001; **p < 0.01; *p < 0.05;
¼ Non significant.
a
mg/dl.
b
n mol. of free fatty acids formed/h/ml of plasma.
sonicated well in phosphate buffer before use. The reaction
mixtures were incubated at 37 ꢁC and after 30 min the reaction was
stopped by adding 0.5 ml glacial acetic acid. The amount of for-
mazone formed was measured at 560 nm on a spectrophotometer.
Percentage inhibition was calculated taking absorption coefficient
of formazone as 7.2 ꢃ 103 Mꢂ1 cmꢂ1. In another set of experiment,
an effect of compounds on generation of hydroxyl radicals ðOHꢂÞ
was also studied by non-enzymic reactants [29]. Briefly OHꢂ were
generated in a non-enzymic system comprised of deoxy ribose
(2.8 mM), FeSO4$7H2O (2 mM), sodium ascorbate (2.0 mM) and
H2O2 (2.8 mM) in 50 mM KH2PO4 buffer, pH 7.4 to a final volume of
2.5 ml. The above reaction mixtures in the absence or presence of
3.5. Statistical evaluation
Data were analyzed using Student’s t-test. The hyperlipidemic
groups were compared with control drug treated groups. Similarly
the generations of oxygen free radicals with different amide based
fibrates were compared with that of their formation without
compounds. P < 0.05 was considered to be significant.
4. Results and discussion
4.1. The lipid lowering activity of amide based fibrates
compounds (100
m
g/ml) were incubated at 37 ꢁC for 90 min.
The present study has been undertaken to evaluate the anti-
dyslipidemic activity of amide based fibrates (8e14 & 18e28) in an
acute triton induced hyperlipidemic model [26,31,32]. Adminis-
tration of triton WRe1339 in rats induced marked hyperlipidemia
as evidenced by increase in the plasma level of total cholesterol TC
Reference samples and reagent blanks were also run simulta-
neously. Malondialdehyde (MDA) content in both experimental and
reference samples were estimated spectrophotometrically by thi-
obarbituric acid method as mentioned above [30].

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
307
(4.05 fold), phospholipids PL (3.31 fold) and triglyceride TG (2.67
fold) as compared to control. Triton treated rats caused inhibition of
plasma PHLA (post heparin lipolytic activity) (28%) as compared to
control. Treatment of hyperlipidemic rats with amide based fibrates
(8e14 & 18e28) at the dose of 100 mg/kg p.o. reversed the plasma
levels of lipid with varying extents. The synthesized derivatives
inhibited cholesterol biosynthesis and potentiated the activity of
lipolytic enzymes to early clearance of lipids from circulation in
triton induced hyperlipidemia. Compound 13 was found to be the
most potent in the series as it showed 26%, 24% and 28%, lowering
in TC, PL and TG respectively, while compounds 8, 10, and 22
showed good activity and compounds 12 and 18 showed moderate
activity. These data were comparable with standard hypolipidemic
drug gemfibrozil which at the dose of 100 mg/kg decreased levels
of TC, PL and TG in plasma by 31%, 33% and 33%, respectively.
Compounds 8 and 13 showed significant reversal of PHLA in plasma
of hyperlipidemic rats by 26% and 24%, respectively, comparable to
gemfibrozil, which caused 31% reversal of activity of this enzyme as
compared to control group and the results are summarized in
Table 1.
variation in the proton-electron transfer by the derivatives due to
difference in their structures and stability.
5. Conclusion
In conclusion, inspired by the molecular hybridization approach,
a series of novel amide based fibrates were synthesized and eval-
uated for their anti-hyperlipidemic and in vitro anti-oxidant activ-
ities. Among the synthesized compounds, the compound 13 was
found to be the most promising, owing to the ability as hypolipi-
demic, together with the reduction of intracellular reactive oxygen
species content and improved lipoprotein lipase activity. This
finding encourages us to continue the efforts towards the optimi-
zation of this structural moiety as an important scaffold for the
potential treatment of dyslipidemia.
6. Experimental
All reagents were commercial and were used without further
purification. Chromatography was carried on silica gel (100e120
mesh). All reactions were monitored by TLC (silica gel plates with
fluorescence F254 were used). Melting points were recorded on an
electrically heated melting point apparatus and are uncorrected.
