Synthesis of some imidazolyl-substituted 2-benzylidene indanone derivatives as potent aromatase inhibitors for breast cancer therapy

Article abstract of DOI:10.1007/s00044-010-9368-4

The synthesis and aromatase inhibitory activity of a new series of 2-benzylidene indanones is presented. The imidazolyl-substituted indanones displayed potent aromatase inhibitory activity. The vanilloid-based derivative 2-[4-(3-imidazol-1-ylpropoxy)-3-me

Full text of DOI:10.1007/s00044-010-9368-4

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:661–669
DOI 10.1007/s00044-010-9368-4
ORIGINAL RESEARCH
Synthesis of some imidazolyl-substituted 2-benzylidene indanone
derivatives as potent aromatase inhibitors for breast cancer
therapy
•
•
•
Ranju Bansal Gaurav Narang Christina Zimmer
Rolf W. Hartmann
Received: 26 January 2010 / Accepted: 5 May 2010 / Published online: 30 May 2010
Ó Springer Science+Business Media, LLC 2010
Abstract The synthesis and aromatase inhibitory activity
of a new series of 2-benzylidene indanones is presented.
The imidazolyl-substituted indanones displayed potent
aromatase inhibitory activity. The vanilloid-based deriva-
tive 2-[4-(3-imidazol-1-ylpropoxy)-3-methoxybenzylidene]-
indan-1-one (26) exhibited maximum inhibition of human
placental aromatase and was found to be 54 times more
potent as compared to aminoglutethimide.
the market and others are in various stages of clinical trials
for the treatment of breast cancer (Njar and Brodie, 1999;
Seralini and Moslemi, 2001). However, due to the lack of
highly selective, orally active, and side effect free inhibi-
tors of this enzyme, the synthesis of more powerful and
more specific aromatase inhibitors still remains a chal-
lenge. This has led many research groups to develop new
leads for inhibition of this cytochrome P450 enzyme
(Altundag and Ibrahim, 2006; Brodie and Njar, 2000;
Recanatini et al., 2001). Among the various nonsteroidal
aromatase inhibitors, a series of pyridyl-substituted inda-
nones, indans, and tetralins have been reported and
developed as potent and selective agents (Hartmann et al.,
1994; Bayer et al., 1991). Of these, indanone derivatives 2-
(4-pyridylmethylene)-1-indanone (1) and its corresponding
saturated pyridyl–methyl analogue (2) (Fig. 1) have been
reported to possess good selectivity and increased potency
toward aromatase as compared to aminoglutethimide
(Hartmann et al., 1994; Bayer et al., 1991).
Keywords Aldol condensation Á Aromatase Á
Breast cancer Á Indanone derivatives Á
Nonsteroidal aromatase inhibitors
Introduction
Inhibition of aromatase, a cytochrome P450 enzyme, has
become of much interest in the treatment of disseminated
estrogen-dependent breast cancer over the last three dec-
ades (Tomera, 1994; Howell and Dowesett, 1997; Buzdar
and Howell, 2001; Bajetta et al., 1999). Aromatase is the
rate-limiting enzyme in the conversion of androgens to
estrogens (Bhatnagar et al., 2001; Sasano and Harada,
1998; Cole and Robinson, 1990). A number of steroidal
and nonsteroidal compounds affecting estrogen biosyn-
thesis through the inhibition of aromatase are presently in
As a part of our ongoing research program pertaining to
the synthesis of monomeric and dimeric 2-benzylidene
indanones as potent aromatase inhibitors (Narang et al.,
2006; Gupta et al., 2004), we now report the aromatase
inhibitory activity of a new series of imidazolyl-substituted
indanone derivatives. This study encompasses the synthesis
of a new series of indanone derivatives by base mediated
O
O
R. Bansal (&) Á G. Narang
University Institute of Pharmaceutical Sciences,
Panjab University, Chandigarh 160014, India
e-mail: ranju29in@yahoo.co.in
N
N
C. Zimmer Á R. W. Hartmann
1
2
Pharmaceutical and Medicinal Chemistry,
Saarland University, 66041, Saarbru¨cken, Germany
Fig. 1 Structures of pyridyl-substituted indanone derivatives
123

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Med Chem Res (2011) 20:661–669
aldol condensation of indan-1-one with various substituted
aldehydes and their evaluation for inhibitory activity
towards aromatase enzyme.
Aldol condensation of 1-indanone with substituted alde-
hydes 3a–f, 5–10, and 17–20 at room temperature in
alkaline conditions resulted in the formation of benzyli-
dene adducts 4a–f, 11–16, and 21–25, respectively.
