Synthesis and evaluation of novel 2-butyl-4-chloro-1-methylimidazole embedded chalcones and pyrazoles as angiotensin converting enzyme (ACE) inhibitors

Article abstract of DOI:10.1016/j.bmc.2011.06.085

A series of novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones and pyrazoles were synthesized and evaluated for their angiotensin converting enzyme (ACE) inhibitory activity. The condensation of 2-butyl-4-chloro-1-meth

Full text of DOI:10.1016/j.bmc.2011.06.085

Bioorganic & Medicinal Chemistry 19 (2011) 4772–4781
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and evaluation of novel 2-butyl-4-chloro-1-methylimidazole
embedded chalcones and pyrazoles as angiotensin converting enzyme
(ACE) inhibitors
Srinivas Kantevari a, , Dinesh Addla a, Pankaj K. Bagul b, Balasubramanian Sridhar c, Sanjay K. Banerjee b,
⇑
⇑
a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500 607, India
b Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500 607, India
c Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel 2-butyl-4-chloro-1-methylimidazole embedded aryl and heteroaryl derived chalcones
and pyrazoles were synthesized and evaluated for their angiotensin converting enzyme (ACE) inhibitory
activity. The condensation of 2-butyl-4-chloro-1-methylimidazole-5-carboxaldehyde with various aryl
and heteroaryl methyl ketones in the presence of 10% aqueous NaOH in methanol proceeded efficiently
to give the respective chalcones in very good yields. Further, the reaction of chalcones with hydrazine
hydrate in acetic acid gave substituted pyrazole analogues. Screening all 36 new compounds using ACE
inhibition assay, resulted chalcones with better ACE inhibitory activity compared to the respective
pyrazole analogues. Among the chalcones 4a–r, three compounds, (E)-3-(2-butyl-4-chloro-1-methyl-
1H-imidazol-5-yl)-1-(5-chlorothiophen-2-yl)prop-2-enone 4i, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imi-
dazol-5-yl)-1-(1H-pyrrol-2-yl)prop-2-enone 4l, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)
-1-(dibenzo[b,d] thiophen-2-yl)prop-2-enone 4q were resulted as most active ACE inhibitors with IC50
Received 14 May 2011
Revised 27 June 2011
Accepted 28 June 2011
Available online 2 July 2011
Keywords:
Angiotensin converting enzyme
Inhibitors
Imidazole
Chalcones
Pyrazoles
of 3.60 lM, 2.24 lM, and 2.68 lM, respectively.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
have identified Butein, a natural a,b-unsaturated ketone, as one of
the safe, potent ACE inhibitory compound isolated from the stems
of Rhus verniciflua.7a The unique pharmacophoric structural feature
of this compound is chalcone architecture.7b Later studies8 on the
evaluation of various aromatic chalcones also revealed potent
ACE inhibitory activity. We therefore envisaged that, linking the
unsaturated enone (chalcone) with various heterocyclic units
could generate potential candidates for screening ACE inhibitory
activity.9 The choice of heterocyclic units is arised from clinically
used drug molecules as potent RAS effectors. Among the several
RAS components, Angiotensin II plays critical integral role in the
pathophysiology of hypertension.10 The drugs such as Losartan,
Eprosartan, etc. developed as Angiotensin II antagonists, are clini-
cally used in conjunction with ACE inhibitors for treating hyperten-
sion and then cardiovascular diseases.11 In an effort to design new
heterocyclic library with drug like properties, the 2-butyl imidaz-
ole unit10 of Losartan or Eprosartan and chalcone architecture of
natural Butein were embedded in one molecular frame (Fig. 1) to
evaluate their potency as ACE inhibitors.12 The choice of five mem-
ber nitrogen containing substituted imidazole unit is also due to
their similarity with proline unit present in Lisinopril Captopril,
etc. With this design strategy, we herein describe an efficient
synthesis and evaluation of ACE inhibitory activity of novel
2-butyl-4-chloro-1-methyl imidazole derived chalcones 4a–r and
pyrazoles 6a–r. Screening all the 36 new compounds using
Research in the field of hypertension has gained worldwide
importance because of its high frequency and concomitant risks
associated with cardiovascular diseases.1 It has been identified as
leading risk factor for mortality and is ranked third as a cause of
disability-adjusted life-years.2 From a patho-physiological view
point, hypertension involves changes in at least one of the hemo-
dynamic variables (cardiac output, arterial stiffness or peripheral
resistance) that determine measurable blood pressure.3 Therefore
each of these variables is a potential target for modulation. It is rec-
ognized that angiotensin converting enzyme (ACE) plays an impor-
tant role as a regulatory site in the Renin-Angiotensin system
(RAS)4 that control excessive activation and then hypertension.
Several ACE inhibitors such as Captopril, Enalapril, and Lisinopril
are in clinical use for treatment of hypertension.5 All these drugs
also produce side effects5,6 (like dry cough, hyperkalemia, rashes,
loss of taste, first dose hypotension and acute renal failure), thus
justifying the search for newer analogues of ACE inhibitors for safe
use. In vitro screening of compounds from ethanobotanical sources
⇑
Corresponding authors. Tel.: +91 4027191618 (S.K.B.); tel.: +91 4027191437;
fax: +91 4027191833 (S.K.).
E-mail addresses: Kantevari@yahoo.com, Kantevari@gmail.com (S. Kantevari),
skbanerjee@iict.res.in (S.KK. Banerjee).
0968-0896/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2011.06.085

S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
4773
Cl
N
N
N
COOH
OH
N
S
Cl
N
R
N
H3C
O
COOH
Eprosartan
N
Chalcone analogues
N
N
NH
Cl
N
Losartan
OH
OH
R
N
HO
OH
O
H3C
N
N
O
CH3
Pyrazole analogues
Butein (Natural ACE Inhibitor)
Figure 1. Design strategy for the development of new ACE inhibitors.
colorimetric ACE inhibition assay resulted three compounds, (E)-3-
(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(5-chlorothiophen-
2-yl) prop-2-enone 4i, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imida
zol-5-yl)-1-(1H-pyrrol-2-yl)prop-2-enone 4l, (E)-3-(2-butyl-4-chloro
-1-methyl-1H-imidazol-5-yl)-1-(dibenzo[b,d]thiophen-2-yl)prop-2-
enone 4q as most active ACE inhibitors.
3h (1.5 equiv) was used. Having succeeded with the reaction, vari-
ous aryl or heteroaryl methyl ketones 3a–r (Fig. 2) were reacted
with imidazole 2 in the presence of 10% aqueous NaOH in methanol
for 3.0–5.0 h at room temperature (Scheme 2). All the reactions
were preceded efficiently and gave the desired chalcones 4a–r in
excellent yields (73–88%). The products 4a–r was fully character-
ized by 1H and 13C NMR, IR and mass (ESI and HR-MS) spectra data.
The single crystal X-ray diffraction studies of 4j unambiguously
confirmed the structure (Fig. 3).
Further to obtain compounds containing pharmacophoric pyra-
zole unit, the chalcones 4a–r was subjected to the condensation
reaction with hydrazine hydrate. After series of experiments, the
reaction of chalcones 4a–r with hydrazine hydrate is successful
in acetic acid at reflux temperature for 3.0–5.0 h (Scheme 3). All
the products 6a–r obtained in excellent yields (85–95%) were fully
characterized by 1H and 13C NMR, IR and mass (ESI and HR-MS)
spectra data. The NMR, IR and mass spectral analysis of pyrazoles
derivatives revealed that the acetic acid is also participated in
the condensation process and yielded pyrazoles 6a–r as N-acyl
derivatives. This observation is consistent with the recent litera-
ture on the synthesis of pyrazoles in acetic acid. The single crystal
X-ray diffraction studies of 6i unambiguously confirmed the struc-
ture as well as the position of N-acyl group on pyrazole ring system
(Fig. 4).
2. Results and discussion
2.1. Synthesis
2-Butyl-4-chloroimidazole-5-carboxaldehyde 1 is a key inter-
mediate in the preparation of an Angiotensin II antagonist, Losartan.
