Design and synthesis of benzimidazole-linked meta-substituted benzylidenes/benzyls as biologically significant new chemical entities

Article abstract of DOI:10.1080/00397911.2012.678461

meta-Linked thiazolidinedione (TZD)-and diethyl malonate (DEM)-based benzylidenes and methyl acetoacetate (MAA)-based benzyl moieties linked to the 2-position of N-methyl benzimidazole were synthesized. TZD-and DEM-based compounds were synthesized by condensation of 2,4-thiazolidinedone and DEM respectively with the corresponding 3-substituted benzaldehyde, whereas MAA-based compounds were obtained by halogen displacement with the corresponding 3-substituted phenol. These new chemical entities were designed to provide a balanced agonism at the peroxisome proliferator activated receptor alpha/gamma (PPARα/γ) in the management of type 2 diabetes: a move from glitazones to selective PPARγ modulators (SPPARγMs). Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file.

Full text of DOI:10.1080/00397911.2012.678461

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Design and Synthesis of Benzimidazole-
Linked meta-Substituted Benzylidenes/
Benzyls as Biologically Significant New
Chemical Entities
Raman K. Verma a , Rajiv Mall a , Prithwish Ghosh a & Vijay Kumar a
a Synthetic Organic and Medicinal Chemistry Laboratory, Department
of Chemistry, Punjabi University, Patiala, India
Accepted author version posted online: 02 Jan 2013.Version of
record first published: 05 Apr 2013.
To cite this article: Raman K. Verma , Rajiv Mall , Prithwish Ghosh & Vijay Kumar (2013): Design and
Synthesis of Benzimidazole-Linked meta-Substituted Benzylidenes/Benzyls as Biologically Significant
New Chemical Entities, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 43:14, 1882-1895
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Synthetic Communications1, 43: 1882–1895, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.678461
DESIGN AND SYNTHESIS OF BENZIMIDAZOLE-LINKED
META-SUBSTITUTED BENZYLIDENES/BENZYLS
AS BIOLOGICALLY SIGNIFICANT NEW
CHEMICAL ENTITIES
Raman K. Verma, Rajiv Mall, Prithwish Ghosh, and
Vijay Kumar
Synthetic Organic and Medicinal Chemistry Laboratory, Department of
Chemistry, Punjabi University, Patiala, India
GRAPHICAL ABSTRACT
Abstract meta-Linked thiazolidinedione (TZD)– and diethyl malonate (DEM)–based
benzylidenes and methyl acetoacetate (MAA)–based benzyl moieties linked to the
2-position of N-methyl benzimidazole were synthesized. TZD- and DEM-based compounds
were synthesized by condensation of 2,4-thiazolidinedone and DEM respectively with the
corresponding 3-substituted benzaldehyde, whereas MAA-based compounds were obtained
by halogen displacement with the corresponding 3-substituted phenol. These new chemical
entities were designed to provide a balanced agonism at the peroxisome proliferator
activated receptor alpha/gamma (PPARa/c) in the management of type 2 diabetes: a
move from glitazones to selective PPARc modulators (SPPARcMs).
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Benzimidazole; benzylidene; diethylmalonate; methyl acetoacetate; 2,4-
thiazolidinedione
Received October 18, 2011.
Address correspondence to Raman K. Verma, Synthetic Organic and Medicinal Chemistry
Laboratory, Department of Chemistry, Punjabi University, Patiala 147 002, India. E-mail: raman_
verma58@yahoo.com
1882