Substituted aldehydes (wherever not commercially avail-
able) were prepared by alkylating the aldehydes with
requisite halogenated derivative in ethyl methyl ketone in
the presence of anhydrous potassium carbonate. Previ-
ously we have reported the formation of dimers during
base mediated aldol condensation of indan-1-one with
various aldehydes (Narang et al., 2006; Gupta et al.,
2004). It was observed that presence of an electron with-
drawing para substituent and electron donating meta sub-
stituent facilitates the dimer formation. In the present case,
monomeric 2-substituted indanone derivatives were
obtained owing to the presence of an electron donating
substituent at para position of aldehydes in concordance
with earlier reports. However in case of 3-hydroxybenzal-
dehyde derivative, attempts to follow the same syn-
thetic route as was adopted for aldehydes vanillin,
isovanillin, and salicylaldehyde did not result in the
formation of desired compound. Therefore, aldol
Materials and methods
Chemistry
The melting points reported are uncorrected. Infrared spectra
were recorded using KBr disks on a Perkin-Elmer 882
spectrophotometer model. 1H NMR was recorded on Bruker
AC-300F, 300 MHz instrument using deuterochloroform
and deuterated dimethylsulfoxide as solvents containing
tetramethylsilane as an internal reference. Elementary
analyses were carried out on a Perkin-Elmer-2400 model.
Plates for TLC were prepared according to Stahl using ethyl
acetate (activated at 110°C for 30 min). The spots were
visualized by exposure to iodine vapors. Anhydrous sodium
sulfate was used as drying agent for organic extracts.
The synthetic routes to the synthesis of various indanone
derivatives have been depicted in Schemes 1 and 2.
Scheme 1 Synthesis of various
aldol derivatives 4a–f and
11–16
O
O
NaOH/MeOH
R
R-CHO
+
3a-f, 5-10
1-Indanone
Compound
4a-f, 11-16
Compound
R
R’
R
No.
No.
CH3
CH3
-CH2CH2N
5, 11
a
b
N
H
CH3
CH3
C2H5
6, 12
7, 13
8, 14
CH
-CH2CH2N
-CH2CH2 N
-CH2CH2N
-CH2CH2N
C2H5
c
O
OMe
O
3, 4
OR'
d
OMe
OMe
OMe
e
f
9, 15
O
N(CH3)2
10, 16
-CH2CH2OH
123

Med Chem Res (2011) 20:661–669
663
Scheme 2 Synthetic route to
various imidazolyl-substituted
indanone derivatives
R1
R1
O
R2
R3
R2
R3
OHC
1-Indanone
+
i) NaOH/MeOH
ii)
imidazole
(17-20)
(21-29)
N
[17,21,26] R1=H, R2= -OCH3, (17,21) R3 = -OCH2CH2CH2Cl ; (26) R 3 = -OCH2CH2CH2-
N
N
N
[18,22,27] R1=H, R3= -OCH3, (18, 22) R2 = -OCH2CH2CH2Cl ; (27) R 2 = -OCH2CH2CH2-
N
N
-
[19,23,28] R2=R3=H (19, 23) R1 = -OCH2CH2CH2Cl ; (28) R1 = -OCH2CH2CH2
N
N
-
[20,24,25,29] R1=R3=H (20, 24) R2 = OH (25) R2 = -OCH2CH2CH2Cl ; (29) R2 = -OCH2CH2CH2
General method for the preparation of benzylidene
condensation of 1-indanone with 3-hydroxybenzaldehyde
was carried out first, which was followed by alkylation
with 1-bromo-3-chloropropane.
derivatives 4a–f, 11–16, and 21–24
A mixture of indanone (0.76 mmol), appropriate aldehyde
3a–f, 5–10, 17–20, and sodium hydroxide (3.75 mmol) in
methanol (10 ml) was shaken manually for 30 min, and it
was allowed to stand at room temperature with occasional
shaking. The completion of reaction was monitored by
TLC. The excess of methanol was removed; crushed ice
was added and the contents were allowed to stand over-
night. The precipitate obtained was filtered, washed thor-
oughly with distilled water, and dried to afford respective
aldol products 4a–f, 11–16, and 21–24. The crude products
were crystallized from methanol.
In view of the earlier observations that azoles exhibit
potent aromatase inhibitory activity because of their
interaction with active site of aromatase, we further con-
sidered introduction of imidazole moiety. The effect of
moving this substituent on various positions of benzylidene
ring on aromatase inhibition was also studied. The struc-
tures of the compounds were established using various
spectral and elemental analyses. The X-ray structure of 2-
(3-indolyl-methylene)-indan-1-one (11) has already been
reported by us (Vasuki et al., 2002).
General method for the preparation of substituted
2-[4-(2-Dimethylaminoethoxy)-3-methoxybenzylidene]-
indan-1-one (4a)
aldehydes 3a–f, 17–19, and 25
Hydrochloride of requisite dialkylaminoethyl chloride
(6.57 mmol) was added to a stirred and refluxing sus-
pension of vanillin (6.57 mmol) and anhydrous potassium
carbonate (2 g) in ethyl methyl ketone (60 ml). The
reaction mixture was further refluxed for 6 h with con-
tinuous stirring until the reaction was completed (moni-
tored by TLC). The reaction mixture was cooled, filtered,
and solvent was removed under reduced pressure to
obtain the corresponding oily residue 3a–e. 2-Chloro-
ethanol was used for the synthesis of 3f. The aldehyds 5–
10 were commercially available. The synthesis of 17–19
was performed by alkylation of vanillin/isovanillin/sali-
cylaldehyde with 1-bromo-3-chloropropane using the
same procedure. The compound 25 was prepared from 24
using the same method by treating with 1-bromo-3-
chloropropane. The residues obtained were used as such
for subsequent reaction.
