European Journal of Medicinal Chemistry 64 (2013) 422e431

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European Journal of Medicinal Chemistry

journal homepage: http://www.elsevier.com/locate/ejmech

Original article

Coumarin chalcone fibrates: A new structural class of lipid lowering

agentsq
Koneni V. Sashidhara a, *, Gopala Reddy Palnati a, Ravi Sonkar b, Srinivasa Rao Avula a,
Chetan Awasthi b, Gitika Bhatia b
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, Uttar Pradesh, India
b
Biochemistry Division, CSIR-Central Drug Research Institute, Lucknow 226 001, India

a r t i c l e i n f o a b s t r a c t

Article history: In our continuing search for safe and efficacious antidyslipidemic agents, structurally interesting
Received 3 February 2013 coumarin-chalcone fibrates were synthesized and evaluated in triton WR-1339 induced hyperlipidemic
Received in revised form rats. The most active compound 41 decreased the total cholesterol (TC), phospholipids (PL) and tri-
8 April 2013
glycerides (TG), of hyperlipidemic rats by 26, 24, and 25% respectively. In addition, the compound 41
Accepted 10 April 2013
significantly reversed the levels of VLDL, LDL HDL and also increased the LPL activity. Altogether, our data
Available online 19 April 2013
suggests that these novel hybrids would be a potential new class of therapeutic agents against
dyslipidemia.
Keywords:
Coumarin chalcone fibrates
Ó 2013 Elsevier Masson SAS. All rights reserved.
Lipid lowering activity
Lipoprotein metabolism
Plasma FFA
Triton model

1. Introduction warning by the US FDA, that statins may increase the risk of dia-
betes mellitus [6,7], calls for an urgent need for novel therapeutic
Metabolic syndrome (MS) remains one of the leading causes of strategies that could halt or reverse the underlying disease process
mortality and has become a major global health challenge of the in lipid disorders, which could have a profound impact on their
21st century. It is associated with many pathological conditions long-term clinical management.
related to insulin resistance, obesity, impaired glucose tolerance, In the search for novel drug leads, the hybrid approach is a
type 2 diabetes, a high level of triglycerides, a low level of HDL promising one since it can effectively target multi factorial diseases
cholesterol, and elevated blood pressure. Hence, such metabolic like metabolic syndrome. “Due to the high potential of natural
modifications lead to a marked increase in cardiovascular risk [1]. products to exhibit pronounced biological activities, natural prod-
Gemfibrozil and fenofibrate are the couple of prominent FDA- ucts have been one of the major sources of components in hybrid
approved agents that reduce the level of triglycerides in the molecules” [8]. Coumarins and chalcones are a family of natural and
blood plasma thereby decreasing the risk of hyperlipidemia. synthetic compounds that have recently drawn much attention due
Peroxisome proliferator-activated receptor a (PPARa) is the mo- to its broad pharmacological activities [9e13]. Esculetin (3 Fig. 1) a
lecular target of fibrates, including clofibrate (1 Fig. 1) and bezafi- coumarin derivative has been shown to inhibit oxidative LDL [14].
brate (2 Fig. 1) [2e5]. Statins (HMG-CoA reductase inhibitors) can Chalcones like licochalcone A (4 Fig. 1) and xanthohumol [15a] (4A
hardly normalize the high density lipoprotein abnormality and Fig. 1) exhibit interesting biological activities including anti-
significant residual cardiovascular risk remains in most patients inflammatory [15b], antioxidant [16], and antihyperglycemic [17].
despite statin therapy. In addition, reports of undesirable side ef- In addition coumarin and chalcone derivatives have the unique
fects (myopathy) of some ‘super statins’ and in light of the recent ability to scavenge reactive oxygen species (ROS) and to protect the
influence of free radical damage [13,18]. Hybrid molecules that
contain multiple structural units of different nature generally
q Part XXIII in the series, “Advances in drug design and discovery”. CSIR-CDRI
possess improved biological activities [19e24]. Inspired by the
#8446.
* Corresponding author. Tel.: þ91 9919317940; fax: þ91 522 2628493.
hybridization concept and our previous results [25e30] we have
E-mail addresses: sashidhar123@gmail.com, kv_sashidhara@cdri.res.in designed and synthesized a novel series of compounds that have
(K.V. Sashidhara). coumarin, chalcone and fibrate entities in one frame (5 Fig. 1) and

0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2013.04.026
 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431 423

Fig. 1. Chemical structures of some representative lipid lowering fibrates, coumarin, chalcones and our synthesized prototype.

have evaluated them for their lipid profile activity. Also, we recently 400 mg/kg body weight intraperitoneally to animals of all the
discovered that coumarin-fibrate hybrids were found to ameliorate groups except the control. These derivatives were macerated with
the symptoms associated with hyperlipidemia and that they have gum acacia (0.2% w/v), suspended in water and fed simultaneously
potential benefits in the prevention of obesity and liver dysfunction with triton with a dose of 100 mg/kg p.o. to the animals of treated
(unpublished results). group and the diet being withdrawn. Animals of control and triton
Fig. 1 shows chemical structure of important fibrates, coumarin, group without treatment with hybrid compounds were given same
chalcones and our synthesized fused prototype containing frag- amount of gum acacia suspension (vehicle). After 18 h of treatment
ments endowed with interesting and complimentary activities. the animals were anaesthetized with thiopentone solution (50 mg/
kg b.w.) prepared in normal saline and then 1.0 mL blood was
2. Chemistry withdrawn from retro-orbital sinus using glass capillary in EDTA
coated eppendorf tube (3.0 mg/ml blood). The blood was centri-
The detailed synthetic route for the preparation of the target fuged (at 2500 g) at 4  C for 10 min and plasma was separated.
compounds (27e38 & 39e42) is summarized in Scheme 1. Plasma was diluted with normal saline (ratio of 1:3) and used for
Following reported procedures, treating 4-hydroxy acetophenone analysis of total cholesterol (TC), triglycerides (TG) and phospho-
with substituted bromoesters in the presence of K2CO3 afforded the lipids (PL) by standard enzymatic methods [31] and post heparin
corresponding ester derivatives (6e10). Commercially available 2- lipolytic activity (PHLA) were assayed [32] using spectrophotom-
alkyl phenols underwent the Duff formylation in the presence of eter, Beckmann auto-analyzer and standard kits purchased from
hexamethylenetetramine (HMTA) and TFA at 120  C to furnish the Beckmann Coulter International, USA.
compounds (11e14). These aromatic dialdehydes on subsequent
reaction with para-substituted acetophenones (6e10) in the pres- 3.3. Lipoprotein measurement in blood plasma of triton induced
ence of a catalytic amount of conc. HCl in dioxane gave the regio- hyperlipidemic rats
selective chalcones (15e26) [23]. These were then engaged in a
Knoevenagel condensation with diethylmalonate in the presence of Plasma was fractionated into very low density lipoprotein
a catalytic amount of piperidine resulted in the formation of (VLDL), low density lipoprotein (LDL) and high density lipoprotein
coumarin-chalcone fibrates (27e38). Some of these diester de- (HDL) by poly anionic precipitation methods. Plasma and lipopro-
rivatives on subsequent alkaline hydrolysis furnished their corre- teins were analyzed for their total cholesterol (TC), phospholipid
sponding acid derivatives (39e42) (Scheme 1) in good yields. The (PL), and triglyceride (TG) by standard procedures reported earlier
structures of all the compounds were established by using 1H NMR, [33].
13
C NMR, IR spectroscopy and mass spectrometry.
3.4. Lipoprotein lipase activity in liver of triton induced
3. Pharmacology hyperlipidemic rats