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1883
INTRODUCTION
The derivatives of chemically significant benzimidazole, an important hetero-
cyclic nucleus in drug discovery research, have been reported with diverse therapeutic
activities such as: antiparasitic,[1] antiprotozoal,[2] antitubercular,[3] antiviral,[4,5]
antifungal,[6] antitumor,[7] antihypertensive,[8] antihistaminic,[9] anxitolytic,[10] and
topoisomerase-I inhibitor[11] activities. Peroxisome proliferator activated receptors
(PPARs), especially the a and c subtypes, are very important therapeutic targets
for the treatment of type 2 diabetes mellitus.
One class of effective chemotherapeutic agents for T2DM is the thiazolidine-
diones (TZDs). These compounds function as sensitizers of endogenous insulin via
activation of peroxisome proliferator activated receptor gamma (PPARc). The full
potential of these drugs has not been realized because of undesirable weight gain,
peripheral edema, and anemia following prolonged usage. Mechanism-based side
effects including weight gain, edema, and congestive heart failure, as well as recently
reported possible bone fracture following rosiglitazone treatment, are among the
major safety hurdles associated with PPARc full agonists.[12,13]
It has recently been suggested that to improve blood glucose lowering and
reduce weight gain and other adverse effects, compounds with marginal PPARa
affinity but with selective PPARc modulating activity provide a possible solution
for effective treatment with lesser side effects.[13] PPARa=c agonists usually possess
essential pharmacophoric elements,[14–16] that is, an acidic group or a hydrogen
bonding part attached to a central flat aromatic ring, a linker, and a large hydro-
phobic group. Dual PPARa=c agonists possess a flexible alkyl ether linkage, which
allows the molecule to adopt a bioactive U-shaped conformation that well fits into
the arms of Y-shaped PPAR active sites.[17] Extensive research has been reported
for the dual agonism of the glitazars with the said scaffold, though they have not
yet made their way to clinical use. In recently reported studies, highly selective
and active PPARa=c dual agonists with nanomolar and picomolar EC50 values were
obtained by replacing the alkyl ether central linker with a rigid linker.[18]
More recently, it has been reported that the meta-substituted aryl unit for the
central flat aromatic ring part has been found to be the best candidate scaffolds in
molecules with a rigid linker on the basis of comparisons of binding energy scores
and binding modes.[19] 2,4-Thizolidinedione[20] (2,4-TZD) compounds with
2,4-TZD unit and 1,3-diester compounds[21] with 1,3-diester unit as the hydrogen
bonding part have been well established as potent PPAR activators in the literature.
Lohray et al. also reported a series of potent benzylidene thiazolidinediones with
euglycemic as well as hypolipidemic acitivities.[22]
Although there are reports related to derivatization with a linker at the
1(N)-position of indoles[22] and benzimidazoles,[22] reports related to derivatization
with a linker at the 2-position of the benzimidazole ring could be found in the literature.
In the present work, new chemical entities were designed by the theoretical
modification of the PPARc full agonist rosiglitazone (Fig. 1), and the designed mole-
cules (being novel) were synthesized. The predicted binding affinities at the PPARa
and PPARc for all the designed at the active site of the receptors protein concerned
for the prediction and synthesized compounds are also reported to support the
design.

1884
R. K. VERMA ET AL.
Figure 1. Design of selective PPARc modulators (SPPARcMs).
RESULTS AND DISCUSSION
New chemical entities were designed by the theoretical modification of the
PPARc full agonist rosiglitazone: The 2-N-methylpyridyl moiety of rosiglitazone
was modified to N-methyl benzimidazole (a fused heterocycle) while simultaneously
reducing the length of the linker from ethoxy (3 atom) of rosiglitazone to methoxy (2
atom), oxy (1 atom), and direct linked (no atom) and further constraining the sub-
sequent expansion by incorporating meta-substituted benzylidene-linked thiazolidi-
nedione and diethyl malonate and also meta-substituted benzyl-linked methyl
acetoacetae rather than the para-substitued benzyl thiazolidinedione as the hydrogen
bonding parts (Fig. 1, Table 1). All the designed molecules (Table 1) possess almost
all the structural features to be expected for achieving marginal PPARa affinity but
selective PPARc modulating activity[19] and were docked (with Surflex dock module
of Sybyl 7.3, a Tripos Inc. software available at our in silico drug design laboratony)
at the active site of the receptors’ protein for the prediction of binding affinities (gold
score energies, Table 1) in reference to some selected standard molecules (template
rosiglitazone). This parameter was used as criteria for the selection of compounds
for synthesis with the aim of achieving marginal PPARa affinity but selective PPARc
modulating activity.
It was found from the analysis of the results of docking studies that benzylidenes
exhibit lesser PPARa affinities (Table 1: compounds 3 and 4) and also PPARc affin-
ities (Table 1: compounds 1 and 2) in comparison to the corresponding benzyls. It was
also observed that introduction of conformational constraint into the linker (with a
double bond, heteroatom or heterocycle) reduces the PPARa affinity to a consider-
able extent (Table 1: compounds 3, 5, and 6). The G-score data thus generated for
the designed new molecules (Table 1) being a reflection of the observation (goodness
of fit) of selected standard molecules, not only provided experimental support to the
hypothesis but has also helped us to set out criteria (much less PPARa affinities and
lesser or comparative PPARc affinities with respect to the template) to select mole-
cules (Table 1: compounds 8, 11, 13, 14, 16, 19, 20, and 22) for further synthesis.
Because two (Table 1: compounds 12 and 18) of the three (Table 1: compounds 12,
18, and 24) of the set of similar benzylidene-based compounds showed greater
PPARa affinities than rosiglitazone were not synthesized, compound 24 therefore
was also not synthesized despite having lower PPARa affinity. GW409544 was