It was prepared from valeronitrile by following the procedure
developed in our laboratory.14 N-Methylation of 1 using CH3I, NaH
in DMF gave methyl derivative 2 in very good yield. The compound
2 was characterized by NMR and mass spectral analysis. With req-
uisite imidazole derivative 2 in hand, initially, the base catalyzed
Claisen–Schmidt condensation15 with 2-acetyl thiophene 3h was
investigated (Scheme 1). After series of experiments, the reaction
was found to be most efficient when equivalent amounts of imidaz-
ole 2 and 2-acetyl thiophene 3h were reacted in the presence of 10%
aqueous sodium hydroxide in methanol to give chalcone 4h in very
good yield (83%). Comparable yield (81%) of the product 4h was also
observed in methanol solvent in the presence of equivmolar
amount of sodium methoxide. But, under these conditions,
formation of compound 5 (8%) was also observed when 2 was trea-
ted with 2-acetylthiophene 3h (1.1 equiv) and sodium methoxide
(1.1 equiv). Such formation of 5 could be due to Michel addition
of the excess amount of 3h on conjugated enone 4h. In case of
10% aqueous NaOH under similar reaction conditions, the formation
compound 5 is not observed even when excess of 2-acetylthiophene
2.2. Pharmacology
The in vitro angiotensin converting enzyme (ACE) inhibitory
activity of new compounds 4a–r and 6a–r were measured using
recent colorimetric high-throughput screening method developed
by Jimsheena and Gowda.16 Most of the antihypertensive
peptides have been characterized by the rabbit lung ACE inhibitor
Cl
N
Cl
N
10% aq. NaOH/ MeOH, RT
CH3
S
+
S
N
R
N
H3C
or
CHO
R=H;
O
NaOMe/ MeOH, RT
O
3h
1
:
4h
Cl
CH3I,
NaH/DMF
N
S
2
:
R=CH3
N
H3C
O
O
5
S
Scheme 1. Synthesis of 2-butyl-4-chloro-1-methylimidazole derived chalcone 4h and its analogue 5.

4774
S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
H3CO
OCH3
OCH3
3e
OCH3
NO2
3b
3a
3c
3f
3d
3g
H
N
COCH3
S
Cl
O
S
Br
S
COCH3
COCH3
COCH3
COCH3
COCH3
N
3i
3j
3k
3h
3l
3m
COCH3
COCH3
COCH3
COCH3
Br
N
COCH3
O
S
N
CH3
3r
3o
3p
3q
3n
Figure 2. Aryl and heteroaryl methyl ketones used in this study.
Cl
N
Cl
N
N
R
CH3
10% aq. NaOH/ MeOH
RT, 3.0-5.0 h
+
N
H3C
R
O
CHO
H3C
O
3a-r
2
4a-r
Scheme 2. Synthesis of 2-butyl-4-chloro-1-methylimidazole derived chalcones 4a–r.
Figure 5. ACE inhibitory activity of chalcones 4a–r (3.0
Lisinopril (3.0 M in DMSO).
lM in DMSO). STD:
Figure 3. ORTEP representation of compound 4j with thermal displacement
ellipsoids drawn at the 30% probability.
l
Cl
N
NH2NH2. H2O
Cl
N
N
N
H3C
R
Acetic acid
Reflux, 3.0-5.0 h
R
N
N
O
H3C
O
6a-r
CH3
4a-r
Scheme 3. Synthesis of 2-butyl-4-chloro-1-methylimidazole derived pyrazoles
6a–r.
Figure 6. ACE inhibitory activity of Pyrazoles 6a–r (3.0
Lisinopril (3.0 M in DMSO).
lM in DMSO). STD:
l
assay, based on the hydrolysis of the synthetic peptide hippuryl-
histidyl-leucine (HHL). HHL is hydrolyzed by ACE to hippuric acid
(HA) and histidyl-leucine (HL). The extent HA released is directly
proportional to the ACE activity. In this screening method, the re-
leased hippuric acid from the substrate hippurryl-histyl-leucine
(HHL) was transformed in to a rapid ACE assay by mixing with
pyridine and benzene sulfonyl chloride. The resulting yellow color
with kmax at 410 nm is directly proportional to the released hip-
puric acid and then ACE activity. All the new compounds 4a–r
and 6a–r tested in the desired concentrations did not show any
significant absorbance at 410 nm under control conditions. Being
Figure 4. ORTEP representation of compound 6i with thermal displacement
ellipsoids drawn at the 30% probability.

S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
4775
the respective pyrazole analogues 6a–r (Figs. 5 and 6). Among the
imidazole derived chalcone analogues 4a–r, the heterocyclic deriv-
atives such as 4i, 4l and 4q posses better ACE inhibitory activity
compared with the substituted aryl analogues 4a–g and 4o. In aryl
substituted chalcone analogues 4a–4g, the trimethoxy derivative
4e is most ACE inhibition and chalcone 4d has least ACE inhibitory
activity. Relating to the standard drug Lisinopril, two chalcone ana-
logues 4l and 4q are more potent with 66% and 56% ACE inhibition,
respectively (Fig. 5). Three compounds 4i, 4l and 4q with greater
than 40% inhibition at 3.0 lM are evaluated for IC50 and dose–
response study (Table 1 and Fig. 9). Further to see the effective
inhibitory concentration for pyrazoles 6a–r, the experiments were
performed at increased concentrations. At 3.0 mM, almost all the
pyrazole derivatives except 6g inhibited ACE activity (Fig. 7). Out
of these pyrazole analogues, six compounds 6c–e, 6i, 6k and 6q
with greater 60% inhibition were evaluated for IC50 and incremental
dose–response study (Table 1). The inhibitory concentration at 50%
(IC50) ACE activity for tested compounds was calculated from dose–
response curves obtained by plotting the percentage inhibition
verses the concentration (see Supplementary data), are summa-
rized in Table 1. The synthetic chalcone analogues 4i, 4l and 4q
Figure 7. ACE inhibitory activity of pyrazoles 6a–r (3.0 mM in DMSO). STD:
Lisinopril (3.0 mM in DMSO).
Table 1
ACE inhibitory activity (IC50) of chalcones 4i, 4l and 4q and pyrazoles 6c–e, 6i, 6k and
6q
a
a
S. No.
Chalcone
IC50
(l
M)
S. No.
Pyrazole
IC50 (mM)
1
2
3
4
5
6
7
8
9
4i
4l
4q
3.60
2.24
2.68
10
11
12
13
14
15
16
6c
6d
6e
6i
6k
6q
13
2.33
2.22
2.12
1.80
2.35
2.01
0.2138
are excellent inhibitors with IC50 of 3.60, 2.24, and 2.68 lM, respec-
Butein 7
Apigenin 8
Luteolin 9
10
11
12
730.07a,8
280.013b,8
290.013b,8
200.013b,8
219.08
tively. On the other hand pyrazole analogues 6c–e, 6i, 6k and 6q
exhibited IC50 from 1.80 to 2.35 mM. It is clear from the data that
chalcone analogues 4i, 4l and 4q possesses nearly 100-folds greater
ACE inhibition compared to the previously described natural ACE
inhibitors, Butein 7,7a,8 Apigenin 8,13b,8 Luteolin 9,13b,8 Quercetin
glucuronide 10,13b,8 kaempferol-3-O-b-galactopyranoside 1213b,8
(Fig. 8) and a known synthetic analogue 11.8 In contrast, the inves-
tigated pyrazole derivatives 6c–e, 6i, 6k and 6q are 10-folds less
ACE inhibitory activity than a literature described synthetic ana-
logue 13.8
Angiotensin converting enzyme (ACE) is zinc containing pepti-
dyl dipeptide hydrolase.17 The active site of ACE is known to con-
sist of three parts: a carboxylate binding functionality such as
guanidinium group of Arginine, a pocket that accommodates a
hydrophobic side chain and Zinc ion. It is evident from the litera-
tures7a,8,13 that, in natural chalcone (for e.g., Butein 7) or flavani-
oids (for e.g., Apigenin 8, Luteolin 9) zinc ion coordinates to
carbonyl of the penultimate peptide bond of the substrate, where
260.013b,8
a
Values are means of three experiments, standard deviation 0.0003.
simple, sensitive and rapid nature, the colorimetric method is
used for evaluating ACE inhibitory activity of new analogues
4a–r and 6a–r. Lisinopril, a known ACE inhibitor drug has been
used as standard for comparison with the inhibitory activity of
synthesized new analogues.
The evaluation results of all 36 new compounds for ACE inhibi-
tory activity are presented in Figures 5–7. The experiments carried
out for test compounds at 3.0
lM concentration reveal that chal-
cones 4a–r possess 3–5 times better ACE inhibition compared to
OH
OH
OH
OH
HO
OH
HO
OH
OH
HO
O
O
O
O
O
HO
OH
O
sugar unit
O
OH
O
OH
OH
OH
Apigenin 8
Butein 7
Luteolin 9
Quercetin glucuronide 10
O
H3CO
H3CO
N
N
HO
OCH3
O
O
H3CO
sugar unit
OCH3
NO2
O
OCH3
NH2
H3CO
H3CO
OH
11
13
Kaempferol -3-O--galactopyranoside 12
Figure 8. Examples of natural and synthetic ACE inhibitors with chalcone and pyrazole unit.
Figure 9. Concentration dependent inhibition of ACE by the most active chalcones 4i, 4l and 4q.

4776
S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
by the carbonyl group becomes polarized and is subjected to nucle-
ophilic attack. Such chelated complex of zinc ion in the pocket of
ACE inhibits the activity. Since the synthesized new chalcones also
possesses structural similarity with natural Butein 7, it also pre-
dicted to show ACE inhibition by forming Zn-chelated complex.