Yield: 23%; m.p. 116–120°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2985, 1695, 1600, 1510, 1230, 1020, 730;
1H NMR (CDCl3, 300 MHz, d, ppm): 2.35 (s, 6H,
–N(CH3)2), 2.81 (t, 2H, –CH2N(CH3)2), 3.94 (s, 3H,
–OCH3), 4.02 (s, 2H, 3-CH2, indanone), 4.18 (t, 2H, –OCH2),
6.97 (d, 1H, Ar–H, J = 8.5 Hz), 7.19 (d, 1H, Ar–H,
J = 1.5 Hz), 7.29 (dd, 1H, Ar–H, J = 1.55 and 8.6 Hz),
7.43 (t, 1H, Ar–H, J = 7.28 Hz, indanone), 7.59 (m, 3H, Ar–
H, indanone and vinylic-H), 7.91 (d, 1H, Ar–H,
J = 7.55 Hz, indanone). Anal. calcd. for C21H23NO3: C:
74.75, H: 6.86, N: 4.15; found; C: 74.71, H: 6.62, N: 4.20%.
2-[4-[2-Diethylaminoethoxy)-3-methoxybenzylidene]-
indan-1-one (4b)
Yield: 30%; m.p. 98–102°C. Spectroscopic analysis: IR
(KBr): vmax/cm-1: 2990, 1695, 1620, 1590, 1510, 1240,
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Med Chem Res (2011) 20:661–669
1
1030, 720; H NMR (CDCl3, 300 MHz, d, ppm): 1.08 (t,
6H, –N(CH2CH3)2), 2.64 (q, 4H, –N(CH2CH3)2), 2.95 (t,
2H, –CH2N(CH2CH3)2), 3.94 (s, 3H, –OCH3), 4.04 (s, 2H,
3-CH2, indanone), 4.16 (t, 2H, –OCH2–), 6.97 (d, 1H, Ar–
H, J = 8.5 Hz), 7.19 (d, 1H, Ar–H, J = 1.88 Hz), 7.30
(dd, 1H, Ar–H, J = 1.86 and 8.6 Hz), 7.43 (t, 1H, Ar–H,
J = 7.03 Hz, indanone), 7.59 (m, 3H, Ar–H, indanone and
vinylic-H), 7.91 (d, 1H, Ar–H, J = 7.59 Hz, indanone).
Anal. calcd. for C23H27NO3: C: 75.58, H: 7.44, N: 3.83;
found; C: 75.68, H: 7.26, N: 3.84%.
2H, 3-CH2, indanone), 4.22 (t, 2H, –OCH2–), 6.97 (d, 1H,
Ar–H, J = 8.49 Hz), 7.20 (d, 1H, Ar–H J = 1.70 Hz),
7.28 (dd, 1H, Ar–H, J = 1.57 and 6.83 Hz), 7.43 (t, 1H,
Ar–H, J = 7.36 Hz, indanone), 7.59 (m, 3H, Ar–H, inda-
none and vinylic-H), 7.91 (d, 1H, Ar–H, J = 7.61 Hz,
indanone). Anal. calcd. for C23H25NO4: C: 72.80, H: 5.04,
N: 3.69; found; C: 72.47, H: 5.38, N: 3.80%.
2-[4-(2-Hydroxy-ethoxy)-3-methoxybenzylidene]-indan-1-
one (4f)
2-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)benzylidene]-
indan-1-one (4c)
Yield: 31%; m.p. 188–192°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2920, 1680, 1570, 1270, 720; H NMR
(CDCl3, 300 MHz, d, ppm): 2.58 (s, 1H, –OH, exchange-
able), 3.95 (s, 3H, –OCH3), 4.01 (m, 4H, 3-CH2, indanone
and –CH2OH–), 4.20 (t, 2H, –OCH2–), 6.98 (d, 1H, Ar–H,
J = 8.49 Hz), 7.19 (d, 1H, Ar–H, J = 1.89 Hz), 7.29 (dd,
1H, Ar–H, J = 1.89 and 6.83 Hz), 7.43 (t, 1H, Ar–H,
J = 7.38 Hz, indanone), 7.60 (m, 3H, Ar–H, indanone and
vinylic-H), 7.91 (d, 1H, Ar–H J = 7.61 Hz, indanone).
Anal. calcd. for C17H18O4: C: 71.31, H: 6.33; found; C:
70.94, H: 5.56%.