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1885
Table 1. Comparison of predicted binding energy scores of the synthesized compounds with the standard
compounds for PPARa and PPARc
Binding energy score (gold scorea)
Serial no.
1
Code
Structure
PPARa
PPARc
Rosiglitazone
ꢀ189.05
ꢀ223.25
2
3[20]b
ꢀ218.99
ꢀ209.91
3
4
5
Tesaglitazar
Tesaglitazar(db)
E[19]b
ꢀ260.26
ꢀ146.68
ꢀ247.50
ꢀ204.54
ꢀ204.21
ꢀ194.87
ꢀ240.04
ꢀ261.57
6
7
F[19]b
GW409544
ꢀ387.26
ꢀ353.17
8
9
5a
ꢀ158.78
ꢀ181.78
ꢀ207.83
ꢀ214.37
5a(sb)
10
11
12
13
5b
5b(sb)
12a(db)
12a
ꢀ125.98
ꢀ235.48
ꢀ213.18
ꢀ288.31
ꢀ202.50
ꢀ222.97
ꢀ184.61
ꢀ250.48
(Continued )

1886
R. K. VERMA ET AL.
Table 1. Continued
Binding energy score (gold scorea)
Serial no.
14
Code
8a
Structure
PPARa
PPARc
ꢀ179.93
ꢀ194.26
15
8a(sb)
ꢀ229.35
ꢀ151.40
ꢀ256.89
ꢀ264.95
16
17
8b
8b(sb)
ꢀ194.63
ꢀ206.89
ꢀ185.64
ꢀ265.15
ꢀ201.08
ꢀ235.31
18
19
20
12b(db)
12b
13a
ꢀ180.07
ꢀ209.66
ꢀ200.93
ꢀ198.86
21
13a(sb)
22
23
24
13b
13b(sb)
—
ꢀ110.77
ꢀ166.75
ꢀ147.32
ꢀ224.75
ꢀ217.10
ꢀ215.66
25
—
ꢀ199.87
ꢀ237.78
aGold score[25] of the best docked conformation.
bThe code written is as given in the reference.
Notes. db, double bond; sb, single bond.

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1887
included in the list of selected standard molecules as it is the bound ligand in the
crystal structure of PPARa (PDB code: 1k7 l).
The synthesis of ether-linked benzylidene TZD and DEM target molecules is
shown in Scheme 1. 2-Mercaptobenzimidazole[24] (2) and 2-bromo-1-methyl-1H-
benzimidazole[25] (4) were prepared in good yields as per reported procedures using
commercially available 1,2-phenylenediamine (1). Compound 4 was converted to
the corresponding benzimidazole-linked 3-substituted benzldehyde (5) by bromo
displacement of 4 with the phenoxide resulting from 3-hydroxybenzaldehyde in
the presence of a base. The synthesized benzaldehyde was subsequently condensed
with 2,4-TZD and DEM to yield the corresponding benzylidene targets 5a and 5b
respectively, in fair yields. The synthesis of methylene ether-linked benzylidene
TZD and diethylmalonate (DEM) target molecules is shown in Scheme 2. 2-Chlor-
omethyl benzimidazole (7) was prepared by condensation of commercially available
N-methyl-1,2-phenylenediamine (6) with chloroacetic acid in the presence of hydro-
chloric acid. The corresponding benzimidazole linked 3-substituted benzldehyde (8)
was obtained from 7 in a similar way for synthesizing 5. The corresponding benzy-
lidene targets 8a and 8b were synthesized similarly in fair yields as described in
Scheme 1. Repeated attempts to condense methyl acetoacetate with the benzimida-
zole linked benzaldehydes (5 and 8) in the presence of a base (piperidinium acetate)
failed to give the desired benzylidene based ketoesters, which could be further
reduced to obtaine the desired compounds 12a and b, which promptd us to optfor
Scheme 1. Synthesis of -O- linked molecules: (a) carbon disulfide, ethanol, water, glacial AcOH, Norit; (b)
HBr=glacial AcOH, Br2, water, NaOH; (c) 1 N NaOH solution, dimethyl sulfate; (d) K2CO3. 3-hydroxy-
benzaldehyde, Cu powder, pyridine; (e) piperidine acetate, toluene, 2,4-thiazolidinedione; and (f)
piperidine acetate, toluene, diethylmalonate.