The 1H NMR and 13C NMR spectra were determined on Bruker
Advance DRX-300 MHz spectrometer using TMS as an internal
reference. All shifts are given in ppm and multiplicity (s ¼ singlet,
d ¼ doublet, m ¼ multiplet). The electrospray mass spectra were
recorded on a Thermo Finnigan LCQ Advantage max ion trap mass
spectrometer. IR spectra were recorded on Perkin Elmer AC-1
4.2. Lipoprotein lipase activity of active compounds
Further these active compounds (8, 10, 13, 18, and 22) were
screened for their lipoprotein lipase activity (LPLA). During triton
WR-1339 induction in rat lipase activity of LPL were partially
deactivated which was responsible for the breakdown of higher
lipids into smaller one. As a result lipids level were increased in
blood plasma, our active compounds re-activated the LPL activity
and improved the lipid profile. Out of the five compounds tested,
compounds 8 and 13 showed 24% and 26% increase in compared to
standard drug gemfibrozil which showed 30% increase, while
remaining compounds exhibited moderate activity. The results are
summarized in Table 2.
spectrophotometer in the range of 400e4000 cmꢂ1
.
6.1. General procedure for synthesis of compounds 6ae7a & 15ae
17a
A round-bottomed flask was charged with phenol or thiophenol
compound (1.0 eq.), ethyl bromoacetate (1.2 eq.) and K2CO3 (3.0 eq.)
followed by acetone (15 ml). The resulting mixture was refluxed in
a pre-heated oil bath for 4 h under magnetic stirring. After cooling
to room temperature, acetone was filtered over a pad of celite and
rinsed with acetone (50 ml). The solvent was removed under
reduced pressure and the residue was purified by column chro-
matography on silica gel with ethyl acetate/hexane (1:9) as eluent
to afford corresponding esters (6ae7a & 15ae17a) in high purity
with good yields.
4.3. Antioxidant activities of amide based fibrates
In another experiment, antioxidant activities of amide based
fibrates 8e14 & 18e28 were evaluated by generating free radicals
in vitro in the absence and presence of these compounds. The
scavenging potential of amide based fibrates 8e14 & 18e28 at
ꢀ
200
m
g/ml against formation of O2 and ꢀOH in non-enzymic system
was studied. Further, their effect on lipid peroxidation in micro-
somes was also studied and the results are shown in Fig. 2. Among
the 18 compounds evaluated, compounds 8, 10, 12, 13, 18, and 22
showed significant decrease in superoxide anions inhibition by
25%, 30%, 27%, 31%, 25%, and 33%, hydroxyl radicals inhibition by
25%, 22%, 25%, 28%, 25%, and 26%, and microsomal lipid perox-
idation inhibition by 22%, 22%, 29%, 35%, 25%, and 26%, respectively.
6.1.1. Ethyl 2-(naphthalen-2-yloxy) acetate (6a)
From 2-naphthalol and ethyl bromoacetate; white crystal solid,
yield: 95%; mp 165e167 ꢁC; IR(KBr, cmꢂ1): 3020, 2925, 1718, 1645,
1566, 1504, 1217, 1073; 1H NMR (CDCl3, 300 MHz)
d: 7.81e7.73 (m,
3H)7.49e7.45 (m, 1H) 7.41e7.38 (m, 1H) 7.28e7.25 (m, 1H) 7.10 (d,
J ¼ 1.9 Hz, 1H) 4.76 (s, 2H) 4.32 (q, J ¼ 7.1 Hz, 2H)1.33 (t, J ¼ 7.1 Hz,
3H); ESIeMS: (m/z): 231 (M þ H)þ.
The standard drug alloperinol at 200
in superoxide anions. Manitol and
m
g/ml showed 41% inhibition
a-tocopherol at the dose of
200 mg/ml showed 41% inhibition of hydroxyl ions and 49% inhi-
bition of microsomal lipid peroxidation respectively. The scav-
enging potential of other derivatives was modest. The wide
variation in the free radical scavenging potential may be due to the
6.1.2. Ethyl 2-(2, 4-dichlorophenoxy) acetate (17a)
From 2,4 dichlorophenol and ethyl bromoacetate; white crystal
solid, yield: 92%; mp 175e177 ꢁC; IR(KBr, cmꢂ1): 3010, 2915, 1715,
Table 2
Lipoprotein lipase activity of active compounds (8, 10, 13, 18, and 22).