3.1. Animals used Liver was homogenized (10%, w/v) in cold 100 mM phosphate
buffer pH 7.2 and used for the assay of total lipolytic activity of li-
Rats (Charles Foster strain, male, adult, body weight 200e225 g) poprotein lipase (LPL) [34].
were kept in a room with controlled temperature (25e26  C), hu-
midity (60e80%) and12/12 h light/dark cycle (light on from 8.00 3.5. Statistical evaluation
A.M. to 8.00 P.M.) under hygienic conditions. Animals, which were
acclimatized for one week before starting the experiment, had free Data were analyzed using student’s t-test. The hyperlipidemic
access to the normal diet and water. groups were compared with control drug treated groups. P < 0.05
was considered to be significant.
3.2. Lipid lowering and post heparin lipolytic activity
4. Results and discussion
Rats were divided into twelve groups control, triton induced,
triton plus 19, 20, 27e42 and gemfibrozil (100 mg/kg) treated 4.1. The lipid lowering activity of coumarin-chalcone fibrates
groups, containing six rats in each group. In this experiment of 18 h,
hyperlipidemia was developed by administration of triton WR- The present study has been undertaken to evaluate the lipid
1339 (Sigma chemical company, St. Louis, MO, USA) at a dose of lowering activity of coumarin-chalcone fibrates (19, 20 & 27e42)
424 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431

Scheme 1. Synthesis of novel coumarin-chalcone fibrates. Reagents and conditions: (i) K2CO3, CH3CN, 100  C, 4 h (ii) (a) HMTA/TFA, 120  C, 3 h; (b) 10% H2SO4, 90e100  C, 2 h (iii)
Conc. HCl, dioxane, 110  C, 8e10 h (iv) Diethylmalonate, cat. Piperidine, Ethanol, 90  C, 1h.(v) 20% aq. KOH, Methanol, r.t, 5e6 h.

in an acute triton induced hyperlipidemic model. Triton admin- 35 showed significant reversal of PHLA in plasma of hyper-
istration caused significant increase in plasma TC, PL and TG lipidemic rats by 17%, 15% and 15% respectively, comparable to
levels by (2.12, 2.28 and 2.49 folds respectively) followed by gemfibrozil, which caused 19% reversal of activity of this enzyme
decrease in PHLA (post heparin lipolytic activity) by (33%). as compared to control group and the results are summarised in
Treatment of hyperlipidemic rats with coumarin-chalcone Table 1. In terms of structure activity relationship of the hybrids
fibrates (19, 20 & 27e42) at the dose of 100 mg/kg p.o. synthesized following observations can be made, first the
reversed the plasma levels of lipid with varying extents. The coumarin moiety is essential as compounds without coumarin
synthesized hybrids inhibited the biosynthesis of cholesterol and nucleus were inactive (19 and 20). Secondly, though in general
enhanced the activity of lipolytic enzymes to facilitate early most hybrids exhibited activity (28, 35 & 36) the acid derivative
clearance of lipids from circulation in triton induced hyperlip- (41) was found to be more active than ester analogues, and
idemia. Compound 41 was found to be the most persuasive in the seems to confer potency and solubility.
series as it showed 26%, 24% and 25%, lowering in TC, PL and TG
respectively, while compounds 35 and 28 showed good activity 4.2. Effect of compounds 41 and 35 on lipid lowering at different
and compound 36 showed moderate activity. These data were doses in triton induced hyperlipidemic rat
comparable with standard hypolipidemic drug gemfibrozil which
at the dose of 100 mg/kg decreased levels of TC, PL and TG in After the confirmation of most active compounds in primary
plasma by 31%, 33% and 33%, respectively. Compounds 41, 28 and screening the efficacy of active compounds 41 and 35 at different
 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431 425

Table 1
Percentage (%) change of plasma lipids with the treatment of coumarin-chalcone fibrate hybrid molecules (19e42) in triton-induced hyperlipidemic rats at the dose of 100 mg/
kg body weight.