1888
R. K. VERMA ET AL.
Scheme 2. Synthesis of -CH2O- linked molecules: (a) chloroacetic acid, HCl; (b) NaH, dry DMF, 3-hydro-
xybenzaldehyde; (c) piperidine acetate, toluene, 2,4-thiazolidinedione; and (d) piperidine acetate, toluene,
diethylmalonate.
an alternative route (Scheme 3) for their synthesis. Condensation of commercially
available m-anisaldehyde (9) and methylacetoacetate (MAA) gave the corresponding
benzylidene (10) as a mixture of the two geometrical isomers (1:2), which upon cata-
lytic hydrogenation gave the corresponding benzyl MAA product (11). The product
11 was subsequently demethylated using BBr3 to obtain the required phenol (12),
which in turn was coupled with 4 (Scheme 1) and 7 (Scheme 2) in a similar way as
for the preparation of 5 (Scheme 1) to generate the desired targets 12a and 12b
respectively. 3-(1-Methyl-1H-benzimidazol-2-yl)benzaldehyde (13) was synthesized
by Suzuki coupling of 4 and 3-boronobenzaldehyde, which subsequently upon con-
densation with 2,4-TZD and DEM gave the required benzylidene targets 13a and
13b respectively in fairly good yields (Scheme 4).
Scheme 3. Synthesis of b-ketoester-based molecule: (a) piperidine acetate, methylacetoacetate, toluene,
Dean–Stark; (b) Pd=C, H2, MeOH=dioxane, parr hydrogenater; (c) BBr3, dichloromethane; (d) 2-bromo-l-
methyl-lH-benzimidazole, pyridine, Cu powder, K2CO3; (e) 2-(chloromethyl)-1-methyl-1H-benzimidazole,
pyridine, Cu powder, K2CO3.

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1889
Scheme 4. Synthesis of benzylidene molecules with no linker. (a) K2CO3, 3-boronobenzaldehyde,
toluene-ethanol, Pd(PPh3)4; (b) piperidine acetate, toluene, 2,4-thiazolidinedione; and (c) piperidine acet-
ate, toluene, diethylmalonate.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker 400-MHz instrument in CDCl3
and dimethylsulfoxide (DMSO-d6) using tetramethylsilane (TMS) as an internal stan-
dard. The mass spectra were recorded on a Shimadzu QP-2010 gas chromatography–
mass spectrometer (GCMS) and APCI corona Liquid chromatography–mass
spectrometer (LCMS). The infrared (IR) spectra (KBr) were recorded on a Perkin-
Elmer Fourier transform (FT)–IR spectrometer. The elemental analyses were per-
formed on a Vario Micro V1 elemental analyzer. Melting points were measured in
a Buchi melting-point apparatus and are uncorrected. Thin-layer chromatographic
(TLC) analysis was carried out on glass plates coated with silica gel-GF254 (Loba
Chemie), and spots were visualized using an ultraviolet (UV) cabinet (Perfit, India).
Column chromatography was performed using silica gel (100–200 mesh, Loba
Chemie). All chemicals were purchased from Sigma Aldrich. Compound 2 and 4 were
prepared as per reported procedures.[23,24]
3-[(1-Methyl-1h-benzimidazol-2-yl)oxy]benzaldehyde (5)
A mixture of 4 (0.211 g; 1 mmol), 3-hydroxybenzaldehyde (0.122 g; 1 mmol),
K2CO3 (0.414 g; 3 mmol), and Cu powder (0.00063 g; 0.01 mmol) in pyridine was
heated to 140 ꢁC for 24 h. The reaction mixture was allowed to cool, taken up in
EtOAc (30 ml), and then washed three times with 0.5 N NaOH. The organic layer
was dried (Na2SO4), filtered, and concentrated under reduced pressure to give an
oil that was subjected to column chromatography using a mixture of acetone=hexane
(1:9) to afford the title compound as a white solid (0.075 g, 30%). Mp: 115–117 ꢁC. IR
(KBr): 3049, 3011, 2947 and 2838, 2806 and 2738, 1701, 1622, 1587, 1520, 1490, 1454,