The increased ACE inhibition for 2-butyl-4-chloro-1-methyl imid-
azole embedded chalcones 4i, 4l and 4q may be due to the in-
creased strength of chelated complexes with zinc ions by
heterocyclic moieties within the active site of enzyme, thus inacti-
vating the ACE activity to the greater extent. The results obtained
here will be explored further study the binding nature and to gen-
erate lead molecules for drug discovery.
4.1. 2-Butyl-4-chloro-1-methyl-1H-imidazole-5-carbaldehyde 2
2-Butyl-4-chloro-1H-imidazole-5-carbaldehyde 1 (5.0 g, 26.7
mmol) in DMF (25 mL), NaH (1.28 g, 53.46 mmol) was added at
0 °C. After 30 min, CH3I (4.71 g, 32.07 mmol) was added and stirred
for 4 h at rt. The reaction mixture was quenched with methanol
(3 mL), DMF was evaporated under vacuum, and ice cold H2O/
EtOAc 1:1 (30 mL) was added. The ethyl acetate layer was washed
with water (25 mL) and brine (25 mL), dried over anhydrous
sodium sulphate and evaporated under vacuum. Purification over
silica gel flash column chromatography gave 2-butyl-4-chloro-1-
methyl-1H-imidazole-5-carbaldehyde 2 (4.79 g, 89.6%) as pale yel-
low syrup. 1H NMR (300 MHz, CDCl3) d 9.72 (s, 1H), 3.85 (s, 3H),
2.65 (t, J = 7.5 Hz, 2H), 1.68–1.78 (m, 2H) 1.36–1.46 (m, 2H), 0.97
(t, J = 7.5 Hz, 3H). IR (neat) 2958, 2866, 1668, 1511, 1471, 1367,
1280, 866, 706 cmÀ1 MS (ESI) m/z 201 [M+H]+.
3. Conclusion
In conclusion, we have described an efficient synthesis and
evaluation of ACE inhibitory activity of novel 2-butyl-4-chloro-1-
methylimidazole derived chalcones and pyrazoles. The chalcones
4a–r was prepared in excellent yields through Claisen–Schmidt
condensation of 2-butyl-4-chloro-1-methyl imidazole-5-carboxal-
dehyde 2 with aryl/heteroaryl methyl ketones 3a–r in the presence
of 10% aqueous NaOH in methanol. These chalcones 4a–r were fur-
ther derivatized with hydrazine hydrate in acetic acid to give pyr-
azole analogues 6a–r. All the products and their structural
characterization was carried out using NMR, IR and mass spectral
data and single crystal X-ray structural analysis. Screening all the
new compounds using colorimetric ACE inhibition assay resulted
chalcones as more potent ACE inhibitors than the respective pyra-
zole analogues by thousand folds. Among the series of chalcones
4a–r, three compounds, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imi-
dazol-5-yl)-1-(5-chlorothio- phen-2-yl)prop-2-enone 4i, (E)-3-(2-
butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(1H-pyrrol-2-yl)pro p
-2-enone 4l, (E)-3-(2-butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(dibenzo[b,d]thiophen-2-yl)prop-2-enone 4q were resulted as most
4.2. General procedure
4.2.1. Synthesis of (E)-3-(2-butyl-4-chloro-1-methyl-1H-imida-
zol-5-yl)-1-(thiophen-2-yl)prop-2-enone 4h
Toasolutionofacetylthiophene(0.2 g,1.5 mmol)inMeOH(2 mL)
was added 10% aqueous NaOH (1.0 mL) at 0 °C with stirring. After
0.5 h, the solution of 2-butyl-4-chloro-1-methyl-1H-imidazole-5-
carbaldehyde(0.3 g,1.5 mmol)inMeOHwasadded.Aftercompletion
(3.5 h, monitored by TLC), reaction mixture was extracted with ethyl
acetate (15 mL), washed with water, (2 Â 10 mL), brine solution
(10 mL),driedoveranhydrousNa2SO4andconcentratedunderreduced
pressure. Flashcolumnchromatography(hexane–ethylacetate;8:2)
ofthecruderesiduegave(E)-3-(2-butyl-4-chloro-1-methyl-1H-imi-
dazol-5-yl)-1-(thio phen-2-yl)prop-2-enone as yellow solid (0.39 g,
83%).
4.2.2. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
phenylprop-2-enone 4a
Yield: 78%; mp 60 °C; 1H NMR (300 MHz, CDCl3) d 7.99 (d,
J = 6.7 Hz, 2H), 7.80 (d, J = 15.8 Hz, 1H), 7.60 (d, J = 15.8 Hz, 1H),
7.39–7.55 (m, 3H), 3.64 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.67–1.77
(m, 2H), 1.36–1.42 (m, 2H), 0.97 (t, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 188.8, 150.1, 138.2, 133.1, 132.7, 128.6, 128.4,
128.0, 127.4, 123.2, 119.5, 30.8, 29.6, 27.0, 22.4, 13.8. IR (KBr);
2956, 2866, 1658, 1591, 1456, 1365, 1270, 1215, 1177, 1017, 974,
779, 705, 642 cmÀ1. MS (ESI) m/z 303 [M+H]+; HR-MS (ESI) calcd
for C17H20N2OCl [M+H]+: 303.1264. Found: 303.1272.
active ACE inhibitors with IC50 of 3.60 lM, 2.24 lM, and 2.68 lM,
respectively. Compared with ACE inhibitory activity (IC50) of various
chalcones and flavanioids of synthetic and natural origin, imidazole
derived chalcones 4i, 4l and 4q are ꢀ100-fold more active. The
results reveal that binding of heteroaryl chalcones at ACE binding
pocket is more pronounced through zinc ion chelation than the
chalcones of natural origin. The information generated here could
be of use to generate lead molecules for drug discovery.
4. Experimental section
4.2.3. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-p-
tolylprop-2-enone 4b
Melting points were measured with a Fischer–Johns melting
point apparatus and are uncorrected. IR spectra were recorded as
Yield: 75%; mp 96 °C; 1H NMR (300 MHz, CDCl3) d 7.90 (d,
J = 8.3 Hz, 2H), 7.80 (d, J = 15.4 Hz, 1H), 7.58 (d, J = 15.4 Hz, 1H),
7.26 (d, J = 7.9 Hz, 2H), 3.64 (s, 3H), 2.66 (t, J = 7.5 Hz, 2H), 2.43
(s, 3H), 1.67–1.77 (m, 2H), 1.36–1.48 (m, 2H), 0.97 (t, J = 7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 188.6, 150.0, 143.3, 135.5, 132.1,
129.2, 128.4, 127.1, 123.1, 119.6, 30.8, 29.5, 26.9, 22.4, 21.6, 13.7.
IR (KBr) 2925, 2857, 1657, 1592, 1458, 1408, 1262, 1180, 1031,
980, 821, 733, 586 cmÀ1. MS (ESI) m/z 317 [M+H]+; HR-MS (ESI)
calcd for C18H22N OCl [M+H]+: 317.1420. Found: 317.1423.
neat liquids or KBr pellets and absorptions are reported in cmÀ1
.
NMR spectra were recorded on 300 (Bruker) and 500 MHz (Varian)
spectrometers in appropriate solvents using TMS as internal stan-
dard or the solvent signals as secondary standards and the chemi-
cal shifts are shown in d scales. Coupling constants J are expressed
in Hertz. 13C NMR spectra were recorded on 75 and 125 MHz spec-
trometers. High-resolution mass spectra were obtained by using
ESI-QTOF mass spectrometry. Reagents and all solvents were ana-
lytically pure and were used without further purification. All the
experiments were monitored by analytical thin layer chromatogra-
phy (TLC) performed on silica gel GF254 pre-coated plates. After
elution, plate was visualized under UV illumination at 254 nm
for UV active materials. Further visualization was achieved by
staining with PMA and charring on a hot plate. Silica gel finer than
200 mesh was used for column chromatography. Appropriate
names for all the new compounds were given with the help of
ChemBioOffice 2010.
4.2.4. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(4-
methoxyphenyl)prop-2-enone 4c
Yield: 73%; mp 102 °C; 1H NMR (300 MHz, CDCl3) d 7.89 (d,
J = 8.4 Hz, 2H), 7.80 (d, J = 15.4 Hz, 1H), 7.57 (d, J = 15.4 Hz, 1H),
6.94 (d, J = 8.6 Hz, 2H), 3.88 (s, 3H), 3.64 (s, 3H), 2.66 (t,
J = 7.5 Hz, 2H), 1.66–1.77 (m, 2H), 1.38–1.44 (m, 2H), 0.96 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 187.3, 163.3, 149.8,
131.9, 131.0, 130.6, 126.7, 123.2, 119.7, 113.8, 55.2, 30.8, 29.7,

S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
4777
27.0, 22.4, 13.8. IR (KBr) 2924, 2854, 1654, 1578, 1456, 1372,
4.2.10. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(5-chlorothiophen-2-yl)prop-2-enone 4i
1255, 1170, 1106, 1018, 828, 736 cmÀ1
. MS (ESI) m/z 333
[M+H]+; HR-MS (ESI) calcd for C18H22N2O2Cl [M+H]+: 333.1369.