Compound no. Structure Lipid profile PHLAb

Total cholesterol (TC)a Phospholipids (PL)a Triglyceride (TG)a

19 12* 13* 11* þ6NS

20 13* 11* 11* þ5NS

27 6NS 8NS 8NS þ2NS

28 21** 20** 22** þ15*

29 13* 11* 11* þ5NS

30 11* 12* 11* þ8NS

31 10* 12* 11* þ6NS

32 10* 9NS 9NS þ5NS

(continued on next page)
426 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431

Table 1 (continued )

Compound no. Structure Lipid profile PHLAb

a a a
Total cholesterol (TC) Phospholipids (PL) Triglyceride (TG)

33 14* 15* 14* þ10*

34 10* 10* 8NS þ5NS

35 22** 23*** 23*** þ15*

36 19* 17* 16* þ12*

37 12* 11* 11* þ5NS

38 13* 12* 12* þ7NS

39 9NS 7NS 8NS þ3NS

40 8NS 9NS 9NS þ3NS

 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431 427

Table 1 (continued )

Compound no. Structure Lipid profile PHLAb

a a a
Total cholesterol (TC) Phospholipids (PL) Triglyceride (TG)

41 26*** 24*** 25*** þ17*

42 8NS 8NS 9NS þ4NS

Gemfibrozil 32*** 30*** 33*** þ19*

Values are mean  SD of six rats, ***P < 0.001; **P < 0.01; *P < 0.05; NS ¼ Non significant.
a
mg/dl.
b
n mol of free fatty acids formed/h/ml of plasma.

doses in 50e200 mg/kg body weight was studied. Compound 41 4.4. Effect of compound 41 on liver-LPL activity in triton induced
lowered the TC by 16%e27%, PL by 15%e24% and TG by 14%e26% hyperlipidemic rats
followed by increase in PHLA level by 12%e17%. Similarly com-
pound 35 lowered the TC by 18%e23%, PL by 16%e24% and TG by Furthermore the compound 41 was studied for liver-LPL activity
16%e25% followed by increase in PHLA level by 13%e15% respec- in triton induced hyperlipidemic rats. Administration of triton in
tively. The results are summarised in Table 2. rats markedly decreases the LPL activity in liver as shown in Fig. 3.
However, the treatment with compound 41 significantly increased
the LPL activity, which underscores the utility of the hybrid (Fig. 3).
4.3. Effect of compound 41 on plasma lipoprotein lipids in triton
The results were comparable with the standard drug gemfibrozil,
induced hyperlipidemic rats
which at the same dose (100 mg/kg) caused marked increase in the
LPL activity.
Next, the most active compound 41 was tested for its effect on
plasma lipoprotein lipids. As shown in Fig. 2, the analysis of
hyperlipidemic plasma of triton administered rats showed marked 5. Conclusion
increase in the level of lipoprotein lipids and these effects were
pronounced for VLDL (Fig. 2A) and LDL (Fig. 2B) followed by a In conclusion, the designed hybrid 41 decreased the total
decrease in HDL (Fig. 2C) as compared to control rats. Interestingly, cholesterol (TC), phospholipids (PL) and triglycerides (TG), of
the treatment with compound 41, significantly reversed the levels hyperlipidemic rats by 26, 24, and 25%, respectively, at 100 mg/
of VLDL, LDL and HDL, the complete lipid profile results are shown kg body weight in triton WR-1339 induced model. In addition,
in Fig. 2. treatment with compound 41 significantly reversed the levels of
VLDL, LDL and HDL also increased the LPL activity. These results
Table 2
suggest that these coumarin-chalcone fibrates constitute a new
Percentage (%) change of plasma lipids with the treatment of compounds 41 and 35
in triton-induced hyperlipidemic rats at the different doses. prototype of lipid lowering agents that act by modulating lipo-
protein lipase, further experimental and mechanistic studies
Compound no. Lipids profilea PHLAb
are however required to advance this series in preclinical
TC PL TG development.
Compound 41
50(mg/kg) 16* 15* 14* þ12*
100(mg/kg) 26*** 24*** 25*** þ17***
6. Experimental
200(mg/kg) 27*** 24*** 26*** þ17***
Compound 35 6.1. General information
50(mg/kg) 18* 16* 16* þ13*
100(mg/kg) 22** 23*** 23*** þ15**
All reagents were commercial and were used without further
200(mg/kg) 23*** 24*** 25*** þ15**
Gemfibrozil purification. Chromatography was carried on silica gel (60e120
100(mg/kg) 32*** 30*** 33*** þ19*** and 100e200 mesh). All reactions were monitored by TLC; silica
Values are mean  SD of six rats, ***P < 0.001; **P < 0.01; *P < 0.05.
gel plates with fluorescence F254 were used. Melting points were
a
mg/dl. uncorrected. The 1H NMR, 2D-NMR (COSY, HMBC, HSQC) and 13C
b
n mol of free fatty acids formed/h/ml of plasma. NMR spectra were determined on 200, 300, MHz and 50, 75,
428 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431

Fig. 3. Effect of compound 41 on LPL activity in triton induced hyperlipidemic rats.

Animals were sacrificed after 18 h of hyperlipidemia was developed by administration
of triton WR-1339 with and without compound 41 and gemfibrozil (100 mg/kg).
Compound 41 and gemfibrozil improve LPL activity in triton induced hyperlipidemic
rats. Values are expressed as the mean  SD (n ¼ 6). *P < 0.05; **P < 0.01; NS (non
significant) compared to triton treated only and aP < 0.05 comparison triton and triton
plus compound 41 treated groups.

6.2. General synthetic procedure for preparation of ester compounds

(6e10)

An oven dried 50-mL round bottom flask was charged with 4-

hydroxy acetophenone (1.0 equiv.), substituted bromoester com-
pound (1.1 equiv.) and acetonitrile (25 mL). K2CO3 (10.0 equiv.) was
then added, and the reaction mixture was heated to 90  C for 4 h.
The acetonitrile was evaporated in vacuum, and the residue was
purified by silica gel (100e200) column chromatography (20%
EtoAc/Hexane) to afford ester compounds 6e10 in good yields.

6.2.1. Ethyl 2-(4-acetylphenoxy) propionate (7)

From 4-hydroxy acetophenone and ethyl 2-bromopropanoate;
white crystalline solid; yield: 92%; mp: 147e149  C; IR(KBr, cm1):
2925, 2352, 1677, 1566, 1207, 1073, 760; 1H NMR (CDCl3, 300 MHz)
d: 7.93 (d, J ¼ 8.7 Hz, 2H) 6.91(d, J ¼ 8.8, 2H) 4.83 (q, J ¼ 6.6 Hz, 1H)
4.23 (q, J ¼ 7.1 Hz, 2H) 2.55 (s, 3H) 1.66 (d, J ¼ 6.7, 3H) 1.26 (t,
J ¼ 7.1 Hz, 3H); ESI e MS: (m/z): 237 (M þ H)þ.