1890
R. K. VERMA ET AL.
l
1383, 1254, 737, 783 and 679 cmꢀ1; H NMR (CDCl3) d: 3.76 (s, 3H, N-CH3),
7.20–7.27 (m, 3H, Ar), 7.56–7.58 (m, 1H, Ar), 7.60–7.64 (m,1H, Ar), 7.69–7.72 (m,
1H, Ar), 7.77–7.80 (m, 1H, Ar), 7.91–7.92 (s, 1H, Ar), 10.03 (s, 1H, -CHO); GCMS
m=z (%): 252 [M]þ (100). Anal. calcd. for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10.
Found: C, 71.66; H, 4.52; N, 10.92.
3-[(1-Methyl-1H-benzimidazol-2-yl)methoxy]benzaldehyde (8)
3-Hydroxybenzaldehyde (0.122 g, 1 mmol) was added to a suspension of sodium
hydride (0.048 g, 2 mmol, 60% dispersion) in dry dimethylformamide (30 ml) at 0 ꢁC.
When hydrogen evolution ceased, a solution of 7 (0.180 g; 1 mmol) in DMF (5 ml) was
added, and the mixture was stirred at room temperature for 24 h. Then the solution
was poured into ice water (50 ml) and extracted with ethyl acetate (3 ꢂ 20 ml). The
combined organic extracts were washed with water (50 ml) and brine (50 mL), dried
over sodium sulfate, and concentrated. The crude product was purified by column
chromatography using a mixture of methanol=chloroform (1:99) as eluent to give
the title compound (0.235 g, 88%) as light greenish solid. Mp: 118–120 ꢁC. IR
(KBr): 3065, 3023, 2942 and 2870, 2817 and 2736, 1698, 1594, 1582, 1523, 1442
l
and 1369, 1255, 747, 788 and 721 cmꢀ1; H NMR(CDCl3) d: 3.89 (s, 3H, N-CH3),
5.44 (s, 2H, -CH2-), 7.29–7.39 (m, 4H, Ar), 7.44–7.52 (m, 2H, Ar), 7.57–7.58 (m,
1H, Ar), 7.79 (d, 1H, Ar), 9.97 (s, 1H, -CHO); GCMS m=z (%): 266 [M]þ (10), 145
(100). Anal. calcd. for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 71.93;
H, 5.57; N, 10.68.
3-(1-Methyl-1H-benzimidazol-2-yl)benzaldehyde (13)
To a solution of 4 (0.211 gm, 1 mmol) and 3-boronobenzaldehyde (0.224 g,
1.5 mmol) in 25 mL of toluene–ethanol (4:1) was added K2CO3 (0.414 g, 3 mmol).
The resulting mixture was degassed and stirred at ambient temperature for 20 min,
and catalytic amount (0.005 mmol) of Pd(PPh3)4 was added. The mixture was
degassed again and then refluxed under nitrogen gas for 8 h. It was allowed to cool,
filtered through celite, and extracted using EtOAc (3 ꢂ 20 ml). The organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure to give an oil that
was subjected to column chromatography using a mixture of acetone=hexane (2:8) to
afford the title compound as a viscous mass (0.200 g, 85%). IR (KBr): 3049, 3011,
2947 and 2838, 2806 and 2738, 1701, 1622, 1587, 1520, 1490, 1454, 1383, 1254, 737,
l
783 and 679 cmꢀ1; H NMR (CDCl3) d: 3.91 (s, 3H, N-CH3), 7.33–7.38 (m, 2H,
Ar), 7.41–7.44 (m, 1H, Ar), 7.72 (t, 1H, Ar), 7.83–7.85 (m, 1H, Ar), 8.01–8.03 (m,
1H, Ar), 8.06–8.09 (m, 1H, Ar), 8.28–8.29 (m, 1H, Ar), 10.14 (s, 1H, -CHO); GCMS
m=z (%): 236 [M]þ (100). Anal. calcd. for C15H12N2O: C, 76.25; H, 5.12; N, 11.86.
Found: C, 76.71; H, 5.27; N, 11.97.
Synthesis of 5a, 8a, 13a, 5b, 8b, and 13b
General procedure. A mixture of (5/8/13) (1 mmol), thiazolidine-2,4-dione=
diethylmalonate (1 mmol), and piperidinium acetate (catalytic amount) in toluene
(25 ml) was refluxed for 7=14 h with continuous removal of water using a Dean–Stark