Yield: 29%; m.p. 94–98°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2860, 1690, 1605, 1505, 1460, 1250,
1
1140, 730; H NMR (CDCl3, 300 MHz, d, ppm): 1.83 (m,
4H, –(CH2)2, pyrrolidine), 2.64 (d, 4H, –N(CH2)2, pyrrol-
idine), 2.99 (t, 2H, –CH2N–), 3.94 (s, 3H, –OCH3), 4.03 (s,
2H, 3-CH2, indanone), 4.22 (t, 2H, –OCH2CH2N–), 6.97
(d, 1H, Ar–H, J = 8.28 Hz), 7.19 (d, 1H, Ar–H,
J = 1.58 Hz), 7.31 (dd, 1H, Ar–H. J = 1.71 and 6.81 Hz),
7.43 (t, 1H, Ar–H, J = 7.29 Hz, indanone), 7.59 (m, 3H,
Ar–H, indanone and vinylic-H), 7.91 (d, 1H, Ar–H,
J = 7.56 Hz, indanone). Anal. calcd. for C23H25NO3: C:
76.00, H: 6.93, N: 3.85; found; C: 76.09, H: 6.49, N:
4.10%.
2-(3-Indolyl-methylene)-indan-1-one (11)
Yield: 21%; m.p. 253–255°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 1690, 1600, 1580, 740; 1H NMR
(CDCl3–DMSO-d6): 3.91 (s, 2H, 3-CH2, indanone), 7.22–
7.61 (m, 6H, Ar–H, indanone and indole), 7.75 (s, 1H,
vinylic-H), 7.90 (m, 2H, Ar–H, indanone and indole), 8.10
(s, 1H, 2-H, indole), 11.62 (s, 1H, –NH, exchangeable).
Anal. calcd. for C18H13NO: C: 83.37, H: 5.05, N: 5.40;
found; C: 83.19, H: 5.43, N: 5.12%.
2-[3-Methoxy-4-(2-piperidin-1-yl-ethoxy)benzylidene]-
indan-1-one (4d)
Yield: 63%; m.p. 100–104°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2920, 1700, 1600, 1240, 1120; 1H NMR
(CDCl3, 300 MHz, d, ppm): 1.47 (brt, 2H, –CH2–, piperi-
dine), 1.62 (p, 4H, –(CH2)2, piperidine), 2.52 (br, 4H,
–N(CH2)2, piperidine), 2.84 (t, 2H, –CH2N–), 3.95 (s, 3H,
–OCH3), 4.03 (s, 2H, 3-CH2, indanone), 4.20 (t, 2H,
–OCH2CH2–), 6.96 (d, 1H, Ar–H, J = 8.62 Hz), 7.19 (s,
1H, Ar–H), 7.29 (dd, 1H, Ar–H, J = 1.59 and 7.62 Hz),
7.43 (t, 1H, Ar–H, J = 7.28 Hz, indanone), 7.59 (m, 3H,
Ar–H, indanone and vinylic-H), 7.91 (d, 1H, Ar–H,
J = 7.59 Hz, indanone). Anal. calcd. for C24H27NO3: C:
76.36, H: 7.20, N: 3.71; found; C: 75.96, H: 7.29, N:
4.01%.
2-(4-Isopropyl-benzylidene)-indan-1-one (12)
Yield: 29%; m.p. 55–57°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2960, 1690, 1610, 740; 1H NMR
(CDCl3, 300 MHz, d, ppm): 1.28 (d, 6H, –CH(CH3)2, 2.96
(m, 1H, –CH(CH3)2), 4.04 (s, 2H, 3-CH2, indanone), 7.33
(d, 2H, Ar–H, J = 8.32 Hz), 7.42 (t, 1H, Ar–H,
J = 7.35 Hz, indanone), 7.54–7.63 (m, 4H, Ar–H), 7.67 (t,
1H, vinylic-H), 7.91 (d, 1H, Ar–H, J = 7.7 Hz, indanone).
Anal. calcd. for C19H18O: C: 86.98, H: 6.91; found; C:
86.35, H: 6.77%.
2-[3-Methoxy-4-(2-morpholin-4-yl-ethoxy)benzylidene]-
indan-1-one (4e)
2-[Benzo{1,3}dioxol-5-yl-methylene]-indan-1-one (13)
Yield: 61%; m.p. 128–130°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2940, 2800, 1680, 1600, 1240, 1120,
Yield: 85%; m.p. 176–180°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2950, 1690, 1630, 1500, 1440, 1040,
1
1
940, 760; H NMR (CDCl3, 300 MHz, d, ppm): 2.61 (t,
4H, –N(CH2)2, morpholine), 2.88 (t, 2H, –CH2N–), 3.74 (t,
740; H NMR (CDCl3, 300 MHz, d, ppm): 4.01 (s, 2H, 3-
CH2, indanone), 6.05 (s, 2H, –O–CH2–O–), 6.91 (d, 1H,
4H, –O(CH2)2, morpholine), 3.94 (s, 3H, –OCH3), 4.03 (s,
Ar–H, J = 8.32), 7.21 (dd, 2H, Ar–H, J = 1.62 and
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Med Chem Res (2011) 20:661–669
665
6.44 Hz), 7.43 (t, 1H, Ar–H, J = 7.32 Hz, indanone),
7.54–7.64 (m, 3H, Ar–H and vinylic-H), 7.91 (d, 1H, Ar–
H, J = 7.6 Hz, indanone). Anal. calcd. for C17H10O3: C:
77.85, H: 3.84; found; C: 77.45, H: 4.16%.