6.2.2. Ethyl 2-(4-acetylphenoxy) butanoate (10)

From 4-hydroxy acetophenone and ethyl 4-bromobutanoate;
white crystalline solid; yield: 90%; mp: 157e159  C; IR(KBr, cm1):
2935, 2352, 1675, 1566, 1207, 1073, 770; 1H NMR (CDCl3, 300 MHz)
d: 7.93 (d, J ¼ 8.7 Hz, 2H) 6.92(d, J ¼ 8.7, 2H) 4.16 (q, J ¼ 7.1 Hz, 2H)
Fig. 2. Effect of compound 41 on lipoprotein metabolism in triton induced hyper-
4.09 (t, J ¼ 6.1 Hz, 2H) 2.56e2.50 (m, 5H) 2.19e2.10 (m, 2H) 1.27 (t,
lipidemic rats. Blood was drawn after 18 h of hyperlipidemia was developed by J ¼ 7.1, 3H); ESI e MS: (m/z): 251 (M þ H)þ.
administration of triton WR-1339 with and without compound 41 and gemfibrozil
(100 mg/kg). Compounds 41 and gemfibrozil improve lipoprotein lipids profile level in
triton induced hyperlipidemic rats. Values are expressed as the mean  SD (n ¼ 6). 6.3. General synthetic procedure for preparation of 4-hydroxy-5-
*P < 0.05; **P < 0.01; ***P < 0.001; NS (non significant) compared to triton treated only alkyl isophthalaldehydes (11e14)
and aP < 0.05; bP < 0.01; cP < 0.001 comparison triton and triton plus compound 41
treated groups. 2-Alkyl phenol (1.0 equiv.) and hexamethylenetetramine
(1.2 equiv.) were dissolved in TFA (25 mL) and the solution was
heated at 120  C for 3 h. After cooling to room temperature 10% aq.
MHz, respectively, using CDCl3 and DMSO-d6 as solvents and TMS H2SO4 (25 mL) was added and again the temperature maintained
as internal standard. All chemical shifts were given in ppm and (at 90e100  C) for two more hours. After completion the solution
multiplicity (s ¼ singlet, brs ¼ broad singlet, d ¼ doublet, was basified with Na2CO3 to pH 8 and extracted 3-fold with 25 mL
brd ¼ broad doublet, dd ¼ double doublet, t ¼ triplet, of CHCl3. The combined organic layers were dried on Na2SO4,
q ¼ quartet, m ¼ multiplet). IR spectra were recorded in the filtered, and concentrated to dryness under reduced pressure. The
range of 500e4000 cm1. crude product was purified on silica gel column (100e200 mesh)
 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431 429