Control
Triton
Triton þ comp. 8 Triton þ comp.10 Triton þ comp.13 Triton þ comp.18 Triton þ comp.22 Triton þ gemfibrozil
LPL
activitya
125.77 ꢄ 10.18 70.33 ꢄ 5.16*** 92.80 ꢄ 8.16***
90.23 ꢄ 7.92**
95.62 ꢄ 8.93***
84.16 ꢄ 6.00**
88.63 ꢄ 5.17**
100.18 ꢄ 9.10***
(ꢂ44)
(þ24)
(þ22)
(þ26)
(þ16)
(þ21)
(þ30)
Over control
Over triton
Over triton
Over triton
Over triton
Over triton
Over triton
Values are mean ꢄ SD of six rats ***P < 0.001; **P < 0.01; *P < 0.05.
a
n mole fatty acid formed/h/mg protein.

308
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
Fig. 2. The effect of amide based fibrate derivatives (200
microsomes (n mol. MDA formed/mg protein) was shown (standard drugs for superoxide anions-alloperinol (200
peroxidation-a-tocopherol (200
g/ml) were used). Values are mean ꢄ SD of six animals.
m
g/ml) on superoxide ion (n mol. formazone formed/min), hydroxyl ion (n mol. MDA formed/h) and lipid peroxidation in
m
g/ml), hydroxyl ions-manitol and for microsomal lipid
m
1635, 1560, 1514, 1210, 1073; 1H NMR (CDCl3, 300 MHz)
d
: 7.40 (d,
on silica gel with MeOH/CH3Cl (0.5:9.5) to afford 4-hydroxy amides
J ¼ 2.4 Hz,1H) 7.40 (dd, J ¼ 2.4 Hz,1H) 6.79 (d, J ¼ 8.7 Hz,1H) 4.69 (s,
2H) 4.28 (q, J ¼ 7.1 Hz, 2H)1.30 (t, J ¼ 7.1 Hz, 3H); ESIeMS: (m/z):
249 (M þ H)þ.
(6ce7c & 15ce17c) in good yields.
6.3.1. N-(4-hydroxyphenyl)-2-(naphthalen-2-yloxy) acetamide (6c)
From 6b and 4-hydroxy aniline; brown colour solid, yield: 85%;
mp 265e267 ꢁC; IR(KBr, cmꢂ1): 3452, 3010, 2915, 1728, 1645, 1556,
6.2. General procedure forsynthesis of compounds 6be7b& 15be17b
1514, 1217, 1073; 1H NMR (DMSO-d6, 300 MHz)
d: 9.89 (s, NH) 9.26
(s, OH) 7.88e7.78 (m, 3H)7.46e7.29 (m, 6H) 6.72 (d, J ¼ 8.79 Hz, 2H)
The ester compound (6ae7a & 15ae17a) was dissolved in meth-
anol (30 ml) then subjected to basic hydrolysis with 30% aq. KOH
(15 ml)inaround-bottomedflask, theresultingmixturewasstirredat
room temperature for 1 h. Aftercompletion of reaction, methanolwas
removed under reduced pressure subsequently neutralized with
dil.HCl. The resulted white solid was filtered and dried in vacuum
produced the respective acid (6be7b & 15be17b) in good yields.
4.76 (s, 2H); ESIeMS: (m/z): 294 (M þ H)þ.
6.3.2. 2-(2, 4-Dichlorophenoxy)-N-(4-hydroxyphenyl) acetamide
(17c)
From 17b and 4-hydroxyaniline; browncolor solid, yield: 85%; mp
215e217 ꢁC; IR(KBr, cmꢂ1): 3450, 3010, 2915, 1735, 1635, 1550, 1514,
1210, 1173; 1H NMR (DMSO-d6, 300 MHz)
d: 9.88 (s, NH) 9.25 (s, OH)
7.59 (d, J ¼ 2.4 Hz,1H) 7.38e7.35 (m, 3H) 7.09 (d, J ¼ 8.9 Hz,1H) 6.70 (d,
6.2.1. 2-(Naphthalen-2-yloxy) acetic acid (6b)
J ¼ 8.7 Hz, 2H) 4.79 (s, 2H); ESIeMS: (m/z): 313 (M þ H)þ.
From 6a; white solid, yield: 90%; mp 265e267 ꢁC; IR(KBr, cmꢂ1):
3452, 3020, 2925,1718,1645,1566,1504,1217,1073; 1H NMR (DMSO-
d6, 300 MHz) d: 7.84e7.76 (m, 3H)7.46e7.41 (m, 1H) 7.36e7.31 (m, 1H)
6.4. General procedure for synthesis of novel amide based fibrates
(8e14 & 18e28)
7.24e7.17 (m, 2H) 4.75 (s, 2H); ESIeMS: (m/z): 203 (M þ H)þ.