Found: 333.1382.
Yield: 80%; mp 96 °C; 1H NMR (300 MHz, CDCl3) d 7.55–7.59 (m,
3H), 6.98 (dd, J = 2.0 Hz, J = 2.0 Hz, 1H), 3.64 (s, 3H), 2.67 (t,
J = 7.7 Hz, 2H), 1.67–1.77 (m, 2H), 1.36–1.46 (m, 2H), 0.97 (t,
J = 7.1 Hz, 3H), 13C NMR (75 MHz, CDCl3) d 180.4, 150.4, 132.8,
130.8, 127.6, 127.1, 122.9, 118.3, 30.9, 29.6, 27.1, 22.5, 13.9. IR
(KBr) 2925, 2855, 1646, 1597, 1459, 1418, 1273, 1218, 1016, 966,
801, 724 cmÀ1. MS (ESI) m/z 343 [M+H]+.
4.2.5. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-(4-
nitrophenyl)prop-2-enone 4d
Yield: 85%; mp 134 °C; 1H NMR (300 MHz, CDCl3) d 8.35 (d,
J = 8.3 Hz, 2H), 8.14 (d, J = 8.3 Hz, 2H), 7.77 (d, J = 15.1 Hz, 1H),
7.65 (d, J = 15.1 Hz, 1H), 3.67 (s, 3H), 2.70 (t, J = 7.5 Hz, 2H),
1.67–1.79 (m, 2H), 1.37–1.47 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 187.5, 151.1, 142.9, 129.2, 129.1, 123.9,
123.1, 118.2, 30.9, 29.7, 29.6, 27.1, 13.8. IR (KBr) 2954, 2862,
1654, 1580, 1518, 1460, 1340, 1269, 1212, 1029, 965, 842, 760,
708 cmÀ1. MS (ESI) m/z 348 [M+H]+; HR-MS (ESI) calcd for
4.2.11. (E)-1-(5-Bromothiophen-2-yl)-3-(2-butyl-4-chloro-1-
methyl-1H-imidazol-5-yl)prop-2-enone 4j
Yield: 88%; mp 118 °C; 1H NMR (300 MHz, CDCl3) d 7.52–7.55
(m, 3H), 7.12 (d, J = 3.9 Hz, 1H), 3.63 (s, 3H), 2.67 (t, J = 7.5 Hz,
2H), 1.67–1.77 (m, 2H), 1.37–1.46 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H).
13C NMR (75 MHz, CDCl3) d 180.2, 150.5, 147.2, 132.8, 131.4,
127.2, 122.9, 122.7, 118.5, 30.9, 29.6, 27.1, 22.5, 13.8. IR (KBr)
2954, 1635, 1580, 1457, 1408, 1270, 1216, 1069, 989, 959, 805,
725, 618 cmÀ1. MS (ESI) m/z 387 [M+H]+; HR-MS (ESI) calcd for
C
17H19N3ClO3Cl [M+H]+: 348.1127. Found: 348.1133.
4.2.6. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(3,4,5-trimethoxyphenyl)prop-2-enone 4e
Yield: 77%; mp110 °C; 1H NMR (300 MHz, CDCl3) d 7.77 (d,
J = 15.4 Hz, 1H), 7.55 (d, J = 15.4 Hz, 1H), 7.23 (s, 2H), 3.94 (s, 6H),
3.87 (s, 3H), 3.65 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.67–1.78 (m,
2H), 1.37–1.46 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 187.5, 153.1, 149.8, 142.6, 133.2, 132.0, 127.0, 123.1,
119.5, 105.9, 60.6, 56.0, 30.7, 29.5, 26.9, 22.4, 13.8. IR (KBr) 2935,
C
15H17N2OSBr Cl [M+H]+: 386.9933. Found: 386.9919.
4.2.12. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(furan-2-yl)prop-2-enone 4k
Yield: 86%; mp 125 °C; 1H NMR (300 MHz, CDCl3) d 7.62 (m,
3H), 7.26 (d, J = 3.0 Hz, 1H), 6.57 (d, J = 2.2 Hz, 1H) 3.66 (s, 3H),
2.68 (t, J = 7.5 Hz, 2H), 1.67–1.77 (m, 2H), 1.36–1.48 (m, 2H),
1652, 1575, 1457, 1410, 1333, 1260, 1124, 999, 829, 710 cmÀ1
.
MS (ESI) m/z 393 [M+H]+; HR-MS (ESI) calcd for C20H26N2ClO4
0.97 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 179.8,
[M+H]+: 393.1581. Found: 393.1582.
153.8, 150.3, 146.3, 132.8, 126.7, 123.1, 119.1, 117.2112.5, 31.0,
29.6, 27.0, 22.4, 13.8. IR (KBr) 2950, 2863, 1653, 1560, 1461,
1263, 1041, 967, 769, 726 cmÀ1. MS (ESI) m/z 293 [M+H]+; HR-
MS (ESI) calcd for C15H18N2O2 Cl [M+H]+: 293.1056. Found:
293.1066.
4.2.7. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(naphthalen-2-yl)prop-2-enone 4f
Yield: 84%; mp106 °C; 1H NMR (300 MHz, CDCl3) d 8.39 (d,
J = 8.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.75–7.93 (m, 4H), 7.45–
7.56 (m, 3H), 3.50 (s, 3H), 2.55 (t, J = 6.9 Hz, 2H), 1.60–170 (m,
2H), 1.33–1.43 (m, 2H), 0.93 (t, J = 7.1 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 189.0, 150.2, 135.5, 132.6, 129.8, 129.6, 128.5, 128.3,
127.7, 127.4, 126.6, 124.3, 123.6, 123.2, 119.7, 30.9, 29.7, 27.0,
22.4, 13.8. IR (KBr) 2958, 2853, 1657, 1564, 1436, 1360, 1276,
1176, 1048, 975, 807, 723 cmÀ1. MS (ESI) m/z 353 [M+H]+;
HR-MS (ESI) calcd for C21H22N2ClO [M+H]+: 353.1420. Found:
353.1428.
4.2.13. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(1H-pyrrol-2-yl)prop-2-enone 4l
Yield: 82%; mp 136 °C; 1H NMR (300 MHz, CDCl3) d 10.08 (br s,
1H), 7.56 (s, 2H), 7.05 (d, J = 16.7 Hz, 2H), 6.26–6.31 (m, 1H), 3.64
(s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.67–1.77 (m, 2H), 1.35–1.48 (m,
2H), 0.96 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d
178.4149.7, 133.3, 122.0, 125.2, 123.2, 120.6, 116.4, 111.1, 30.9,
29.7, 27.1, 22.5, 13.9. IR (KBr) 2924, 2861, 1613, 1455, 1274,
1214, 964, 735 cmÀ1. MS (ESI) m/z 292 [M+H]+; HR-MS (ESI) calcd
for C15H19N3OCl [M+H]+: 292.1216. Found: 292.1221.
4.2.8. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(naphthalen-1-yl)prop-2-enone 4g
Yield: 82%; mp 68 °C; 1H NMR (300 MHz, CDCl3) d 8.45 (d,
J = 8.3 Hz, 1H), 7.96 (d, J = 8.3 Hz,1H), 7.81–7.87 (m, 2H),
7.49–7.58 (m, 5H), 3.63 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.67–
1.77 (m, 2H), 1.36–1.48 (m, 2H), 0.97 (t, J = 7.3 Hz 3H).13C NMR
4.2.14. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(pyridin-3-yl)prop-2-enone 4m
Yield: 74%; mp 98 °C; 1H NMR (300 MHz, CDCl3) d 9.21 (s, 1H),
8.78 (s, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.75 (d, J = 15.8 Hz 1H), 7.65 (d,
J = 15.8 Hz, 1H), 7.45 (dd, J = 4.5 Hz, J = 3.0 Hz, 1H), 3.67 (s, 3H),
2.69 (t, J = 6.7 Hz, 2H), 1.67–1.78 (m, 2H), 1.36–1.49 (m, 2H), 0.97
(t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 187.6, 152.9, 150.8,
149.5, 135.6, 133.3, 128.4, 123.5, 122.9, 118.2, 30.6, 29.5, 27.0,
22.3, 13.7. IR (KBr) 2925, 1638, 1580, 1401, 1256, 1105, 1047,
967, 731 cmÀ1. MS (ESI) m/z 304 [M+H]+; HR-MS (ESI) calcd for
(75 MHz, CDCl3)
d 193.9, 150.7, 137.1, 133.8, 131.9, 130.4,
128.4, 128.0, 127.4, 127.3, 126.4, 125.7, 124.5, 123.9, 122.9,
31.1, 29.5, 27.0, 22.3, 13.7. IR (KBr) 2957, 2865, 1657, 1584,
1461, 1272, 1100, 969, 804, 779, 725 cmÀ1. MS (ESI) m/z 353
[M+H]+; HR-MS (ESI) calcd for C21H22N2ClO [M+H]+: 353.1420.