Anal. calcd. for C20H19O3Cl: C: 70.07, H: 5.58; found; C:
69.91, H: 5.43%.
2-[3-(3-Chloropropoxy)-4-methoxybenzylidene]-indan-1-
one (22)
2-(4-Methoxybenzylidene)-indan-1-one (14)
Yield: 43%; m.p. 115–118°C. Spectroscopic analysis: IR
1
Yield: 29%; m.p. 136–138°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 1690, 1600, 1510, 1480, 1250, 1020,
(KBr) vmax/cm-1: 2900, 1680, 1600, 1260, 1140, 730; H
NMR (CDCl3, 300 MHz, d, ppm): 2.32 (p, 2H,
–OCH2CH2–), 3.81 (t, 2H, –CH2Cl–), 3.88 (s, 3H, –OCH3),
3.96 (s, 2H, –OCH2, indanone), 4.23 (t, 2H, –OCH2–), 6.95
(d, 1H, Ar–H, J = 8.3 Hz), 7.21 (s, 1H, Ar–H), 7.29 (dd,
J = 1.62 and 8.56 Hz, 1H, Ar–H), 7.40 (t, 1H, Ar–H,
J = 7.10 Hz, indanone), 7.56 (m, 3H, Ar–H, indanone and
vinylic-H), 7.88 (d, 1H, Ar–H, J = 7.56, indanone). Anal.
calcd. for C20H19O3Cl: C: 70.07, H: 5.59; found; C: 63.78,
H: 5.64%.
1
720; H NMR (CDCl3, 300 MHz, d, ppm): 3.87 (s, 3H,
–OCH3), 4.02 (s, 2H, 3-CH2, indanone), 6.98 (d, 2H, Ar–H,
J = 8.6 Hz), 7.42 (t, 1H, Ar–H, J = 7.35 Hz, indanone),
7.54–7.66 (m, 5H, Ar–H and vinylic-H), 7.91 (d, 1H, Ar–
H, J = 7.6 Hz, indanone). Anal. calcd. for C17H11O2: C:
82.57, H: 4.48; found; C: 81.03, H: 5.74%.
2-(3,4-Dimethoxybenzylidene)-indan-1-one (15)
Yield: 62%; m.p. 170–173°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2920, 2840, 1685, 1590, 1510, 1460,
2-[2-(3-Chloropropoxy)benzylidene]-indan-1-one (23)
Yield: 67%; m.p. 130–134°C. Spectroscopic analysis: IR
1
1010; H NMR (CDCl3, 300 MHz, d, ppm): 3.95 (s, 6H,
1
–(OCH3)2), 4.03 (s, 2H, 3-CH2, indanone), 6.95 (d,
J = 8.6 Hz, 1H, Ar–H), 7.2 (d, 1H, Ar–H, J = 1.98 Hz),
7.31 (dd, 1H, Ar–H, J = 1.98 and 8.3 Hz), 7.43 (t, 1H, Ar–
H, J = 7.6 Hz, indanone), 7.6 (m, 3H, Ar–H and vinylic-
H), 7.9 (d, 1H, Ar–H, J = 7.7 Hz, indanone). Anal. calcd.
for C18H16O3: C: 77.05, H: 5.70; found; C: 76.85, H:
5.17%.
(KBr) vmax/cm-1: 2970, 1680, 1600, 1440, 1230, 740; H
NMR (CDCl3, 300 MHz, d, ppm): 2.31 (p, 2H,
–OCH2CH2–), 3.81 (t, 2H, –CH2Cl–), 3.98 (s, 2H, 3-CH2,
indanone), 4.19 (t, 2H, –OCH2–), 6.96 (d, 1H, Ar–H,
J = 8.49 Hz), 7.03 (t, 1H, Ar–H, J = 7.52 Hz), 7.33 (dd,
1H, Ar–H, J = 6.83 Hz), 7.40 (t, 1H, Ar–H, J = 7.34 Hz),
7.59 (m, 3H, Ar–H, indanone), 7.89 (d, 1H, Ar–H,
J = 7.61 Hz, indanone), 8.11 (s, 1H, vinylic-H). Anal.
calcd. for C19H17O2Cl: C: 72.95, H: 5.47; found; C: 72.31,
H: 5.39%.
2-(4-Dimethylaminobenzylidene)-indan-1-one (16)
Yield: 70%; m.p. 163–165°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2910, 1670, 1590, 1530, 1170, 1095; H
2-(3-Hydroxybenzylidene)-indan-1-one (24)
NMR (CDCl3, 300 MHz, d, ppm): 3.05 (s, 6H, –N(CH3)2),
3.99 (s, 2H, 3-CH2, indanone), 6.74 (dd, 2H, Ar–H,
J = 1.74 and 9.0 Hz), 7.42 (t, 1H, Ar–H, J = 6.6 Hz,
indanone), 7.6 (m, 5H, Ar–H and vinylic-H), 7.9 (d, 1H,
Ar–H, J = 7.8 Hz, indanone). Anal. calcd. for C18H17NO:
C: 82.14, H: 6.46, N: 5.32; found; C: 82.20, H: 6.16, N:
5.40%.