using hexane-ethyl acetate (12:88, v/v) as eluent to afford com- 6.5.1. (E)-Ethyl 6-(3-(4-(2-ethoxy-2-oxoethoxy) phenyl)-3-oxoprop-
pounds 11e14 in good yields. 1-enyl)-8-methyl-2-oxo-2H-chromene-3-carboxylate (27)
From 15 and diethylmalonate; white solid; yield: 84%; mp: 168e
6.3.1. 4-Hydroxy-5-methylisophthalaldehyde (11) 170  C; IR(KBr, cm1): 2965, 2358, 1744, 1654, 1600, 1505, 1340,
From 2-methyl phenol and HMT; white solid; Yield: 60%; mp: 1216, 1027, 767; 1H NMR (CDCl3, 300 MHz) d: 8.51 (s, 1H) 8.04 (d,
125e127  C; IR (neat): 3262, 2865, 1703, 1626, 1013 cm1; 1H NMR J ¼ 8.7 Hz, 2H)7.79e7.74 (m, 2H) 7.65 (s, 1H) 7.52 (d, J ¼ 15.6 Hz, 1H)
(CDCl3, 300 MHz) d: 11.82 (s, 1H), 9.97 (s, 1H), 9.90 (s, 1H), 7.97 (d, 7.00 (d, J ¼ 8.7, 2H) 4.71 (s, 2H) 4.42 (q, J ¼ 7.0 Hz, 2H) 4.29 (q,
J ¼ 1.8, 1H), 7.93 (brs, 1H), 2.33 (s, 3H); ESI-MS: m/z: 164 (M þ H)þ. J ¼ 7.1 Hz, 2H) 2.50 (s, 3H) 1.41 (t, J ¼ 7.0 Hz, 3H) 1.30 (t, J ¼ 7.1 Hz,
3H); 13C NMR (CDCl3 75 MHz) d:188.0, 168.2, 162.8, 161.7, 156.3,
6.3.2. 5-tert-Butyl-4-hydroxyisophthalaldehyde (13) 154.6, 148.4, 141.7, 134.3, 131.7, 131.5, 130.9,127.5, 127.3, 122.5, 118.7,
From 2-tertbutyl phenol and HMT; Oily; Yield: 65%; IR (neat): 118.0, 114.6, 65.3, 62.1, 61.7, 15.6, 14.3, 14.2; ESI e MS: (m/z): 465
3252, 2865, 1703, 1626, 1013 cm1; 1H NMR (CDCl3, 300 MHz) d: (M þ H)þ.
12.39 (s, 1H), 9.99 (s, 1H), 9.93 (s, 1H), 8.07 (brs, 1H), 7.99 (brs, 1H),
1.46 (s, 9H); ESI-MS: m/z: 207 (M þ H)þ. 6.5.2. (E)-Ethyl6-(3-(4-(2-ethoxy-2-oxoethoxy)phenyl)-3-oxoprop-
1-enyl)-8-isopropyl-2-oxo-2H-chromene-3-carboxylate (28)
From 16 and diethylmalonate; white solid; yield: 79%; mp: 163e
6.4. General synthetic procedure for preparation of para substituted
165  C; IR(KBr, cm1): 2972, 2368, 1757, 1659, 1611, 1515, 1376, 1288,
chalcones (15e26)
1079, 775; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s, 1H) 8.04 (d,
J ¼ 8.8 Hz, 2H)7.81e7.76 (m, 2H) 7.67 (d, J ¼ 1.6 Hz 1H) 7.51 (d,
To a solution of 4-hydroxy-5-alkyl isophthalaldehyde 11e14
J ¼ 15.6 Hz, 1H) 7.00 (d, J ¼ 8.8, 2H) 4.71(s, 2H) 4.42 (q, J ¼ 7.1 Hz,
(1.0 equiv.) and 4-substutited acetophenone 6e10 (1.0 equiv.) in
2H) 4.29 (q, J ¼ 7.1 Hz, 2H) 3.67 e 3.58 (m, 1H) 1.41 (t, J ¼ 7.1 Hz, 3H)
dioxane (15 mL) was treated with conc. HCl (2 mL). The solution
1.36 (m , 9H); 13C NMR (CDCl3 75 MHz) d:188.1, 168.2, 162.8, 161.6,
was refluxed for 8e10 h after completion of required time the re-
156.2, 153.5, 148.6, 142.0, 137.5, 131.6, 130.8, 130.5,127.1, 122.5, 118.6,
action mixture was cooled and most of the excess dioxane was
118.0, 114.5, 65.2, 62.0, 61.5, 26.7, 22.4, 14.2, 14.1 ; ESI e MS: (m/z):
evaporated under reduced pressure, and the residue was sus-
493 (M þ H)þ.
pended in water (50 mL) and extracted 3-fold with CHCl3 (50 mL).
The combined organic layers were dried on Na2SO4, filtered, and
6.5.3. (E)-Ethyl8-tert-butyl-6-(3-(4-(2-ethoxy-2-oxoethoxy)
concentrated to dryness under reduced pressure. The residue was
phenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (29)
purified on a silica gel (230e400 mesh) column chromatography
From 17 and diethylmalonate; light brown solid; yield: 85%; mp:
using hexane-ethyl acetate (90:10, v/v) as eluent to afford regio-
165e167  C; IR(KBr, cm1): 2985, 2359, 1767, 1665, 1621, 1518, 1366,
selective para chalcones 15e26 in moderate yields.
1298, 1079, 760; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s, 1H) 8.28 (d,
J ¼ 8.8 Hz, 2H) 7.85 (d, J ¼ 1.8, 1H) 7.78 (d, J ¼ 15.6 Hz, 1H) 7.70 (d,
6.4.1. (E)-Ethyl2-(4-(3-(3-formyl-4-hydroxy-5-methylphenyl)
J ¼ 1.8 Hz, 1H) 7.50 (d, J ¼ 15.6 Hz, 1H)7.00 (d, J ¼ 8.8, 2H) 4.71 (s,
acryloyl) phenoxy) propanoate (19)
2H) 4.42 (q, J ¼ 7.1 Hz, 2H) 4.28 (q, J ¼ 7.1 Hz, 2H) 1.53 (s, 9H) 1.41 (t,