6.2.2. 2-(2, 4-Dichlorophenoxy) acetic acid (17b)
A round-bottomed flask was charged with 4-hydroxy amide
compounds (6ce7c & 15ce17c) (1.0 eq.), different substituted
bromoesters (1.2 eq.) and K2CO3 (3.0 eq.) followed by acetone
(15 ml). The resulting mixture was refluxed under magnetic stirring
in a pre-heated oil bath until the 4-hydroxy amide had been
completely consumed as judged by TLC. After cooling to room
temperature, acetone was filtered over a pad of celite and rinsed
with acetone (50 ml). The solvent was removed under reduced
pressure and the residue was purified by column chromatography
on silica gel with ethyl acetate/hexane (4:6) as eluent to afford
target amide based fibrates (8e14 & 18e28) in good yields.
From 17a; white crystal solid, yield: 87%; mp 205e207 ꢁC; IR(KBr,
cmꢂ1): 3412, 3010, 2915, 1715, 1635, 1560, 1514, 1210, 1073; 1H NMR
(DMSO-d6, 300 MHz)
d
: 7.56 (d, J ¼ 2.4 Hz,1H) 7.33 (dd, J ¼ 2.4 Hz,1H)
7.05 (d, J ¼ 8.9 Hz, 1H) 4.81 (s, 2H); ESIeMS: (m/z): 222 (M þ H)þ.
6.3. General procedure for synthesis of compounds 6ce7c & 15ce17c
A 50 ml round-bottomed flask was charged with a magnetic
stirrer, dry benzene (10 ml), acid compound (6be7b & 15be17b)
and thionyl chloride (1.0 ml). The reaction mixture was refluxed
for 2 h, after completion of required time remove the solvent and
excess SOCl2 under reduced pressure. This acid chloride was again
dissolved in dry benzene (10 ml) followed by addition of 4-hydroxy
aniline in excess, the resulted mixture was refluxed until the acid
chloride had been completely consumed as judged by TLC. After
completion of reaction the solvent was removed under reduced
pressure and the residue was purified by column chromatography
6.4.1. Ethyl2-(4-(2-(naphthalen-2-yloxy)acetamido)phenoxy)
propanoate (8)
From 6c and ethyl 2-bromopropionate; white solid, yield: 80%;
mp: 265e267 ꢁC; IR(KBr, cmꢂ1): 3401, 2940, 2285, 1718, 1645, 1566,
1504, 1217, 1059; 1H NMR (CDCl3, 300 MHz)
d: 8.22 (s, NH) 7.83e
7.74 (m, 3H) 7.50e7.37 (m, 4H) 7.26e7.21 (m, 2H) 6.87 (d,

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
309
J ¼ 9.0 Hz, 2H) 4.75e4.68 (m, 3H) 4.21 (q, J ¼ 7.1 Hz, 2H) 1.61 (d,
J ¼ 9.0 Hz, 2H) 4.47 (t, J ¼ 6.2 Hz, 1H) 4.18 (q, J ¼ 7.1 Hz, 2H) 3.84 (s,
2H) 1.99e1.90 (m, 2H) 1.22 (t, J ¼ 7.1 Hz, 3H) 1.04 (t, J ¼ 7.3 Hz, 3H);
J ¼ 6.7 Hz, 3H) 1.25 (t, J ¼ 7.1 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d:
171.2, 166.0, 154.9, 154.8, 134.3, 130.8, 129.6, 127.8, 127.1, 126.9,
124.6, 121.9, 118.1, 115.7, 107.9, 73.0, 67.6, 61.4, 18.6, 14.2; ESIeMS:
(m/z): 394 (M þ H)þ.
13C NMR (CDCl3, 75 MHz)
d: 171.7, 165.9, 155.1, 133.8, 132.1, 131.7,
131.2, 129.2, 127.8, 127.3, 127.0, 126.6, 126.3, 126.1, 121.8, 115.7, 78.2,
61.2, 38.2, 26.2, 14.2, 9.7; ESIeMS: (m/z): 423 (M þ H)þ.