Yield: 41%; m.p. 200–203°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2950, 1670, 1610, 1250, 690; H NMR
(CDCl3, 300 MHz, d, ppm): 4.04 (s, 2H, 3-CH2, indanone),
6.89 (dd, 1H, Ar–H, J = 2.06 and 8.14 Hz), 7.17 (m, 2H,
Ar–H), 7.27 (t, 1H, Ar–H), 7.42 (t, 1H, Ar–H, indanone),
7.61 (m, 3H, Ar–H, indanone and vinylic-H), 7.85 (d, 1 H,
Ar–H, J = 7.7 Hz, indanone), 9.25 (br, 1H, –OH,
exchangeable); Anal. calcd. for C16H12O2: C: 81.34, H:
5.12; found; C: 80.95, H. 5.08%.
2-[4-(3-Chloropropoxy)-3-methoxybenzylidene]-indan-1-
one (21)
Yield: 28%; m.p. 140–144°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2240, 1700, 1605, 1240, 1140; 1H NMR
(CDCl3, 300 MHz, d, ppm): 2.33 (p, 2H, –OCH2CH2–),
3.79 (t, 2H, –CH2Cl–), 3.95 (s, 3H, –OCH3), 4.04 (s, 2H, 3-
CH2, indanone), 4.25 (t, 2H, –OCH2–), 6.99 (d, 1H, Ar–H,
J = 8.41 Hz), 7.20 (d, 1H, Ar–H, J = 1.91 Hz), 7.31 (dd,
1H, Ar–H, J = 1.92 and 6.58 Hz), 7.43 (t, 1H, Ar–H,
J = 6.96 Hz, indanone), 7.59 (m, 3H, Ar–H, indanone and
vinylic-H), 7.91 (d, 1H, Ar–H, J = 7.56 Hz, indanone).
2-(3-(3-Chloropropoxybenzylidene)-indan-1-one (25)
Yield: 67%; m.p. 73–75°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2900, 1680, 1440. 1220, 740; H NMR
(CDCl3, 300 MHz, d, ppm): 2.28 (p, 2H, –OCH2CH2–);
3.78 (t, 2H, –CH2Cl), 4.05 (s, 2H, 3-CH2, indanone), 4.18
(t, 2H, –OCH2), 6.96 (dd, 1H, Ar–H, J = 2.99 and
8.03 Hz), 7.19 (d, 1H, Ar–H, J = 1.63 Hz), 7.25–7.64 (m,
6H, Ar–H and vinylic-H), 7.91 (d, 1H, Ar–H, J = 7.62 Hz,
123

666
Med Chem Res (2011) 20:661–669
indanone). Anal. calcd. for C19H17O2Cl: C: 72.95, H: 5.48;
found; C: 72.56, H: 5.41%.
3.94 (t, 2H, –CH2N–), 4.00 (s, 2H, 3-CH2, indanone), 4.25
(t, 2H, –OCH2–), 6.85 (d, 1H, Ar–H, J = 8.18 Hz), 6.93 (s,
1H, imidazole), 7.05 (m, 2H, Ar–H, and imidazole), 7.33
(m, 1H, Ar–H), 7.38 (m, 1H, Ar–H), 7.43 (s, 1H, imidaz-
ole), 7.58 (m, 2H, Ar–H, indanone), 7.69 (d, 1H, Ar–H,
J = 8.5 Hz, indanone), 7.90 (d, 1H, Ar–H, J = 7.76 Hz,
indanone), 8.18 (s, 1H, vinylic-H). Anal. calcd. for
C22H20O2N2: C: 76.72, H: 5.85, N: 8.16; found; C: 76.48,
H: 5.55, N: 8.19%.
General method for the preparation of imidazolyl
substituted benzylidene derivatives 26–29
A finely triturated mixture of 21–23 and 25 (0.3 g,
0.87 mmol) and imidazole (0.7 g, in excess) was thermally
fused at 80–90°C for 3 h with continuous stirring. The
completion of the reaction was monitored with TLC. Water
was added to remove excess of imidazole. The solid
product obtained was filtered, dried, and crystallized from a
mixture of acetone and diethyl ether to afford 26–29,
respectively.
2-[3-(3-Imidazol-1-yl-propoxy)benzylidene]-indan-1-one
(29)
Yield: 47%; m.p. 48–50°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2940, 1690, 1610, 1240, 1085, 740; H
2-[4-(3-Imidazol-1-yl-propoxy)-3-methoxybenzylidene]-
indan-1-one (26)
NMR (CDCl3, 300 MHz, d, ppm): 2.27 (p, 2H,
–OCH2CH2–), 3.96 (t, 2H, –CH2N–), 4.03 (s, 2H, 3-CH2,
indanone), 4.22 (t, 2H, –OCH2–), 6.94 (m, 2H, Ar–H and
imidazole), 7.07 (s, 1H, Ar–H), 7.16 (s, 1H, imidazole),
7.26–7.45 (m, 3H, Ar–H), 7.50 (s, 1H, imidazole), 7.55–
7.62 (m, 3H, Ar–H, indanone, and vinylic-H), 7.92 (d, 1H,
Ar–H, J = 7.53 Hz, indanone). Anal. calcd. for
C22H20O2N2: C: 76.72, H: 5.85, N: 8.16; found; C: 76.68,
H: 5.86, N: 8.10%.