Found: 353.1410.
C
16H19N3ClO [M+H]+: 304.1216. Found: 304.1219.
4.2.9. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(thiophen-2-yl)prop-2-enone 4h
4.2.15. (E)-1-(6-Bromopyridin-2-yl)-3-(2-butyl-4-chloro-1-
methyl-1H-imidazol-5-yl)prop-2-enone 4n
Yield: 83%; mp 99 °C; 1H NMR (300 MHz, CDCl3) d 7.80 (d,
J = 3.7 Hz, 1H), 7.63–7.70 (m, 2H), 7.57 (d, J = 15.1 Hz, 1H), 7.15
(t, J = 3.7 Hz, 1H), 3.65 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.68–1.78
(m, 2H), 1.36–1.46 (m, 2H), 0.97 (t, J = 7.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 180.5, 150.2, 145.7, 133.6, 131.5, 128.1, 126.7,
122.9, 119.6, 30.8, 29.5, 27.0, 22.4, 13.8. IR (KBr) 2929, 2865,
1643, 1586, 1411, 1262, 1225, 1063, 967, 840, 727 cmÀ1. MS
(ESI) m/z 309 [M+H]+.
Yield: 77%; mp 120 °C; 1H NMR (300 MHz, CDCl3) d 8.20 (d,
J = 16.2 Hz, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.69–7.75 (m, 2H), 7.64
(d, J = 6.7 Hz, 1H), 3.73 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H), 1.68–1.78
(m, 2H), 1.36–1.49 (m, 2H), 0.97 (t, J = 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 186.9, 154.9, 150.9, 141.3, 139.0, 134.7, 131.2,
128.4, 123.6, 121.5, 117.6, 31.5, 29.6, 27.0, 22.4, 13.8. IR (KBr)
2925, 2856, 1656, 1584, 1456, 1427, 1256, 1148, 1031, 974, 810,

4778
S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
783, 701, 609 cmÀ1. MS (ESI) m/z 382 [M+H]+; HR-MS (ESI) calcd
4.3. General procedure
for C16H18N3OClBr [M+H]+: 382.0321. Found: 382.0341.
4.3.1. Synthesis of (E)-3-(2-butyl-4-chloro-1-methyl-1H-imida-
zol-5-yl)-1-(thiophen-2-yl)prop-2-enone 6h
4.2.16. (E)-1-(Anthracen-2-yl)-3-(2-butyl-4-chloro-1-methyl-
1H-imidazol-5-yl)prop-2-enone 4o
To a solution of chalcone 4h (0.5 g, 1.62 mmol) in acetic acid
(15 ml) was added drop wise hydrazine hydrate (0.4 ml, 8.12
mmol) and heated at 120 °C for 3.0 h. After completion (TLC) the
reaction mixture was poured in ice water, extracted with ethyl ace-
tate (3 Â 10 ml), dried over sodium sulfate and evaporated under
reduced pressure. The crude residue was chromatographed over
silica gel column to give product 6h as a crystalline solid.
Yield: 80%; mp 138 °C; 1H NMR (300 MHz, CDCl3) d 8.68 (s, 1H),
8.60 (s, 1H), 8.41 (s, 1H), 7.97–8.08 (m, 5H), 7.67 (d, J = 15.8 Hz,
1H), 7.46–7.54 (m, 2H), 3.68 (s, 3H), 2.69 (t, J = 7.5 Hz, 2H),
1.67–1.80 (m, 2H), 1.37–1.51 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 188.6, 150.1, 134.8, 133.1, 132.5, 132.0,
131.1, 130.3, 129.5, 129.1, 128.8, 128.4, 128.1, 127.1, 126.5,
126.1, 125.8, 123.2, 119.4 30.8, 29.5, 26.9, 22.4, 13.8. IR (KBr)
2924, 2853, 1657, 1586, 1460, 1265, 1175, 1096, 877, 735 cmÀ1
MS (EI) m/z 367 [MÀCl].
.
4.3.2. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
phenyl-4,5-dihydro-1H-pyrazolyl)ethanone 6a
Yield: 86%; mp 102 °C; 1H NMR (300 MHz, CDCl3) d 7.13 (t,
J = 3.7 Hz, 2H), 7.35–7.40 (m, 3H), 5.40 (dd, J = 5.2 Hz, J = 6.7 Hz,
1H), 3.66 (s, 3H), 3.41–3.62 (m, 2H), 2.59 (t, J = 6.7 Hz, 2H), 2.32
(s, 3H), 1.62–1.72 (m, 2H), 1.33–1.43 (m, 2H), 0.94 (t, J = 7.5 Hz,
3H). 13C NMR (75 MHz, CDCl3) d 168.4, 153.2, 146.3, 130.9, 130.0,
128.4, 126.3, 125.2, 124.5, 49.6, 38.5, 30.5, 29.4, 26.6, 22.2, 21.4,
13.6. IR (KBr); 2925, 2862, 1657, 1590, 1416, 1357, 1326, 1252,
1138, 1029, 948, 854, 762, 690 cmÀ1. MS (ESI) m/z 359 [M+H]+;
HR-MS (ESI) calcd for C19H24N4OCl [M+H]+: 359.1638. Found:
359.1649.
4.2.17. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(dibenzo[b,d]furan-2-yl)prop-2-enone 4p
Yield: 84%; mp 122 °C; 1H NMR (300 MHz, CDCl3) d 8.62 (s, 1H),
8.17 (t, J = 6.7 Hz, 1H), 8.03 (d, J = 8.3 Hz, 1H), 7.95 (d,
J = 15.1 Hz,1H), 7.56–7.68 (m, 3H), 7.47 (t, J = 6.7 Hz, 1H), 7.36 (t,
J = 7.5 Hz, 1H), 3.67 (s, 3H), 2.68 (t, J = 7.5 Hz, 2H), 1.69–1.79 (m,
2H), 1.37–1.49 (m, 2H), 0.98 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) d 188.3, 158.9, 156.9, 150.2, 133.4, 128.0, 127.9, 127.4,
123.3, 121.7, 121.0, 119.7, 111.9, 30.9, 29.6, 27.1, 22.5, 13.8. IR
(KBr) 2951, 1655, 1597, 1267, 1194, 1016, 812, 748 cmÀ1. MS (EI)
m/z 357 [MÀCl].
4.3.3. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-p-
tolyl-4,5-dihydro-1H-pyrazolyl)ethanone 6b
4.2.18. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(dibenzo[b,d]thiophen-2-yl)prop-2-enone 4q
Yield: 89%; mp 116 °C; 1H NMR (300 MHz, CDCl3) d 7.61 (d,
J = 8.3 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.38 (dd, J = 5.8 Hz,
J = 6.6 Hz, 1H), 3.69 (s, 3H), 3.59 (dd, J = 12.4 Hz, J = 5.0 Hz,1H),
3.46 (dd, J = 6.0 Hz, J = 11.5 Hz, 1H), 2.60 (t, J = 6.6 Hz, 2H), 2.40
(s, 3H), 2.32 (s, 3H), 1.64–1.74 (m, 2H), 1.36–1.46 (m, 2H), 0.94
(t, J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.9, 153.7, 146.7,
140.6, 129.4, 128.3, 126.5, 125.4, 49.7, 38.8, 30.8, 29.6, 26.9, 22.4,
21.7, 21.5, 13.8. IR (KBr) 2925, 2855, 1660, 1436, 1323, 1250,
1140, 1033, 858, 819, 754, 619 cmÀ1. MS (ESI) m/z 373 [M+H]+;
HR-MS (ESI) calcd for C20H26N4OCl [M+H]+: 373.1795. Found:
373.1799.
Yield: 87%; mp 120 °C; 1H NMR (300 MHz, CDCl3) d 8.76 (s, 1H),
8.24 (t, J = 3.9 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.90–7.96 (m, 2H),
7.83 (t, J = 5.8 Hz, 1H), 7.65 (d, J = 15.4 Hz, 1H), 7.46–7.49 (m,
2H), 3.65 (s, 3H), 2.67 (t, J = 7.5 Hz, 2H), 1.68–1.78 (m, 2H), 1.39–
1.49 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d
188.1, 150.0, 144.4, 139.7, 135.3, 134.7, 127.4, 127.3, 126.4,
124.9, 122.9, 122.7, 122.0, 121.9, 119.6, 30.9, 29.6, 27.1, 22.5,
13.9. IR (KBr) 2928, 2859, 1655, 1594, 1458, 1416, 1265, 1191,
1072, 966, 824, 731, 616 cmÀ1. MS (ESI) m/z 409 [M+H]+; HR-MS
(ESI) calcd for C23H22N2OSCl [M+H]+: 409.1141. Found: 409.1127.