6.4.2. Ethyl 2-(4-(2-(naphthalen-2-yloxy)acetamido)phenoxy)
butanoate (9)
6.4.8. Ethyl 2-(4-(2-(2-sec-butylphenoxy)acetamido)phenoxy)
propanoate (18)
From 6c and ethyl 2-bromobutyrate; white solid, yield: 75%;
From 15c and ethyl 2-bromopropionate; yellow liquid, yield:
mp: 285e287 ꢁC; IR(KBr, cmꢂ1): 3502, 2940, 2282, 1727, 1680, 1528,
82%; IR(KBr, cmꢂ1): 3405, 2275, 1678, 1556, 1217, 1049; 1H NMR
1417, 1219, 1059, 762; 1H NMR (CDCl3, 300 MHz)
d
: 8.22 (s, NH)
(CDCl3, 300 MHz)
d
: 8.21 (s, NH) 7.47 (d, J ¼ 8.9 Hz, 2H) 7.26e7.16
7.83e7.74 (m, 3H) 7.50e7.39 (m, 4H) 7.37e7.21 (m, 2H) 6.88 (d,
J ¼ 8.9 Hz, 2H) 4.72 (s, 2H) 4.52 (t, J ¼ 6.2 Hz, 1H) 4.21 (q, J ¼ 7.1 Hz,
2H) 2.03e1.93 (m, 2H) 1.24 (t, J ¼ 7.1 Hz, 3H) 1.07 (t, J ¼ 7.3 Hz, 3H);
ESIeMS: (m/z): 408 (M þ H)þ.
(m, 2H) 7.06e7.01 (m, 1H) 6.89e6.84 (m, 3H) 4.72 (q, J ¼ 6.6 Hz,
1H) 4.59 (s, 1H) 4.25e4.18 (m, 2H) 3.19e3.08 (m, 1H) 1.61 (d,
J ¼ 6.7 Hz, 3H) 1.30e1.23 (m, 6H) 0.91 (t, J ¼ 7.3 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d:172.0,166.2,154.7,154.5,135.7,130.9,127.3,127.0,
122.5, 121.4, 115.7, 112.3, 73.0, 68.0, 61.2, 34.2, 30.0, 20.5, 18.5, 14.1,
6.4.3. Ethyl2-methyl-2-(4-(2-(naphthalen-2-yloxy)acetamido)
phenoxy)propanoate (10)
12.4; ESIeMS: (m/z): 400 (M þ H)þ.
From 6c and ethyl 2-bromo -2-methylpropionate; white solid,
6.4.9. Ethyl 2-(4-(2-(2-sec-butylphenoxy)acetamido)phenoxy)
butanoate (19)
yield: 80%; mp: 275e277 ꢁC; IR(KBr, cmꢂ1): 3401, 2940, 2285, 1718,
1645, 1566, 1504, 1217, 1059; 1H NMR (CDCl3, 300 MHz)
d
: 8.22 (s,
From 15c and ethyl 2-bromobutyrate; yellow liquid, yield: 80%;
NH) 7.83e7.74 (m, 3H) 7.50e7.37 (m, 4H) 7.26e7.21 (m, 2H) 6.86 (d,
J ¼ 8.8 Hz, 2H) 4.72 (s, 2H) 4.23 (q, J ¼ 7.1 Hz, 2H) 1.57 (s, 6H) 1.26 (t,
IR(KBr, cmꢂ1): 3415, 2275, 1688, 1556, 1217, 1039; 1H NMR (CDCl3,
300 MHz)
d
: 8.21 (s, NH) 7.46 (d, J ¼ 8.9 Hz, 2H) 7.26e7.16 (m, 2H)
J ¼ 7.0 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d
: 174.1, 165.9, 154.8, 152.4,
7.06e7.01 (m,1H)6.90e6.84(m, 3H) 4.60(s, 2H)4.52(t, J ¼ 6.2 Hz,1H)
4.21 (q, J ¼ 7.1 Hz, 2H) 3.17e3.10 (m, 1H) 2.03e1.93 (m, 2H) 1.71e1.63
(m, 2H) 1.30e1.23 (m, 6H) 1.08 (t, J ¼ 7.3 Hz, 3H) 0.91 (t, J ¼ 7.3Hz, 3H);
134.2, 131.4, 130.0, 129.6, 127.7, 127.0, 126.8, 124.5, 121.3, 120.1, 118.0,
107.9, 79.5, 67.6, 61.4, 25.3, 14.1; ESIeMS: (m/z): 408 (M þ H)þ.
13C NMR (CDCl3, 75 MHz)
d: 171.6, 166.3, 155.2, 154.6, 135.9, 130.9,
6.4.4. Ethyl 2-(4-(2-(naphthalen-2-yloxy)acetamido)phenoxy)
acetate (11)
127.4, 127.1, 122.6, 121.6, 115.9, 112.4, 78.3, 68.1, 61.2, 34.3, 30.1, 26.2,
20.6, 14.3, 12.5, 9.7; ESIeMS: (m/z): 414 (M þ H)þ.