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1891
trap. The reaction mixture was cooled to room temperature, refrigerated overnight,
and concentrated. The precipitate was collected by filtration under vacuum, washed
with cold hexane, and dried=purified by column chromatography using methanol=
chloroform (1:99) as eluent to give the target compound (5a/8a/13a/5b/8b/13b).
5-f3-[(1-Methyl-1H-benzimidazol-2-yl)oxy]benzylideneg-1,3-thiazolidine-
2,4-dione (5a). Yield: 77%. Mp: 262–265 ꢁC. IR (KBr): 3500–3300, 3060, 2944 and
2840, 1741, 1699, 1610, 1517, 1485, 1458 and 1325, 1237, 744, 762 and 683; lH NMR
(DMSO-d6) d: 3.70 (s, 3H, N-CH3), 7.11–7.20 (m, 4H, Ar), 7.31–7.34 (m, 2H, Ar),
7.44–7.48 (m, 2H, Ar), 7.59 (s, 1H, benzylidene); LCMS m=z (%): 352 [M þ 1]þ
(100). Anal. calcd. for C19H15N3O3S: C, 62.45; H, 4.14; N, 11.50. Found: C,
62.71; H, 4.27; N, 11.37.
5-[3-(1-Methyl-1H-benzoimidazol-2-ylmethoxy)-benzylidene]-thiazo-
lidine-2,4-dione (8a). Yield 82%. Mp: 265–268 ꢁC. IR (KBr): 3341, 3061, 2943
and 2840, 1741and 1709, 1611, 1599, 1582, 1484, 1446 and 1374, 1254, 733, 770
l
and 679 cmꢀ1; H NMR (CDCl3) d: 3.90 (s, 3H, N-CH3), 5.46 (s, 2H, -CH2O-),
7.15–7.24 (m, 3H, Ar), 7.26–7.31 (m, 2H, Ar), 7.40–7.44 (m, 1H, Ar), 7.50–7.52
(m, 1H, Ar), 7.64–7.67 (m, 2H, 1Ar and 1 benzylidene); LCMS m=z (%): 366
[M þ 1]þ (100). Anal. calcd. for C19H15N3O3S: C, 62.45; H, 4.14; N, 11.50; S,
8.78. Found: C, 62.80; H, 4.49; N, 11.42; S, 8.25.
5-[3-(1-Methyl-1H-benzimidazol-2-yl)benzylidene]-1,3-thiazolidine-2,4-
dione) (13a). Yield: 88%. Mp: 265–267 ꢁC. IR (KBr): 3500–3300, 3060, 2929 and
2855, 2739, 1741, 1701, 1614, 1576, 1485, 1458 and 1384, 1325, 1237, 918, 801,
l
762 and 689; H NMR (CDCl3) d: 3.93 (s, 3H, N-CH3), 7.35 (m, 3H, Ar), 7.64
(m, 2H, Ar), 7.85 (m, 3H, Ar), 7.90 (s, 1H, Ar); LCMS m=z (%): 336 [M þ 1]þ
(100). Anal. calcd. for C18H13N3O2S: C, 64.46; H, 3.91; N, 12.53; S, 9.56. Found:
C, 64.51; H, 4.07; N, 12.67; S, 9.64.
2-[3-(1-Methyl-1H-benzoimidazol-2-yloxy)-benzylidene]-malonic acid
diethyl ester (5b). Yield: 50%. Mp: 185–187 ꢁC. IR (KBr): 3475, 2918 and 2850,
l
1727, 1622, 1520, 1453, 1226, 746, 798 and 702; H NMR (CDCl3) d: 1.18 (t, 3H,
-OCH2CH3), 1.26 (t, 3H, -OCH2CH3), 3.66 (s, 3H, N-CH3), 4.22 (two overlapping
quartets, 4H, -OCH2CH3), 7.12–7.19 (m, 3H, Ar), 7.28–7.29 (m, 1H, Ar),
7.38–7.39 (m, 2H, Ar), 7.42 (d, 1H, Ar), 7.48–7.50 (m, 1H, Ar), 7.65 (s, 1H, benzy-
lidene); LCMS m=z (%): 395 [M þ 1]þ (45), 320 (100). Anal. calcd. for C22H22N2O5:
C, 66.99; H, 5.62; N, 7.10. Found: C, 66.74; H, 5.43; N, 6.86.
2-[(1-Methyl-1H-benzoimidazol-2-ylmethoxy)-benzylidene]-malonic acid
diethyl ester (8b). Yield: 60%. Mp: 120–123 ꢁC. IR (KBr): 3017, 2982, 2962,
l
2933, 2858, 1740, 1733, 1586, 1483, 1447, 1406, 1370, 1256, 755, 668 cmꢀ1; H
NMR (CDCl3) d: 1.27 (t, J ¼ 7.16 Hz, 3H, -OCH2CH3), 1.33 (t, J ¼ 7.16 Hz, 3H,
-OCH2CH3), 3.87 (s, 3H, N-CH3), 4.30 (two overlapping quartets, J ¼ 7.08, 2H each,
-OCH2CH3), 5.37 (s, 2H, -CH2O-), 7.08–7.09 (d, 1H, Ar), 7.13–7.16 (m, 2H, Ar),
7.26–7.36 (m, 4H, Ar), 7.69 (s, 1H, benzylidene), 7.78 (d, 1H, Ar); LCMS m=z
(%): 409 [M þ 1]þ (100). Anal. calcd. for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86.
Found: C, 67.41; H, 5.57; N, 6.92.