4.3.4. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazolyl)ethanone 6c
Yield: 92%; mp 140 °C; 1H NMR (300 MHz, CDCl3) d 7.65 (d,
J = 8.3 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 5.38 (dd, J = 6.0 Hz,
J = 6.7 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 3H), 3.58 (dd, J = 12.8 Hz,
J = 4.5 Hz, 1H), 3.45 (dd, J = 6.0 Hz, J = 11.3 Hz, 1H), 2.60 (t,
J = 6.7 Hz, 2H), 2.32 (s, 3H), 1.64–1.74 (m, 2H),1.36–1.46 (m, 2H),
0.95 (t, J = 7.5 Hz, 3H), 13C NMR (75 MHz, CDCl3) d 168.8, 161.3,
153.4, 146.7, 128.1, 124.8, 123.7, 114.2, 55.3, 49.7, 38.9, 30.8,
29.7, 26.9, 22.5, 21.7, 13.9. IR (KBr) 2924, 2852, 1664, 1607,
1460, 1405, 1326, 1258, 1173, 1024, 831, 755, 616, 544 cmÀ1. MS
(ESI) m/z 389 [M+H]+; HR-MS (ESI) calcd for C20H26N4O2Cl
[M+H]+: 389.1744. Found: 389.1761.
4.2.19. (E)-3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1-
(9-methyl-9H-carbazol-3-yl)prop-2-enone 4r
Yield: 81%; mp 163 °C; 1H NMR (300 MHz, CDCl3) d 8.82 (d,
J = 1.5 Hz, 1H), 8.17–8.24 (m, 2H), 8.05 (d, J = 15.8 Hz, 1H), 7.70
(d, J = 15.8 Hz, 1H), 7.50–7.55 (m, 1H), 7.40–7.46 (m, 2H), 7.29–
7.34 (m, 1H), 3.90 (s, 3H), 3.67 (s, 3H), 2.71 (t, J = 7.5 Hz, 2H),
1.69–1.80 (m, 2H), 1.37–1.51 (m, 2H), 0.97 (t, J = 6.7 Hz, 3H), 13C
NMR (75 MHz, CDCl3) d 189.9, 150.0, 143.7, 129.5, 126.7, 126.6,
126.2, 123.0, 122.2, 121.8, 120.6, 120.5, 120.1, 119.9, 30.9, 29.6,
29.3, 27.0, 22.4, 13.7. IR (KBr) 2931, 2863, 1624, 1543, 1463,
1245, 1189, 1016, 735, 607 cmÀ1. MS (ESI) m/z 406 [M+H]+: HR-
MS (ESI) calcd for
406.1668.
C
24H25N3OCl [M+H]+: 406.1686. Found:
4.3.5. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-(4-
nitrophenyl)-4,5-dihydro-1H-pyrazolyl)ethanone 6d
4.2.20. 3-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-1,5-di
(thiophen-2-yl)pentane-1,5-dione 5
Yield: 95%; mp 125 °C; 1H NMR (300 MHz, CDCl3) d 8.26 (d,
J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz, 2H), 5.46 (dd, J = 6.0 Hz,
J = 6.7 Hz, 1H) 3.71 (s, 3H), 3.48–3.67 (m, 2H), 2.62 (t, J = 6.7 Hz,
2H), 2.35 (s, 3H), 1.63–1.73 (m, 2H), 1.33–1.43 (m, 2H), 0.94 (t,
J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 169.1, 151.2, 148.5,
147.1, 137.0, 127.1, 125.6, 124.5, 124.0, 114.2, 50.3, 38.4, 30.8,
29.6, 26.8, 22.4, 21.6, 13.8. IR (KBr) 2924, 2853, 1670, 1575,
Yield 8%: syrup, 1H NMR (300 MHz, CDCl3) d 7.68 (d, J = 3.5 Hz,
2H), 7.59 (d, J = 4.9 Hz, 2H), 7.08 (t, J = 3.9 Hz, 2H), 4.00–4.10 (m,
1H), 3.80 (dd, J = 6.7 Hz, J = 10.0 Hz, 2H), 3.69 (s, 3H), 3.14 (dd,
J = 4.7 Hz, J = 12.0 Hz, 2H), 2.53 (t, J = 7.7 Hz, 2H), 1.53–1.63 (m,
2H), 1.23–1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 191, 146.3, 143.7, 134.0, 132.2, 128.2, 126.4,
124.9, 42.0, 30.7, 29.6, 26.9, 26.1, 22.3, 13.7. IR (neat) 3095,
2925, 2856, 1660, 1413, 1359, 1266, 855, 725 cmÀ1. MS (ESI) m/
z 435 [M+H]+.
1518, 1441, 1402, 1344, 1320, 1249, 1140, 848, 751, 690 cmÀ1
.
MS (ESI) m/z 404 [M+H]+; HR-MS (ESI) calcd for C19H23N5O3Cl
[M+H]+: 404.1489. Found: 404.1494.

S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
4779
4.3.6. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-(3,
4.3.11. 1-(3-(5-Bromothiophen-2-yl)-5-(2-butyl-4-chloro-1-
4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazolyl)ethanone 6e
Yield: 94%;mp 120 °C; 1H NMR (300 MHz, CDCl3) d 6.91 (s, 2H),
5.41 (dd, J = 6.0 Hz, J = 6.7 Hz,1H), 3.89 (s, 6H), 3.86 (s, 3H),
3.35–3.68 (m, 5H), 2.61 (t, J = 6.7 Hz, 2H), 2.33 (s, 3H), 1.62–
1.72 (m, 2H), 1.35–1.45 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 168.3, 153.2, 146.4, 140.2, 126.2, 125.0,
124.6, 103.8, 60.4, 55.9, 49.7, 38.7, 30.5, 29.5, 26.5, 22.2, 21.4,
17.5, 13.7. IR (KBr) 2933, 2871, 1657, 1572, 1463, 1415, 1364,
methyl-1H-imidazol-5-yl)-4,5-dihydro-1H-pyrazolyl)ethanone
6j
Yield: 85%; mp 142 °C; 1H NMR (500 MHz, CDCl3) d 7.00 (d,
J = 3.6 Hz, 1H), 6.95 (d, J = 3.9 Hz, 1H), 5.38 (dd, J = 5.6 Hz,
J = 7.1 Hz, 1H), 3.67 (s, 3H), 3.56 (dd, J = 12.7 Hz, J = 4.6 Hz, 1H),
3.42 (dd, J = 5.6 Hz, J = 11.7 Hz, 1H), 2.59 (td, J = 2.6 Hz, J = 4.9 Hz,
2H), 2.27 (s, 3H), 1.65–1.71 (m, 2H), 1.36–1.43 (m, 2H), 0.94 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.6148.1, 146.7,
136.2, 130.3, 128.3, 125.7, 124.3, 116.4, 50.6, 38.8, 30.7, 29.6,
26.9, 22.5, 21.6, 13.3. IR (KBr) 2927, 2858, 1658, 1549, 1453,
1408, 1318, 1249, 1128, 1022, 949, 843, 792, 744 cmÀ1. MS (ESI)
m/z 443 [M+H]+; HR-MS (ESI) calcd for C17H21N4OSClBr [M+H]+:
443.0307. Found: 443.0325.
1248, 1209, 1127, 1000, 851, 765 cmÀ1
. MS (ESI) m/z 449
[M+H]+; HR-MS (ESI) calcd for C22H30N4O4Cl [M+H]+: 449.1955.
Found: 449.1970.
4.3.7. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(naphthalen-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6f
Yield: 91%; mp142 °C; 1H NMR (300 MHz, CDCl3) d 8.02 (d,
J = 8.3 Hz, 1H), 7.89 (s, 1H), 7.81 (d, J = 6.0 Hz, 3H), 7.48 (t,
J = 4.5 Hz, 2H), 5.38 (dd, J = 6.0 Hz, J = 6.0 Hz, 1H), 3.51–3.67 (m,
5H), 2.59 (t, J = 8.3 Hz, 2H), 2.36 (s, 3H), 1.62–172 (m, 2H),
1.34–1.44 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 168.7, 153.5, 146.7, 134.1, 132.9, 128.6, 128.4, 127.8, 127.1,
126.8, 126.6, 125.4, 124.7, 123.2, 49.9, 38.6, 30.7, 29.6, 26.7, 22.4,
21.6, 13.8. IR (KBr); 2926, 2853, 1652, 1466, 1392, 1306, 1251,
1120, 981, 945, 808, 781 cmÀ1. MS (ESI) m/z 409 [M+H]+; HR-MS
(ESI) calcd for C23H26N4OCl [M+H]+: 409.1795. Found: 409.1806.