From 6c and ethyl bromoacetate; white solid, yield: 82%; mp:
255e257 ꢁC; IR(KBr, cmꢂ1): 3501, 2930, 2285, 1718, 1645, 1556,
6.4.10. Ethyl2-(4-(2-(2-sec-butylphenoxy)acetamido)phenoxy)-2-
methylpropanoate (20)
1504, 1227, 1019; 1H NMR (CDCl3, 300 MHz)
d: 8.23 (s, NH) 7.83e
7.74 (m, 3H) 7.53e7.37 (m, 3H) 7.26e7.21 (m, 3H) 6.90 (d,
J ¼ 8.9 Hz, 2H) 4.72 (s, 2H) 4.60 (s, 2H) 4.26 (q, J ¼ 7.0 Hz, 2H) 1.29 (t,
From 15c and ethyl 2-bromo -2-methylpropionate; yellow
liquid, yield: 86%; IR(KBr, cmꢂ1): 3405, 2272, 1678,1556, 1217, 1039;
J ¼ 7.1 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d
: 168.9,166.0,155.0,154.9,
1H NMR (CDCl3, 300 MHz)
d
: 8.22 (s, NH) 7.44 (d, J ¼ 8.9 Hz, 2H)
134.3, 130.9, 130.1, 129.6, 127.7, 127.1, 126.9, 124.6, 122.0, 118.1, 115.2,
7.26e7.16 (m, 2H) 7.06e7.01 (m, 1H) 6.88e6.84 (m, 3H) 4.59 (s, 2H)
4.23 (q, J ¼ 7.1 Hz, 2H) 3.19e3.07 (m, 1H) 1.71e1.64 (m, 2H) 1.57 (s,
6H) 1.30e1.24 (m, 6H) 0.91 (t, J ¼ 7.3 Hz, 3H); 13C NMR (CDCl3,
107.9, 67.6, 65.8, 61.5, 14.2; ESIeMS: (m/z): 380 (M þ H)þ.
6.4.5. Ethyl 4-(4-(2-(naphthalen-2-yloxy)acetamido)phenoxy)
butanoate(12)
75 MHz) d: 174.2, 166.3, 154.6, 152.4, 135.8, 131.6, 127.4, 127.1, 122.6,
121.0, 120.3, 112.4, 79.6, 68.1, 61.5, 34.3, 30.1, 25.4, 20.6, 14.2, 12.5;
From 6c and ethyl 4-bromobutyrate; white solid, yield: 78%;
ESIeMS: (m/z): 414 (M þ H)þ.
mp: 272e274 ꢁC; IR(KBr, cmꢂ1): 3502, 2940, 2272, 1727, 1680, 1518,
1417, 1219, 1059, 762; 1H NMR (CDCl3, 300 MHz)
d
: 8.22 (s, NH)
6.4.11. Ethyl 4-(4-(2-(2-sec-butylphenoxy)acetamido)phenoxy)
butanoate (21)
7.83e7.74 (m, 3H) 7.50e7.37 (m, 4H) 7.27e7.21 (m, 2H) 6.87 (d,
J ¼ 8.9 Hz, 2H) 4.72 (s, 2H) 4.14 (q, J ¼ 7.0 Hz, 2H) 3.99 (t, J ¼ 6.0 Hz,
2H) 2.50 (t, J ¼ 7.2 Hz, 2H) 2.14e2.05 (m, 2H) 1.26 (t, J ¼ 7.1 Hz, 3H);
ESIeMS: (m/z): 408 (M þ H)þ.
From 15c and ethyl 4-bromobutyrate; yellow liquid, yield: 86%;
mp: 215e217 ꢁC; IR(KBr, cmꢂ1): 3409, 2283, 1689, 1524, 1219, 1049,
726; 1HNMR(CDCl3, 300 MHz)
d:8.22(s, NH)7.49e7.46 (m, 2H) 7.28e
7.18 (m, 2H) 7.08e7.03 (m, 1H) 6.91e6.87 (m, 3H) 4.62 (s, 2H) 4.17 (q,
J ¼ 7.1 Hz, 2H) 4.02 (t, J ¼ 6.1 Hz, 2H) 3.20e3.10 (m, 1H) 2.53 (t,
J ¼ 6.3 Hz, 2H) 2.17e2.08 (m, 2H) 1.74e1.66 (m, 2H) 1.33e1.25 (m, 6H)
6.4.6. Ethyl 2-(4-(2-(naphthalen-2-ylthio)acetamido)phenoxy)
propanoate (13)
From 7c and ethyl 2-bromopropionate; white solid, yield: 80%;
0.93 (t, J ¼ 7.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
d: 173.2,166.3,156.1,
154.7, 135.9, 130.2, 127.4, 127.1, 122.6, 121.7, 115.0, 112.4, 68.1, 67.1, 60.5,
mp: 292e294 ꢁC; IR(KBr, cmꢂ1): 3511, 2910, 2285, 1718, 1556, 1504,
1227,1019; 1HNMR(CDCl3, 300MHz)
d:8.52(s,NH)7.79e7.72 (m, 4H)
34.3, 30.9, 30.1, 24.7, 20.6, 14.3, 12.5; ESIeMS: (m/z): 414 (M þ H)þ.