1892
R. K. VERMA ET AL.
Diethyl [3-(1-Methyl-1H-benzimidazol-2-yl)benzylidene]
propanedioate (13b)
A mixture of 13 (0.236 g, 1 mmol), diethylmalonate (0.160 g, 1 mmol), and
piperidinium acetate (catalytic amount) in toluene (25 ml) was refluxed for 14 h with
continuous removal of water using a Dean–Stark trap. After cooling to the room tem-
perature, the solution was concentrated to crude reaction mixture, which was purified
by column chromatography using methanol=chloroform (1:99) as eluent to afford the
title compound (13b) (0.250 g, 66%) as a viscous mass. IR (KBr): 3369, 2917 and 2849,
1726, 1631, 1607, 1514, 1460, 1266, 798, 745 and 702; lH NMR (CDCl3) d: 1.27 (t, 3H,
-OCH2CH3), 1.35 (t, 3H, -OCH2CH3), 3.89 (s, 3H, N-CH3), 4.33 (two overlapping
quartets, 4H, -OCH2CH3), 7.34 (m, 2H, Ar), 7.42 (m, 1H, Ar), 7.58 (m, 2H, Ar),
7.84 (s, 4H, Ar); LCMS m=z (%): 379 [M þ 1]þ (100). Anal. calcd. for C22H22N2O4:
C, 69.83; H, 5.86; N, 7.40. Found: C, 69.91; H, 5.97; N, 7.47.
Methyl 2-(3-Hydroxybenzyl)-3-oxobutanoate (12)
Boron tribromide (1.0 N solution of dichloromethane, 4 ml) was added to a
solution of 11 (0.944 g, 4 mmol) in dichloromethane (7 ml) at 0 ꢁC. The reaction mix-
ture was stirred at room temperature overnight. The reaction was then quenched
with ice water and partitioned. The organic layer was washed with water and dried
over sodium sulfate. After filtering the drying agent, the filtrate was evaporated and
the residue was purified by silica-gel chromatography eluting with a mixture of
EtOAc=hexane (3:7) to give the title compound (0.75 g, 84%) as a brown viscous
l
mass. IR (KBr): 3300–3400, 1737, 1719, 756 cmꢀ1; H NMR (CDCl3) d: 2.18 (s,
3H, -COCH3), 3.10 (d, 2H, -CH2-), 3.70 (s, 3H, -OCH3), 3.80 (t, 1H, -CH-),
6.66–6.72 (m, 3H, Ar), 7.11–7. 15 (m, 1H, Ar); GCMS m=z (%): 222 [M]þ (10),
204 (30), 179 (30), 147 (100). Anal. calcd. for C12H14O4: C, 64.85; H, 6.35. Found:
C, 64.61; H, 6.22.
Synthesis of 12a and 12b
General procedure. A mixture of 4/7 (1 mmol), 12 (1 mmol), K2CO3 (0.414 g,
3 mmol), and Cu powder (0.00063 g; 0.01 mmol) in pyridine was heated to 140 ꢁC for
24 h. The reaction mixture was allowed to cool and taken up in EtOAc (30 ml), and
then the organic extracts were washed three times with 0.5 N NaOH. The organic
layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to give
a brown viscous mass, which was subjected to column chromatography to afford
title compound (12a/12b) as a yellow viscous mass.
Methyl
tanoate (12a). Yield: 20%; IR (KBr): 3019, 2954, 2850, 1742, 1715, 1455, 1360,
2-f3-[(1-methyl-1H-benzimidazol-2-yl)oxy]benzylg-3-oxobu-
l
1232, 756, 695, 667 cmꢀ1; H NMR (CDCl3) d: 2.07 (s, 3H, -COCH3), 2.85 (dd,
1H, -CH-), 2.71 (overlapping double doublet, 1H, benzylic), 3.40 (s, 3H, N-CH3),
3.63 (overlapping dd, 1H, benzylic), 3.66 (s, 3H, -OCH3), 6.58 (m, 1H, Ar),
6.99–7.01(m, 1H, Ar), 7.11–7.16 (m, 4H, Ar), 7.24–7.26 (m, 1H, Ar), 7.36 (m, 1H,
Ar); LCMS m=z (%): 353 [M þ 1]þ (47), 295 (100). Anal. calcd. for C20H20N2O4:
C, 68.17; H, 5.72; N, 7.95. Found: C, 68.46; H, 5.48; N, 8.12.