Yield: 34%; m.p. 123–127°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2920, 1670, 1585, 1249, 1080, 760; H
NMR (CDCl3, 300 MHz, d, ppm): 2.33 (p, 2H,
–OCH2CH2–), 3.99 (s, 3H, –OCH3–), 4.01 (m, 4H, –CH2N
and 3-CH2, indanone), 4.29 (t, 2H, –OCH2–), 6.89 (d, 1H,
Ar–H, J = 7.65 Hz), 6.99 (s, 1H, imidazole), 7.12 (s, 1H,
imidazole), 7.21 (s, 1H, Ar–H), 7.26 (s, 1H, Ar–H), 7.43
(m, 1H, Ar–H, indanone), 7.60 (m, 3H, Ar–H, indanone
and vinylic-H), 7.72 (s, 1H, imidazole), 7.92 (d, 1H, Ar–H,
J = 7.65 Hz, indanone). Anal. calcd. for C23H22N2O3: C:
73.78, H: 5.92, N: 7.48; found; C: 73.60, H: 5.93, N:
7.66%.
Biological activity
Preparation of aromatase
The enzyme was obtained from the microsomal fraction of
freshly delivered human term placental tissue according to
the procedure of Thompson and Siiteri. The isolated
microsomes were suspended in the minimum volume of
phosphate buffer (0.05 M, pH 7.4) and stored at -30°C as
described (Thompson and Siiteri 1974). No loss of activity
was observed within 4 months.
2-[3-(3-Imidazol-1-yl-propoxy)-4-methoxybenzylidene]-
indan-1-one (27)
Yield: 56%; m.p. 176–180°C. Spectroscopic analysis: IR
(KBr) vmax/cm-1: 2900, 1680, 1590, 1250, 1070, 740; H
1
NMR (CDCl3, 300 MHz, d, ppm): 2.30 (p, 2H,
–OCH2CH2–), 3.93 (s, 3H, –OCH3–), 3.96 (s, 2H, 3-CH2,
indanone), 4.01 (t, 2H, –CH2N–), 4.26 (t, 2H, –OCH2),
6.96 (d, 2H, Ar–H, J = 8.46 Hz, and imidazole), 7.07 (s,
1H, imidazole), 7.13 (s, 1H, Ar–H), 7.31 (d, 1H, Ar–H
J = 8.58 Hz), 7.38 (m, 1H, Ar–H, indanone), 7.49–7.62
(m, 4H, Ar–H, indanone, imidazole, and vinylic-H), 7.88
(d, 1H, Ar–H, J = 7.53 Hz, indanone). Anal. calcd. for
C23H22O3N2: C: 73.78, H: 5.92, N: 7.48; found; C: 73.90,
H: 5.93, N: 7.66%.
Inhibition of aromatase in vitro
This assay was performed similar to the described methods
(Foster et al., 1983; Graves and Salhanick, 1979), moni-
3
toring the enzyme activity by measuring the H2O formed
from [1 b, 2 b-3H] testosterone during aromatization. Each
incubation tube contained 0.225 lCi of [1 b, 2 b-3H] tes-
tosterone, 5 lM unlabeled testosterone, 2 mM NADPH,
20 mM glucose-6-phosphate, 1EU glucose-6-phosphate
dehydrogenase, and inhibitor (0–250 lM) in phosphate
buffer (0.05 M, pH7.4). The test compound had been dis-
solved in EtOH and diluted with buffer. The final ethanol
concentration of the control and inhibitor incubation was
2%. Each tube was preincubated for 5 min at 30°C in a
shaking water bath. Microsomal protein (0.5 mg) was
2-[2-(3-Imidazol-1-yl-propoxy)benzylidene]-indan-1-one
(28)
Yield: 60%; m.p. 76–78°C. Spectroscopic analysis: IR
1
(KBr) vmax/cm-1: 2960, 1680, 1600, 1140, 750; H NMR
(CDCl3, 300 MHz, d, ppm): 2.27 (p, 2H, –OCH2CH2–),
123

Med Chem Res (2011) 20:661–669
667
RPb
Table 1 Aromatase inhibitory data of various compounds
Compound no. (code)
Structure
Inhibition on CYP 19a
O
4a (DPJ-1026)
No inhibition at 36 lM
OMe
OCH2CH2N
11 (DPJ-1007)
6% inhibition at 36 lM
8.5% inhibition at 36 lM
8% inhibition at 36 lM
8% inhibition at 36 lM
13% inhibition at 36 lM
IC50 = 0.55 lM
O
O
N
H
21 (DPJ-RG-1039)
22 (DPJ-RG-1091)
23 (DPJ-1045)
OMe
OCH2CH2CH2Cl
O
OCH2CH2CH2Cl
OMe
OCH2CH2CH2Cl
O
O
25 (DPJ-1054)
OCH2CH2CH2Cl
26 (RG-DPJ-195)
54.1
O
OMe
OCH CH CH
2N
2
2
N
27 (DPJ-RG-1090)
IC50 = 1.34 lM
22.5
O
OCH2CH2CH
OMe
2 N
N
123

668
Med Chem Res (2011) 20:661–669
Table 1 continued
Compound no. (code)
Structure
Inhibition on CYP 19a
RPb
26.6
28 (DPJ-1055)
IC50 = 1.1 lM
O
OCH2CH2CH2N
N
29 (DPJ-RG-1088)
IC50 = 0.7 lM
42.5
O
OCH2CH2CH
2 N
N
a
[1 b, 2 b-3H] testosterone
b
Relative potency; relative to aminoglutethimide (RP = 1, IC50 = 28.5 lM)
added to start the reaction. The total volume of each
incubation was 0.5 ml. The reaction was terminated by
withdrawing 100 ll aliquots at 0, 7, 14, and 21 min and
pipetting them into 200 ll of a cold 1 mM HgCl2 solution.