4.3.12. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(furan-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6k
Yield: 88%; mp 138 °C; 1H NMR (300 MHz, CDCl3) d 7.53 (d,
J = 1.5 Hz, 1H), 6.78 (d, J = 3.3 Hz, 1H), 6.51 (dd, J = 1.7 Hz,
J = 1.7 Hz, 1H), 5.36 (dd, J = 6.0 Hz, J = 6.4 Hz, 1H), 3.40–3.69 (m,
5H), 2.60 (t, J = 6.7 Hz, 2H), 2.31 (s, 3H), 1.64–1.74 (m, 2H),
1.34–1.46 (m, 2H), 0.95 (t, J = 7.3 Hz, 3H), 13C NMR (75 MHz, CDCl3)
d 168.6, 146.9, 146.5, 145.0, 144.3, 125.6, 124.5, 111.9, 111.6, 49.4,
38.5, 30.7, 29.7, 26.9, 22.5, 21.7, 13.9. IR (KBr) 2927, 2853, 1660,
1550, 1434, 1383, 1319, 1253, 1165, 1131, 1006, 947, 852, 763,
588 cmÀ1. MS (ESI) m/z 349 [M+H]+; HR-MS (ESI) calcd for
4.3.8. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(naphthalen-1-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6g
Yield: 93%; mp 148 °C; 1H NMR (300 MHz, CDCl3) d 9.16 (d,
J = 8.4 Hz, 1H), 7.87 (t, J = 7.3 Hz, 2H), 7.40–7.60 (m, 4H), 5.39
(dd, J = 5.6 Hz, J = 6.9 Hz, 1H), 3.63–3.89 (m, 5H), 2.61 (t,
J = 6.7 Hz, 2H), 2.42 (s, 3H), 1.65–1.75 (m, 2H), 1.33–1.44 (m,
2H), 0.95 (t, J = 7.3 Hz, 3H), 13C NMR (75 MHz, CDCl3) d 168.7,
153.7, 146.6, 134.2, 131.5, 130.8, 128.7, 127.7, 127.6, 126.8,
126.3, 125.5, 124.9, 124.7, 123.4, 48.8, 41.4, 30.8, 29.7, 26.9, 22.5,
21.9, 14.0. IR (KBr):2924, 2857, 16521461, 1420, 1387, 1304,
1249, 1140, 1028, 952, 807, 779. MS (ESI) m/z: 409 [M+H]+; HR-
C
17H22N4O2Cl [M+H]+: 349.1431. Found: 349.1439.
4.3.13. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(1H-pyrrol-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6l
Yield: 94%; mp 157 °C; 1H NMR (300 MHz, CDCl3) d 9.06 (s, 1H),
6.91 (s, 1H), 6.41 (s, 1H), 6.22 (s,1H), 5.35 (dd, J = 6.0 Hz,
J = 6.6 Hz,1H), 3.38–3.68 (m, 5H), 2.60 (t, J = 6.9 Hz, 2H), 2.26 (s,
3H), 1.63–1.73 (m, 2H), 1.33–1.43 (m, 2H), 0.94 (t, J = 7.1 Hz, 3H),
13C NMR (75 MHz, CDCl3) d 169.5, 150.7, 147.1, 133.1, 129.0,
125.3, 21.6, 112.5, 110.3, 49.4, 38.6, 30.8, 29.8, 26.9, 22.5, 21.7,
13.9. IR (KBr) 2925, 2856, 1641, 1464, 1406, 1255, 1115, 1028,
959, 737, 607 cmÀ1. MS (ESI) m/z 348 [M+H]+; HR-MS (ESI) calcd
for C17H23N5OCl [M+H]+: 348.1591. Found: 348.1574.
MS (ESI) calcd for
409.1805.
C
23H26N4OCl [M+H]+: 409.1795. Found:
4.3.9. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(thiophen-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6h
Yield: 94%; mp 90 °C; 1H NMR (300 MHz, CDCl3) d 7.42 (dd,
J = 1.1 Hz, J = 3.9 Hz, 1H), 7.24 (dd, J = 1.1 Hz, J = 2.6 Hz, 1H), 7.07
(dd, J = 3.7 Hz, J = 1.3 Hz, 1H), 5.43 (dd, J = 5.8 Hz J = 11.7 Hz, 1H),
3.60–3.70 (m, 4H), 3.47 (dd, J = 5.8 Hz, J = 11.7 Hz, 1H), 2.61 (t,
J = 7.7 Hz, 2H), 2.32 (s, 3H), 1.63–1.73 (m, 2H), 1.35–1.45 (m, 2H),
0.93 (t, J = 7.3 Hz, 3H), 13C NMR (75 MHz, CDCl3) d 168.9, 149.3,
146.9, 134.4, 128.6, 128.4, 127.5, 125.4, 124.5, 49.9, 39.4, 30.7,
29.6, 26.8, 22.4, 21.6, 13.7. IR (KBr) 2923, 2855, 1653, 1456,
1409, 1317, 1252, 1138, 1024, 948, 836, 720, 619, 580 cmÀ1. MS
(ESI) m/z 365 [M+H]+: HR-MS (ESI) calcd for C17H22N4OSCl
[M+H]+: 365.1202. Found: 365.1200.
4.3.14. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(pyridin-3-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6m
Yield: 92%; mp 46 °C; 1H NMR (300 MHz, CDCl3) d 8.88 (s, 1H),
8.66 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 5. 8 Hz,
J = 3.0 Hz, 1H), 5.45 (dd, J = 6.0 Hz, J = 6.7 Hz, 1H), 3.71 (s, 3H),
3.47–3.67 (m, 2H), 2.63 (t, J = 6.7 Hz, 2H), 2.34 (s, 3H), 1.63–1.73
(m, 2H), 1.33–1.43 (m, 2H), 0.94 (t, J = 7.5 Hz, 3H). 13C NMR
(75 MHz, CDCl3) d 169.0, 150.6, 147.4, 133.8, 127.4, 125.5, 124.6,
123.7, 122.3, 49.9, 38.3, 30.8, 29.7, 26.8, 22.4, 21.6, 13.9. IR (KBr)
2958, 2928, 1661, 1595, 1460, 1410, 1262, 1178, 1047, 966, 811,
720, 684 cmÀ1. MS (ESI) m/z 360 [M+H]+; HR-MS (ESI) calcd for
C
18H23N5OCl [M+H]+: 360.1591. Found: 360.1587.
4.3.15. 1-(3-(6-Bromopyridin-2-yl)-5-(2-butyl-4-chloro-1-met
hyl-1H-imidazol-5-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6n
Yield: 91%; mp 120 °C; 1H NMR (300 MHz, CDCl3) d 7.98 (d,
J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.42 (d, J = 7.5 Hz, 1H) 5.35
(dd, J = 6.0 Hz, J = 6.7 Hz, 1H), 3.62–3.74 (m, 4H), 3.52 (dd,
J = 6.0 Hz, J = 12.8 Hz, 1H), 2.56 (t, J = 7.5 Hz, 2H), 2.26 (s, 3H),
1.57–1.67 (m, 2H), 1.29–1.39 (m, 2H), 0.88 (t, J = 7.5 Hz, 3H). 13C
NMR (75 MHz, CDCl3) d 169.2, 153.9, 151.4, 146.8, 141.6, 138.4,
128.6, 125.2, 124.6, 119.7, 50.2, 38.5, 30.7, 29.5, 26.7, 22.3, 21.5,
13.7. IR (KBr) 2924, 2855, 1666, 1549, 1465, 1402, 1325, 1255,
1157, 1129, 1037, 950, 858, 798, 752 cmÀ1. MS (ESI) m/z 438
[M+H]+; HR-MS (ESI) calcd for C18H22N5OClBr [M+H]+: 438.0696.
Found: 438.0695.
4.3.10. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-(5-
chlorothiophen-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6i
Yield: 92%; mp 150 °C; 1H NMR (300 MHz, CDCl3) d 6.98 (s, 1H),
6.87 (s, 1H), 5.38 (dd, J = 4.8 Hz, J = 7.6 Hz, 1H), 3.68 (s, 3H), 3.55 (t,
J = 12.5 Hz, 1H), 3.43 (dd, J = 4.8 Hz, J = 12.5 Hz, 1H), 2.60 (t,
J = 7.6 Hz, 2H), 2.27 (s, 3H), 1.63–1.72 (m, 2H), 1.32–1.42 (m, 2H),
0.95 (t, J = 6.7 Hz, 3H), 13C NMR (75 MHz, CDCl3) d 168.9, 148.5,
147.0, 133.6, 133.1, 127.7, 126.7, 125.5, 124.4, 50.1, 38.8, 30.8,
29.6, 26.8, 22.4, 21.6, 13.7. IR (KBr) 2938, 2871, 1660, 1593,
1551, 1455, 1409, 1319, 1255, 1132, 1011, 953, 845, 820,
747 cmÀ1. MS (ESI) m/z 399 [M+H]+; HR-MS (ESI) calcd for
C
17H21N4OSCl2 [M+H]+: 399.0813. Found: 399.0814.