7.48e7.39(m, 3H)7.34(d, J¼ 9.0Hz,2H)6.80(d, J¼ 8.9Hz,2H)4.67(q,
J ¼ 6.8 Hz,1H) 4.18 (q, J ¼ 8.9 Hz, 2H) 3.84(s, 2H) 1.58 (d, J ¼ 6.7 Hz, 3H)
6.4.12. Ethyl 2-(4-(2-(2-chlorophenoxy)acetamido)phenoxy)
propanoate (22)
1.22 (t, J ¼ 7.1 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d: 172.1, 165.9, 154.8,
133.8, 132.1, 131.7, 131.3, 129.2, 127.8, 127.3, 127.0, 126.6, 126.3, 126.2,
From 16c and ethyl 2-bromopropionate; white solid, yield: 85%;
121.8, 115.7, 73.1, 61.4, 38.2, 18.6, 14.2; ESIeMS: (m/z): 410 (M þ H)þ.
mp: 215e217 ꢁC; IR(KBr, cmꢂ1): 3315, 3013, 2275, 1678, 1556, 1504,
1327, 1019; 1H NMR (CDCl3, 300 MHz)
d: 8.58 (s, NH) 7.55e7.52 (m,
6.4.7. Ethyl 2-(4-(2-(naphthalen-2-ylthio)acetamido)phenoxy)
butanoate (14)
2H) 7.46e7.43 (m, 1H) 7.32e7.26 (m, 1H) 7.06e6.96 (m, 2H) 6.90 (d,
J ¼ 9.0 Hz, 2H) 4.74 (q, J ¼ 6.8 Hz, 1H) 4.66 (s, 2H) 4.23 (q, J ¼ 7.1 Hz,
2H) 1.62 (d, J ¼ 6.7 Hz, 2H) 1.27 (t, J ¼ 7.3 Hz, 3H);13C NMR (CDCl3,
From 7c and ethyl 2-bromo -2-methylpropionate; white solid,
yield: 82%; mp: 295e297 ꢁC; IR(KBr, cmꢂ1): 3305, 3013, 2275, 1718,
75 MHz) d: 172.2,165.5, 154.8, 152.7,130.9, 130.5, 128.3, 123.2, 123.0,
1556, 1504, 1327, 1019; 1H NMR (CDCl3, 300 MHz)
d
: 8.52 (s, NH)
121.6, 115.8, 114.3, 73.1, 68.3, 61.4, 18.6, 14.2; ESIeMS: (m/z): 378
7.79e7.72 (m, 4H) 7.48e7.39 (m, 3H) 7.33 (d, J ¼ 8.9 Hz, 2H) 6.81 (d,
(M þ H)þ.

310
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 57 (2012) 302e310
6.4.13. Ethyl 2-(4-(2-(2-chlorophenoxy)acetamido)phenoxy)
acetate (23)
for technical support, SAIF for NMR, IR, and Mass spectral data.
G.R.P., R.P.D. and R.S. are thankful to CSIR, New Delhi, India for
financial support. This is CSIR-CDRI communication number 8324.
From 16c and ethyl bromoacetate; white solid, yield: 84%; mp:
205e207 ꢁC; IR(KBr, cmꢂ1): 3325, 3023, 2265, 1678, 1556, 1514,
1327, 1020; 1H NMR (CDCl3, 300 MHz)
d: 8.59 (s, NH) 7.55 (d,
J ¼ 8.9 Hz, 2H) 7.46e7.44 (m, 1H) 7.32e7.27 (m, 1H) 7.06e6.92 (m,
4H) 4.66 (s, 2H) 4.63 (s, 2H) 4.29 (q, J ¼ 7.1 Hz, 2H) 1.32 (t, J ¼ 7.1 Hz,
3H); ESIeMS: (m/z): 364 (M þ H)þ.
Appendix A. Supporting information
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2012.09.040.