After the addition of 200 ll of an aqueous dextran-coated
charcoal suspension (2%), the vials were shaken for 20 min
and centrifuged at 15009g for 5 min to separate the
charcoal-adsorbed steroids. Aliquots of the supernatant
not screened and study was focused on imidazole-derived
indanones. As expected all the imidazolyl substituted
derivatives 26–29 exhibited strong inhibition of the
enzyme and were found to be more potent as compared to
aminoglutethimide even up to 50 times in case of com-
pound 26. These imidazolyl-derived indanones displayed
higher activity in comparison to earlier reported pyridyl-
substituted compounds [1 (RP = 1.5), 2 (RP = 2.2)]
(Hartmann et al., 1994). Having such a high binding
affinity, it is expected that the compounds interact with the
active site of aromatase by complexing the Fe(III) iron of
cytochrome P450 with one of the imidazole-nitrogens as
previously described (Hartmann et al., 1994; Gupta et al.,
2004). While comparing the effect of substitution pattern of
imidazolyl substituents on benzylidene ring, it has been
observed that vanilloid-based derivative 26 exhibited
maximum activity (RP-54.1, IC50 = 0.55 lM). Various
imidazolyl-substituted derivatives displayed activity in
the order vanillin [ 3-hydroxybenzaldehyde [ salicylal-
dehyde [ isovanillin. The substitution pattern on benzyli-
dene ring affects the aromatase inhibitory activity probably
because the orientation of side chain affects the binding
properties of compounds with active site of aromatase
enzyme and so the difference in the inhibitory potential.
In conclusion, a new series of 2-benzylidene indanone
derivatives has been synthesized and screened for aroma-
tase inhibitory activity. Of all, imidazolyl substituted
derivatives 26–29 exhibited potent inhibitory activity
toward aromatase enzyme with vanilloid-based compounds
exhibiting approximately 50 times more activity as com-
pared to aminoglutethimide. It can be inferred that suitable
selection and positioning of side substituents on 2-ben-
zylidene ring may result in better binding affinity of
indanone derivatives with aromatase enzyme.
3
were assayed for H2O by counting in a scintillation mix-
ture in a 1209 Rackbeta Wallac liquid scintillation spec-
trometer (Phamacia LKB, Freiburg, Germany).
Results and discussion
The monomeric 2-substituted indan-1-one derivatives have
been synthesized by aldol condensation of indan-1-one
with substituted aldehydes in alkaline conditions. Initially,
the work was focused on vanilloid-based derivatives and
other commercially available aldehydes. Afterwards on the
basis of biological results, the imidazole functionality
bearing basic nitrogen, which can bind to active site of the
enzyme, was introduced at various positions of benzylidene
ring through various aldehydes such as vanillin, isovanillin,
salicylaldehyde, and 3-hydroxybenzaldehyde. The aroma-
tase inhibitory activity of the newly synthesized 2-substi-
tuted indanone derivatives was determined in vitro using
human placental microsomes and [1 b, 2 b-3H] testoster-
one. The compounds without the presence of a basic
nitrogen either did not show or only exhibited marginal
inhibition of aromatase enzyme as is evident from binding
affinity data of compounds 4a, 11, 21–23, and 25 (Table 1).
In view of the insignificant inhibition of aromatase by these
compounds, the other similar compounds of the series were
123

Med Chem Res (2011) 20:661–669
669
Acknowledgment The authors are thankful to University Grants
Commission, India for providing financial assistance.
pyridylmethyl)-1-indanone as a novel nonsteroidal aromatase
inhibitor. Arch Pharm (Weinheim) 337:398–401
Hartmann RW, Bayer H, Gru¨n G (1994) Aromatase inhibitors.
Syntheses and structure-activity studies of novel pyridyl-substi-
tuted indanones, indans, and tetralins. J Med Chem 37:1275–
1281
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