4780
S. Kantevari et al. / Bioorg. Med. Chem. 19 (2011) 4772–4781
4.3.16. 1-(3-(Anthracen-2-yl)-5-(2-butyl-4-chloro-1-methyl-1H-
imidazol-5-yl)-4,5-dihydro-1H-pyrazolyl)ethanone 6o
15,000 rpm for 60 min at 4 °C. Supernatant was used as a source
of ACE enzyme for this assay. ACE activity was assayed by monitor-
ing the release of Hippuric acid (HA) from the hydrolysis of hippu-
Yield: 87%; mp 184 °C; 1H NMR (300 MHz, CDCl3) d 8.38 (d,
J = 5.0 Hz, 2H), 7.95–8.05 (m, 5H), 7.43–7.52 (m, 2H), 5.39–5.45
(m, 1H), 3.71 (s, 3H), 3.64–3.69 (m, 2H), 2.63 (t, J = 7.7 Hz, 2H),
2.39 (s, 3H), 1.65–1.76 (m, 2H), 1.37–1.47 (m, 2H), 0.95 (t,
J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 169.1, 153.7, 146.9,
132.5, 132.1, 131.7, 130.9, 128.8, 128.2, 128.1, 127.9, 127.4,
126.4, 126.1, 125.9, 122.6, 50.8, 38.9, 30.1, 29.7, 26.9, 22.5, 21.7,
13.8. IR (KBr): 2922, 2853, 1665, 1412, 1325, 1254, 1135, 895,
855, 744 cmÀ1. MS (ESI) m/z: 459 [M+H]+; HR-MS (ESI) calcd for
ryl-histidyl-leucine (HHL) (Sigma–Aldrich, USA). 15
solution was preincubated with test and standard drug solution
(75 l each) for 10 min at 37 °C. The enzyme reaction was started
by adding 125 l of 0.05 M sodium borate buffer (pH 8.2) contain-
ing 0.3 M NaCl and 50 l of 5 mM substrate (HHL) followed by
ll of ACE
l
l
l
incubation at 37 °C for 30 min. The reaction was arrested by the
addition of 0.2 mL of 1 M HCl. After stopping the reaction, 0.4 mL
of pyridine (SD Fine chemical, India) was added followed by
0.2 mL of BSC (SD Fine chemical, India). The solution was mixed
by inversion for 1 min and cooled on ice. The yellow color devel-
oped was measured at 410 nm. The decreased concentration of
HA in the test reaction compared with the control reaction was ex-
pressed as percentage inhibition and calculated from the equation:
Inhibition% = 100 À [T/C] Â 100, where T = absorbance of test reac-
tion and C = absorbance of control reaction. The therapeutic drug
Lisinopril was used as reference ACE inhibitor. The inhibitory con-
centration 50% (IC50) was calculated by nonlinear regression. The
dose–response curve was obtained by plotting the percentage inhi-
bition versus the concentrations.
C
27H28N4OCl [M+H]+: 459.1951. Found: 459.1952.
4.3.17. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(dibenzo[b,d]furan-2-yl)-4,5-dihydro-1H-pyrazolyl)ethanone
6p
Yield: 93%; mp 145 °C; 1H NMR (300 MHz, CDCl3) d 8.26 (s, 1H),
7.96 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 8.4 Hz,1H), 7.57 (d, J = 9.2 Hz,
2H), 7.46 (t, J = 7.3 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 5.43 (dd,
J = 5.0 Hz, J = 6.6 Hz, 1H), 3.52–3.69 (m, 5H), 2.61 (t, J = 7.5 Hz,
2H), 2.38 (s, 3H), 1.63–1.73 (m, 2H), 1.33–1.43 (m, 2H), 0.94 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.6, 157.1, 156.5,
153.4, 146.6, 127.6, 126.0, 125.6, 124.6, 123.5, 123.0, 120.7,
118.9, 111.9, 111.7, 109.6, 49.8, 38.9, 30.6, 29.5, 26.7, 22.3, 21.6,
13.7. IR (KBr) 2957, 2927, 2856, 1659, 1436, 1414, 1363, 1324,
1255, 1197, 1125, 1021, 842, 752, 622 cmÀ1. MS (ESI) m/z 449
[M+H]+; HR-MS (ESI) calcd for C25H26N4O2Cl [M+H]+: 449.1744.
Found: 449.1733.
Acknowledgments
Authors are thankful to Dr. J.S. Yadav, Director, Heads of Organic
Chemistry Division-II and Chemical Biology, IICT, Hyderabad for
encouragement and support. Financial assistance from MLP pro-
jects (S.K.), DBT Project (BT/HRD/35/02/09/2008 to SKB) is also
duly acknowledged. D.A. (SRF) is thankful to CSIR for fellowship.
4.3.18. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-
(dibenzo[b,d]thiophen-2-yl)-4,5-dihydro-1H-
pyrazolyl)ethanone 6q
Yield: 87%; mp 130 °C; 1H NMR (300 MHz, CDCl3) d 8.39 (s, 1H),
8.14–8.19 (m, 1H), 7.82–7.89 (m, 3H), 7.44–7.47 (m, 2H), 5.43 (dd,
J = 5.4 Hz, J = 6.0 Hz, 1H), 3.60–3.17 (m, 5H), 2.62 (t, J = 7.7 Hz, 2H),
2.39 (s, 3H), 1.64–1.74 (m, 2H), 1.36–1.46 (m, 2H), 0.95 (t,
J = 7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3) d 168.7, 153.4, 146.6,
141.6, 139.8, 135.9, 135.1, 127.6, 127.2, 124.7, 124.6, 122.9,
121.8, 119.6, 49.9, 38.9, 30.9, 29.7, 26.8, 22.5, 21.7, 13.9. IR (KBr)
2957, 2866, 1658, 1593, 1415, 1313, 1255, 1136, 1025, 858, 760,
618 cmÀ1. MS (ESI) m/z 465 [M+H]+; HR-MS (ESI) calcd for
Supplementary data
Copies of 1H, 13C NMR and mass spectra of all the new com-
pounds 4a–r, 5, 6a–r; CCDC 823201 (for 4j) and CCDC 823202
(for 6i) contain the crystallographic data and can be obtained free
of charge from the Cambridge Crystallographic Data centre via
http://www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2011.06.085.
C
25H26N4OSCl [M+H]+: 465.1515. Found: 465.1494.
References and notes
4.3.19. 1-(5-(2-Butyl-4-chloro-1-methyl-1H-imidazol-5-yl)-3-(9-
methyl-9H-carbazol-3-yl)-4,5-dihydro-1H-pyrazolyl)ethanone
6r
1. Sharma, S. K.; Ghimire, A.; Radhakrishnan, J.; Thapa, L.; Shrestha, N. R.; Paudel,
N.; Gurung, K.; Maskey, R.; Budathoki, A.; Baral, N.; Brodie, D. Int. J. Hypertens.
2011. doi:10.4061/2011/ 821971; Messerli, F. H.; Williams, B.; Ritz, E. Lancet
2007, 370, 591.
2. World Health Organization, Global Health Risks: Mortality and Burden of
Disease Attributable to Selected Major Risk, WHO, Geneva, Switzerland,
2009. http://www.who.int/healthinfo/globalburdendisease/GlobalHealthRisks_
report_full.pdf.; (b) American Heart Assoc., Heart disease and stroke
statistics—2009 update. Circulation, 2009, 119, e21–e181.; (c) Kearney, P. M.;
Whelton, M.; Reynolds, K.; Muntner, P.; Whelton, P. K.; He, J. Lancet 2005, 365,
217.
Yield: 85%; mp 194 °C; 1H NMR (300 MHz, CDCl3) d 8.27 (s,1H),
8.04 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 8.3 Hz, 1H), 7.44 (t, J = 7.5 Hz,
1H), 7.31 (t, J = 8.3 Hz, 2H), 7.22 (t, J = 7.5 Hz,1H), 5.23 (dd,
J = 6.0 Hz, J = 5.2 Hz, 1H), 3.79 (s, 3H), 3.59 (s, 3H), 3.30–3.55 (m,
2H), 2.58 (t, J = 7.5 Hz, 2H), 2.36 (s, 3H), 1.60–1.70 (m, 2H),
1.31–1.43 (m, 2H), 0.92 (t, J = 7.5 Hz, 3H). 13C NMR (75 MHz, CDCl3)
d 168.4, 154.4, 146.5, 141.8, 141.3, 126.6, 124.9, 124.2, 122.7,
122.5, 121.9, 120.3, 119.5, 118.9, 108.6, 108.5, 49.6, 39.0, 30.6,
29.6, 29.0, 26.7, 22.4, 21.6, 13.8. IR (KBr); 2926, 2861, 1652,
1443, 1412, 1323, 1250, 1125, 950, 853, 747, 621 cmÀ1. MS (ESI)
m/z 462 [M+H]+; HR-MS (ESI) calcd for C26H29N5OCl [M+H]+:
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