6.4.14. Ethyl 4-(4-(2-(2-chlorophenoxy)acetamido)phenoxy)
butanoate (24)
From 16c and ethyl 2-bromo -2-methylpropionate; white solid,
References
yield: 80%; mp: 235e237 ꢁC; IR(KBr, cmꢂ1): 3466, 3020, 2374, 1690,
1598, 1527, 1377, 1222, 1051, 765; 1H NMR (CDCl3, 300 MHz)
d: 8.56
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(s, NH) 7.52 (d, J ¼ 8.9 Hz, 2H) 7.46e7.44 (m, 1H) 7.32e7.27 (m, 1H)
7.06e6.97 (m, 2H) 6.90 (d, J ¼ 8.9 Hz, 2H) 4.67 (s, 2H) 4.16 (q,
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propanoate (25)
From 17c and ethyl 2-bromopropionate; white solid, yield: 85%;
mp: 265e267 ꢁC; IR(KBr, cmꢂ1): 3415, 3013, 2275, 1678, 1556, 1327,
1019; 1H NMR (CDCl3, 300 MHz)
d: 8.46 (s, NH) 7.53e7.50 (m, 2H)
7.46 (d, J ¼ 2.4 Hz, 1H) 7.28e7.24 (m, 1H) 6.92e6.88 (m, 3H) 4.74 (q,
J ¼ 6.7 Hz, 1H) 4.63 (s, 2H) 4.23 (q, J ¼ 7.1 Hz, 2H) 1.63 (d, J ¼ 6.7 Hz,
3H) 1.27 (t, J ¼ 7.1 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d: 172.1, 164.9,
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6.4.16. Ethyl2-(4-(2-(2, 4-dichlorophenoxy) acetamido) phenoxy)-
2-methylpropanoate (26)
From 17c and ethyl 2-bromo -2-methylpropionate; white solid,
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1556, 1327, 1019; 1H NMR (CDCl3, 300 MHz)
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7.44 (m, 3H) 7.26e7.23 (m, 1H) 6.90e6.85 (m, 3H) 4.61 (s, 2H)
4.23 (q, J ¼ 7.1 Hz, 2H) 1.56 (s, 6H) 1.26 (t, J ¼ 7.1 Hz, 3H);13C NMR
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6.4.17. Ethyl 2-(4-(2-(2, 4-dichlorophenoxy)acetamido)phenoxy)
butanoate (27)
From 17c and ethyl 2-bromobutyrate white solid, yield: 85%;
mp: 270e272 ꢁC; IR(KBr, cmꢂ1): 3425, 3013, 2275, 1678, 1556, 1327,
1029; 1H NMR (CDCl3, 300 MHz)
d: 8.44 (s, NH) 7.50e7.43 (m, 3H)
7.26e7.23 (m, 1H) 6.90e6.87 (m, 3H) 4.61 (s, 2H) 4.52 (t, J ¼ 6.2 Hz,
1H) 4.21 (q, J ¼ 7.1 Hz, 2H) 2.03e1.93(m, 2H) 1.25 (t, J ¼ 7.1 Hz, 3H)
1.08 (t, J ¼ 7.1 Hz, 3H);13C NMR (CDCl3, 75 MHz)
d
: 171.6, 164.9,
155.2, 151.5, 130.7, 130.3, 128.2, 127.8, 123.8, 121.6, 115.8, 115.0, 78.2,
68.5, 61.2, 26.2, 14.2, 9.7; ESIeMS: (m/z): 426 (M þ H)þ.
6.4.18. Ethyl 4-(4-(2-(2, 4-dichlorophenoxy)acetamido)phenoxy)
butanoate (28)
From 17c and ethyl 4-bromobutyrate; white solid, yield: 78%;
mp: 278e280 ꢁC; IR(KBr, cmꢂ1): 3541, 3013, 2289, 1686, 1533, 1218,
1102, 769; 1H NMR (CDCl3, 300 MHz)
d: 8.43 (s, NH) 7.50e7.43 (m,
3H) 7.26e7.23 (m, 1H) 6.90e6.86 (m, 3H) 4.61 (s, 2H) 4.14 (q,
J ¼ 7.1 Hz, 2H) 3.99 (t, J ¼ 6.1 Hz, 2H) 2.51 (t, J ¼ 7.2 Hz, 2H) 2.14e
2.05(m, 2H) 1.25 (t, J ¼ 7.1 Hz, 3H); ESIeMS: (m/z): 426 (M þ H)þ.
Acknowledgments
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The authors are grateful to the Director, CDRI, Lucknow, India for
constant encouragement in drug development program, S.P. Singh
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