From 7 and 11; white solid; yield: 72%; mp: 145e147  C; IR(KBr,
J ¼ 7.1 Hz, 3H) 1.30 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3 75 MHz)
cm1): 3445, 2925, 2352, 1718, 1677, 1566, 1504, 1207, 1073, 760; 1H
d:188.1, 168.2, 162.9, 161.6, 155.7, 154.9, 148.9, 142.2, 138.9, 131.6,
NMR (CDCl3, 300 MHz) d: 11.50 (s,OH) 9.93 (s, CHO) 8.02 (d,
131.3, 131.2, 130.8, 127.5, 122.4, 118.7, 118.2, 114.5, 65.2, 62.0, 61.6,
J ¼ 8.8 Hz, 2H) 7.77e7.72 (m, 2H) 7.64 (d, J ¼ 1.9, 1H) 7.44 (d, J ¼ 15.5,
35.1, 29.6, 14.2, 14.1; ESI e MS: (m/z): 507 (M þ H)þ.
1H) 6.75 (d, J ¼ 8.8, 2H) 4.48 (q, J ¼ 6.7 Hz, 1H) 4.23 (q, J ¼ 7.1 Hz,
2H) 2.32 (s, 3H) 1.66 (d, J ¼ 6.7, 3H) 1.25 (t, J ¼ 7.1 Hz, 3H); ESI e MS:
6.5.4. (E)-Ethyl8-sec-butyl-6-(3-(4-(2-ethoxy-2-oxoethoxy)phenyl)-
(m/z): 383 (M þ H)þ.
3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (30)
From 18 and diethylmalonate; white solid; yield: 90%; mp:
6.4.2. (E)-Ethyl2-(4-(3-(3-sec-butyl-5-formyl-4-hydroxyphenyl)
164e166  C; IR(KBr, cm1): 2970, 2368, 1757, 1659, 1601, 1459,
acryloyl)phenoxy)propanoate (20)
1376, 1288, 1213, 1027, 767; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s,
From 7 and 14; white solid; yield: 74%; mp: 142e144  C; IR(KBr,
1H) 8.04 (d, J ¼ 8.8 Hz, 2H) 7.81e7.75 (m, 2H) 7.68 (s, 1H) 7.51 (d,
cm1): 3419, 2965, 2358, 1744, 1654, 1600, 1505, 1340, 1218, 1027,
J ¼ 15.6 Hz 1H) 7.00 (d, J ¼ 8.8 Hz, 2H) 4.71 (s, 2H) 4.42 (q,
769; 1H NMR (CDCl3, 300 MHz) d: 11.59 (s, OH) 9.94 (s, CHO) 8.02 (d,
J ¼ 7.0 Hz, 2H) 4.29 (q, J ¼ 7.1 Hz, 2H) 3.45e3.38 (m, 1H) 1.77e1.68
J ¼ 8.8 Hz, 2H) 7.76 (d, J ¼ 15.6 Hz, 1H)7.69 (s, 1H) 7.67 (s, 1H) 7.43 (d,
(m, 2H) 1.41 (t, J ¼ 7.1 Hz, 3H) 1.33e1.28 (m, 6H) 0.88 (t, J ¼ 7.3 Hz,
J ¼ 15.6, 1H) 6.96 (d, J ¼ 8.8, 2H) 4.48 (q, J ¼ 6.7 Hz, 1H) 4.22 (q,
3H); 13C NMR (CDCl3 75 MHz) d:188.1, 168.1, 162.8, 161.6, 156.2,
J ¼ 7.1 Hz, 2H) 3.20e3.13 (m, 1H) 1.75e1.63 (m, 6H) 1.28e1.23 (m,
153.8, 148.6, 142.0, 136.6, 131.6, 131.3, 130.8,127.0, 122.5, 118.6, 118.1,
6H) 0.88 (t, J ¼ 7.3 Hz, 3H); ESI e MS: (m/z): 425 (M þ H)þ.
114.5, 65.2, 62.0, 61.6, 33.4, 29.6, 20.4, 14.2, 14.1, 11.9; ESI e MS: (m/
z): 507 (M þ H)þ.
6.5. General synthetic procedure for preparation coumarin-chalcone
fibrates (27e38) 6.5.5. (E)-Ethyl 6-(3-(4-(1-ethoxy-1-oxopropan-2-yloxy) phenyl)-3-
oxoprop-1-enyl)-8-methyl-2-oxo-2H-chromene-3-carboxylate (31)
An oven dried 50 mL round bottom flask was charged with From 19 and diethylmalonate; white solid; yield: 80%; mp: 160e
chalcone 15e26 (1.0 mmol), diethylmalonate (1.2 mmol) and ab- 162  C; IR(KBr, cm1): 2970, 2368, 1757, 1659, 1601, 1510, 1376,
solute ethanol (15 mL). This was treated with piperidine (0.30 mL) 1288, 1079, 762; 1H NMR (CDCl3, 300 MHz) d: 8.51 (s, 1H) 8.02 (d,
and refluxed for 30 min after completion of reaction (monitor by J ¼ 8.8 Hz, 2H)7.78e7.73 (m, 2H) 7.65 (s, 1H) 7.52 (d, J ¼ 15.6 Hz, 1H)
TLC) the reaction mixture was cooled and evaporated under 6.95 (d, J ¼ 8.8, 2H) 4.84 (q, J ¼ 6.7 Hz, 1H) 4.41 (q, J ¼ 7.1 Hz, 2H)
reduced pressure, the residue was acidified with acetic acid and 4.29 (q, J ¼ 7.0 Hz, 2H) 2.49 (s, 3H) 1.66 (d, J ¼ 6.7, 3H) 1.40 (t,
extracted 3-fold with CHCl3 (20 mL). The combined organic layers J ¼ 7.1 Hz, 3H) 1.25 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3 75 MHz)
were dried on Na2SO4, filtered, and concentrated to dryness under d:187.9, 171.4, 162.8, 161.5, 156.2, 154.5, 148.3, 141.6, 134.2, 131.4,
reduced pressure. The crude product was washed with ethanol 131.3, 130.8,127.4, 127.2, 122.5, 118.6, 117.9, 114.8, 72.5, 62.0, 61.5,
gave pure coumarin chalcone fibrates (27e38) in good yields. 18.4, 15.5, 14.2, 14.1; ESI e MS: (m/z): 479 (M þ H)þ.
430 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431