BENZIMIDAZOLE-LINKED CHEMICAL ENTITIES
1893
Methyl
2-f3-[(1-methyl-1H-benzimidazol-2-yl)methoxy]benzylg-3-
oxobutanoate (12b). Yield: 20%; IR (KBr): 3437, 1731, 1711, 1095 cmꢀ1; H
NMR (CDCl3) d: major 2.05 (s, 3H, -COCH3), 3.57 (overlapping dd, 2H, benzylic),
3.64 (s, 3H, N-CH3), 3.88 (s, 3H, -OCH3), 5.38 (s, 2H, -CH2O-), minor 2.50 (s, 3H,
-COCH3), 3.62 (s, 3H, N-CH3), 3.85 (overlapping dd, 2H, -CH2-, 3.87 (s, 3H,
-OCH3), d 5.35 (s, 2H, -CH2O-), 6.82 (t, 2H, aromatic: one each of the major and
minor), 6.96 (d, 4H, aromatic: one each of the major and minor), 7.19–7.36 (m,
6H, aromatic: one each of the major and minor), 7.65–7.67 (d, 2H, aromatic: one
each of the major and minor), 7.74–7.76 (d, 2H, Aromatic: one each of the major
and minor). LCMS m=z (%): 367 [M þ 1]þ (77), 335 (54). Anal. calcd. for
C21H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.55; H, 6.19; N, 7.49.
l
Molecular Docking Studies
All the theoretically designed molecules along with the standard molecules were
built by ‘‘sketch molecule’’ module of Sybyl 7.3 on the crystal structure of rosiglita-
zone obtained from the crystal structure of the ligand with PPARc (PDB code: 2prg).
They were assigned Gasteiger–Huckel charges and subsequently minimized using the
Powel method. The energy-optimized sketched molecules were subjected to docking
run at the ligand binding site of PPARc (PDB code: 2prg) and PPARa (PDB code:
1k7 l) by Surflex dock in Sybyl.[23] The predicted binding affinities in terms of gold
score[19] energies of the synthesized molecules were recorded and compared to that
of the selected standard molecules previously reported in the literature.
Complete spectral and experimental details are available online in the Sup-
plemental Materials.
ACKNOWLEDGMENTS
We are thankful to the Punjabi University authorities for providing the neces-
sary research facilities. We are also grateful to the director and Avtar Singh of RSIC,
Panjab University, Chandigarh, and director, NIPER, SAS Nagar, Mohali, Punjab,
for extending the facilities for spectral analysis of the compounds reported in this
article. One of the authors (R.M.) is thankful to the Ministry of Social Justice and
Empowerment, government of India, for providing a research fellowship.
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