6.5.6. (E)-Ethyl8-sec-butyl-6-(3-(4-(1-ethoxy-1-oxopropan-2-yloxy) 6.5.11. (E)-Ethyl8-tert-butyl-6-(3-(4-(4-ethoxy-4-oxobutoxy)

phenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (32) phenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (37)
From 20 and diethylmalonate; white solid; yield: 85%; mp: 153e From 25 and diethylmalonate; white solid; yield: 69%; mp: 172e
155  C; IR(KBr, cm1): 2973, 2358, 1757, 1659, 1611, 1459, 1366, 174  C; IR(KBr, cm1): 2972, 2368, 1757, 1659, 1611, 1515, 1376, 1288,
1288, 1223, 1027, 757; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s, 1H) 8.03 1079, 775; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s, 1H) 8.03 (d,
(d, J ¼ 8.8 Hz, 2H) 7.81e7.74 (m, 2H) 7.68 (d, J ¼ 1.7 Hz, 1H)7.51 (d, J ¼ 8.6 Hz, 2H) 7.85 (s, 1H) 7.78 (d, J ¼ 15.6 Hz 1H)7.71 (s, 1H) 7.52 (d,
J ¼ 15.6 Hz 1H) 6.97 (d, J ¼ 8.8 Hz, 2H) 4.85 (q, J ¼ 6.7 Hz, 1H) 4.42 (q, J ¼ 15.5 Hz, 1H) 6.98 (d, J ¼ 8.6, 2H) 4.42 (q, J ¼ 7.1 Hz, 2H)4.19e4.09
J ¼ 7.0 Hz, 2H) 4.23 (q, J ¼ 7.1 Hz, 2H) 3.45e3.38 (m, 1H) 1.75e1.65 (m, 4H) 2.53 (t, J ¼ 7.2 Hz, 2H) 2.19e2.11 (m, 2H) 1.54 (s, 9H) 1.41 (t,
(m, 5H) 1.41 (t, J ¼ 7.1 Hz, 3H) 1.33e1.24 (m, 6H) 0.88 (t, J ¼ 7.2 Hz, J ¼ 7.0 Hz, 3H) 1.26 (t, J ¼ 7.1 Hz, 3H); 13C NMR (CDCl3 75 MHz)
3H); 13C NMR (CDCl3 75 MHz) d:188.1, 171.4, 162.8, 161.5, 156.2, d:188.1, 173.0, 162.9, 155.7, 154.8, 148.9, 141.9, 138.9, 131.3, 131.2,
153.8, 148.5, 141.9, 136.6, 131.6, 131.4, 131.3, 130.8,126.9, 122.6, 118.7, 130.8, 130.7,127.4, 122.6, 118.7, 118.2, 114.4, 67.0, 61.9, 60.5, 35.1, 30.6,
118.1, 114.8, 72.5, 62.0, 61.5, 33.4, 29.6, 20.4, 18.4, 14.2, 14.1, 11.9; 29.6, 24.4 14.2; ESI e MS: (m/z): 535 (M þ H)þ.
ESI e MS: (m/z): 521 (M þ H)þ.
6.5.12. (E)-Ethyl8-sec-butyl-6-(3-(4-(4-ethoxy-4-oxobutoxy)
6.5.7. (E)-Ethyl 6-(3-(4-(1-ethoxy-1-oxobutan-2-yloxy)phenyl)-3- phenyl)-3-oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylate (38)
oxoprop-1-enyl)-8-methyl-2-oxo-2H-chromene-3-carboxylate (33) From 26 and diethylmalonate; pale brown solid; yield: 80%;
From 21 and diethylmalonate; pale yellow solid; yield: 70%; mp: mp: 168e170  C; IR(KBr, cm1): 2995, 2369, 1767, 1655, 1621, 1508,
154e156  C; IR(KBr, cm1): 2963, 2356, 1754, 1654, 1640, 1505, 1356, 1298, 1074, 766; 1H NMR (CDCl3, 300 MHz) d: 8.52 (s, 1H)
1347, 1216, 1027, 767; 1H NMR (CDCl3, 300 MHz) d: 8.54 (s, 1H) 8.02 8.03 (d, J ¼ 8.7 Hz, 2H)7.81e7.75 (m, 2H) 7.68 (d, J ¼ 1.9 Hz, 1H)
(d, J ¼ 8.7 Hz, 2H)7.81e7.76 (m, 2H) 7.68 (s, 1H) 7.55 (d, J ¼ 15.5 Hz, 7.53 (d, J ¼ 15.6 Hz, 1H) 6.98 (d, J ¼ 8.8 Hz, 2H) 4.42 (q, J ¼ 7.2 Hz,
1H) 6.99 (d, J ¼ 8.8, 2H) 4.68 (t, J ¼ 6.1 Hz, 1H) 4.44 (q, J ¼ 7.1 Hz, 2H) 2H) 4.19 e 4.09 (m, 4H) 3.46e3.39 (m, 1H) 2.53 (t, J ¼ 7.2 Hz, 2H)
4.25 (q, J ¼ 7.1 Hz, 2H) 2.53 (s, 3H) 2.10e2.01 (m, 2H) 1.43 (t, J ¼ 7.0, 2.17e2.13 (m, 2H) 1.73 (t, J ¼ 7.4 Hz, 2H) 1.41(t, J ¼ 7.1 Hz, 3H) 1.33
3H) 1.27 (t, J ¼ 7.0 Hz, 3H) 1.12 (t , J ¼ 7.3 Hz, 3H); ESI e MS: (m/z): e 1.24 (m, 6H) 0.89 (t, J ¼ 7.3 Hz, 3H); 13C NMR (CDCl3 75 MHz)
493 (M þ H)þ. d:188.1, 173.0, 162.9, 162.8, 156.2, 153.7, 148.6, 141.8, 136.5, 131.7,
131.3, 130.8, 130.7,126.9,122.6, 118.6, 118.1, 114.4, 67.0, 62.0, 60.5,
6.5.8. (E)-Ethyl 6-(3-(4-(1-ethoxy-2-methyl-1-oxopropan-2-yloxy) 33.4, 30.6, 29.6, 24.4, 20.4, 14.2, 12.0; ESI e MS: (m/z): 535
phenyl)-3-oxoprop-1-enyl)-8-methyl-2-oxo-2H-chromene-3- (M þ H)þ.
carboxylate (34)
From 22 and diethylmalonate; white solid; yield: 75%; mp: 171e 6.6. General synthetic procedure for preparation of acids (39e42)
173  C; IR(KBr, cm1): 2971, 2368, 1757, 1659, 1611, 1510, 1376, 1288,
1079, 765; 1H NMR (CDCl3, 300 MHz) d: 8.51 (s, 1H) 7.98 (d, A 50 mL round bottom flask was charged with coumarin-
J ¼ 8.8 Hz, 2H)7.79e7.74 (m, 2H) 7.65 (s, 1H) 7.52 (d, J ¼ 15.6 Hz, 1H) chalcones diester (28, 30, 31 and 35) and methanol (15 mL). To this
6.89 (d, J ¼ 8.8, 2H) 4.42 (q, J ¼ 7.1 Hz, 2H) 4.23 (q, J ¼ 7.1 Hz, 2H) 2.51 10% aq KOH was added and stirred at room temperature for 5e6 h.
(s, 3H) 1.67 (s, 6H) 1.41 (t, J ¼ 7.1 Hz, 3H) 1.23 (t, J ¼ 7.1 Hz, 3H); 13C After completion of reaction (conformed by TLC), excess methanol
NMR (CDCl3 75 MHz) d:188.1, 173.7, 162.8, 160.0, 156.3, 154.6, 148.4, was removed under reduce pressure and acidified with dil. HCl the
141.6, 134.3, 131.5, 131.3, 130.5,127.5, 127.3, 122.6, 118.7, 118.0, 117.6, resulted solid was filtered and dried under vacuum to get com-
79.5, 62.1, 61.7, 25.4, 15.6, 14.3, 14.1; ESI e MS: (m/z): 479 (M þ H)þ. pounds 39e42 in good yields.

6.5.9. (E)-Ethyl8-sec-butyl-6-(3-(4-(1-ethoxy-2-methyl-1- 6.6.1. (E)-6-(3-(4-(carboxymethoxy)phenyl)-3-oxoprop-1-enyl)-8-

oxopropan-2-yloxy)phenyl)-3-oxoprop-1-enyl)-2-oxo-2H- isopropyl-2-oxo-2H-chromene-3-carboxylic acid (39)
chromene-3-carboxylate (35) From 28; white solid; yield: 82%; mp: 265e267  C; IR(KBr,
From 23 and diethylmalonate; white solid; yield: 90%; mp: 154e cm1):3749, 3661, 3038, 2365, 1742, 1664, 1584, 1275, 1225, 1019,
156  C; IR(KBr, cm1): 2985, 2359, 1767, 1665, 1621, 1518, 1366, 839; 1H NMR (DMSO-d6, 300 MHz) d: 8.67 (s, 1H) 8.25e8.15(m, 4H)
1298, 1079, 760; 1H NMR (CDCl3, 300 MHz) d: 8.53 (s, 1H) 7.99 (d, 7.99 (d, J ¼ 15.6 Hz, 1H) 7.73 (d, J ¼ 15.5 Hz, 1H) 7.09 (d, J ¼ 8.7 Hz,
J ¼ 8.7 Hz, 2H) 7.81e7.75 (m, 2H) 7.68 (d, J ¼ 1.5 Hz, 1H) 7.51 (d, 2H) 4.84 (s, 2H) 4.34e4.27(m, 1H)1.33(d, J ¼ 6.7 Hz, 6H); ESI e MS:
J ¼ 15.6 Hz, 1H) 6.89 (d, J ¼ 8.7 Hz, 2H) 4.42 (q, J ¼ 7.1 Hz, 2H) 4.23 (m/z): 437 (M þ H)þ.
(q, J ¼ 7.1 Hz, 2H) 3.48e3.38 (m, 1H) 1.77e1.67 (m, 8H) 1.41(t,
J ¼ 7.1 Hz, 3H) 1.31(d , J ¼ 6.9 Hz, 3H) 1.22(t , J ¼ 7.1 Hz, 3H) 1.41(t, 6.6.2. (E)-8-sec-butyl-6-(3-(4-(carboxymethoxy)phenyl)-3-
J ¼ 7.1 Hz, 3H) 0.88 (t, J ¼ 7.2 Hz, 3H); 13C NMR (CDCl3 75 MHz) oxoprop-1-enyl)-2-oxo-2H-chromene-3-carboxylic acid (40)
d:188.2, 173.7, 162.9, 160.0, 156.3, 153.9, 148.6, 142.0, 136.7, 131.8, From 30; pale yellow solid; yield: 85%; mp: 270e272  C; IR(KBr,
131.4, 130.5, 127.0,122.7, 118.8, 118.2, 117.7, 79.5, 62.1, 61.7, 33.5, 29.7, cm1):3749, 3651, 3028, 2365, 1752, 1664, 1584, 1375, 1222, 1029,
25.5, 20.5, 14.3, 14.1, 12.0; ESI e MS: (m/z): 535 (M þ H)þ. 829; 1H NMR (DMSO-d6, 300 MHz) d: 13.17 (bs, 1H) 8.69 (d,
J ¼ 7.9 Hz, 1H) 8.24e8.15(m, 4H) 7.98 (d, J ¼ 15.0 Hz, 1H) 7.73 (d,
6.5.10. (E)-Ethyl 6-(3-(4-(4-ethoxy-4-oxobutoxy) phenyl)-3- J ¼ 15.6 Hz, 1H) 7.39 (d, J ¼ 8.6 Hz, 2H) 4.83 (s, 2H) 4.34e4.27 (m,
oxoprop-1-enyl)-8-methyl-2-oxo-2H-chromene-3-carboxylate (36) 1H) 1.73e1.72 (m, 2H) 1.31(d, J ¼ 6.9 Hz, 3H) 0.83(t, J ¼ 6.9 Hz, 3H);
From 24 and diethylmalonate; white solid; yield: 74%; mp: 178e ESI e MS: (m/z): 423 (M þ H)þ.
180  C; IR(KBr, cm1): 2965, 2358, 1744, 1654, 1600, 1505, 1340,
1216, 1027, 767; 1H NMR (CDCl3, 300 MHz) d: 8.51 (s, 1H) 8.03 (d, 6.6.3. (E)-6-(3-(4-(1-carboxyethoxy)phenyl)-3-oxoprop-1-enyl)-8-
J ¼ 8.6 Hz, 2H)7.78e7.73 (m, 2H) 7.65 (s, 1H) 7.53 (d, J ¼ 15.5 Hz, 1H) methyl-2-oxo-2H-chromene-3-carboxylic acid (41)
6.97 (d, J ¼ 8.5, 2H) 4.41 (q, J ¼ 7.1 Hz, 2H) 4.18e4.08(m, 4H) 2.55e From 31; pale yellow solid; yield: 80%; mp: 260e262  C; IR(KBr,
1
2.50 (m, 5H) 2.16 (q, J ¼ 6.3 Hz, 2H) 1.41 (t, J ¼ 7.1 Hz, 3H) 1.26 (t, cm ):3749, 3651, 3028, 2365, 1752, 1664, 1584, 1375, 1222, 1029,
J ¼ 7.0 Hz, 3H); 13C NMR (CDCl3 75 MHz) d:187.8, 173.0, 162.9, 162.7, 829; 1H NMR (DMSO-d6, 300 MHz) d: 8.63 (s, 1H) 8.17e8.11(m, 4H)
156.2, 154.4, 148.3, 141.4, 134.2, 131.5, 130.8, 130.7,127.4, 127.2, 122.5, 7.92 (d, J ¼ 15.4 Hz, 1H) 7.63 (d, J ¼ 15.5 Hz, 1H) 7.01 (d, J ¼ 8.6 Hz,
118.5, 117.9, 114.3, 67.0, 62.0, 60.5, 30.6, 24.4, 15.5, 14.2; ESI e MS: 2H) 5.03 (q, J ¼ 6.3 Hz, 1H) 2.39 (s, 3H) 1.55(d, J ¼ 6.6 Hz, 3H); 13C
(m/z): 493 (M þ H)þ. NMR (DMSO-d6, 75 MHz) d: 187.4, 173.0, 164.2, 161.9, 156.7, 154.3,
 K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 64 (2013) 422e431 431

148.7, 141.7, 134.8, 131.4, 131.3, 131.1, 129.2, 126.3, 122.9, 118.9, 118.4, [10] M.E. Riveiro, N.D. Kimpe, A. Moglioni, R. Vazquez, F. Monczor, C. Shayo,
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cm1):3749, 3661, 3038, 2365, 1742, 1664, 1584, 1275, 1225, 1019, [15] (a) P.J. Magalhaes, D.O. Carvalho, J.M. Cruz, L.F. Guido, A.A. Barros, Nat. Prod.
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and Mass spectral data. G.R.P., S.R.A. and R.S. are thankful to CSIR, [21] H.Y. Song, M.H. Ngai, Z.Y. Song, P.A. MacAry, J. Hobley, M.J. Lear, Org. Biomol.
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