Synthesis and preliminary evaluation of 2-substituted-1,3-benzoxazole and 3-[(3-substituted)propyl]-1,3-benzoxazol-2(3H)-one derivatives as potent anticancer agents

Article abstract of DOI:10.1007/s00044-010-9353-y

The synthesis and cytotoxic activity studies of a new series of cyclic amine containing benzoxazole and benzoxazolone derivatives are described. The 2-cyclic amine-1,3-benzoxazoles 5a-k, 5-chloro-3-(3-chloropropyl)- 1,3-benzoxazol-2(3H)-one 8 and 3-[3-(cyclic amino)- propyl]-1,3-benzoxazol-2(3H) -ones 9a-f were synthesized. The newly synthesized compounds with the influence of the presence of cyclic amine moiety in the benzoxazole scaffold have been evaluated with respect to their cytotoxic effect toward four human cancer cell lines. The new compounds were evaluated to see whether substitution at the second and third position of the benzoxazole motif influence their cytotoxic effect toward cancer cells. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-010-9353-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2011) 20:576–586
DOI 10.1007/s00044-010-9353-y
ORIGINAL RESEARCH
Synthesis and preliminary evaluation of 2-substituted-1,3-
benzoxazole and 3-[(3-substituted)propyl]-1,3-benzoxazol-2(3H)-
one derivatives as potent anticancer agents
•
M. S. R. Murty Kesur R. Ram Rayudu Venkateswara Rao
•
•
•
J. S. Yadav Janapala Venkateswara Rao
•
•
Vino T. Cheriyan Ruby John Anto
Received: 17 December 2009 / Accepted: 21 April 2010 / Published online: 9 May 2010
Ó Springer Science+Business Media, LLC 2011
Abstract The synthesis and cytotoxic activity studies
of a new series of cyclic amine containing benzoxazole
and benzoxazolone derivatives are described. The 2-cyclic
amine-1,3-benzoxazoles 5a–k, 5-chloro-3-(3-chloropro-
pyl)-1,3-benzoxazol-2(3H)-one 8 and 3-[3-(cyclic amino)-
propyl]-1,3-benzoxazol-2(3H)-ones 9a–f were synthesized.
The newly synthesized compounds with the influence of the
presence of cyclic amine moiety in the benzoxazole scaffold
have been evaluated with respect to their cytotoxic effect
toward four human cancer cell lines. The new compounds
were evaluated to see whether substitution at the second and
third position of the benzoxazole motif influence their
cytotoxic effect toward cancer cells.
activities, such as anticancer (Kumar et al., 2002; Easmon
et al., 2001; Jauhari et al., 2008; Rida et al., 2005), anti-
microbial (Kumar et al., 2002; Temiz-Arpacı et al., 2005),
anti HIV (Rida et al., 2005; Temiz-Arpacı et al., 2005) and
dopamine D4 agonists (Wang et al., 2005). The substitu-
tion at second position in benzoxazole skeleton is influ-
ential for the biological activity of the molecule. The
2-substituted bis(benzoxazole), UK-1 (A) is a natural
product (Fig. 1), and it showed that a wide spectrum of
potent anticancer activity against leukemia and lymphoma
(Ueki et al., 1993). The synthetic analogs of UK-1, i.e.,
2-(20-hydroxyphenyl)benzoxazole derivatives exhibited
cytotoxicity toward selective cancer cells (Kerwin and
Mckee, 2008). Chlorzoxazone (B) a muscle relaxant,
benoxaprofen (C), and flunoxaprofen (D) are anti-inflam-
matory drugs and these molecules contain benzoxazole
pharmacophore. The chemical structures of the drugs are
depicted in Fig. 1.
Keywords Benzoxazole ꢀ Cyclic amine ꢀ Alkylation ꢀ
Zinc ꢀ Anticancer ꢀ Cell lines
Introduction
The benzoxazolone heterocycles are considered as
‘‘privileged scaffolds’’ in the design of pharmacological
probes. The benzoxazolone heterocycles and its bioisos-
teric surrogates, such as 2(3H)-benzothiazolinone and
benzoxazinone have received considerable attention from
the medicinal chemists due to their capacity to mimic a
phenol or a catechol moiety in a metabolically stable
template (Poupaert et al., 2005). The benzoxazolone het-
erocycles have high flexibility for chemical modifications,
allowing changes to the characteristics of side-chains on a
rigid platform (Chiarotto et al., 2009). Due to its ability, the
therapeutic applications of the benzoxazolone template
have very broad applications. Thus, the benzoxazolone
heterocycles exhibits various biological activities like anti-
HIV (Deng et al., 2006), anticancer (Ivanova et al., 2007),
analgesic (Unlu et al., 2003), anti-inflammatory (Koksal
et al., 2005), antinociceptive (Onkol et al., 2001),
Benzoxazole derivatives are biologically significant com-
pounds and are known to exhibit various biological
M. S. R. Murty (&) ꢀ K. R. Ram ꢀ R. V. Rao ꢀ J. S. Yadav
Organic Chemistry Division-I, Discovery Laboratory,
Indian Institute of Chemical Technology, Uppal Road,
Hyderabad 500607, India
e-mail: msrmurty@ymail.com
J. V. Rao
Toxicology Unit, Biology Division, Indian Institute of Chemical
Technology, Uppal Road, Hyderabad 500607, India
V. T. Cheriyan ꢀ R. J. Anto
Integrated Cancer Research Program, Division of Cancer
Research, Rajiv Gandhi Centre for Biotechnology,
Thycaud 695014, India
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Med Chem Res (2011) 20:576–586
577
Fig. 1 Structures of
benzoxazole drugs and bio
molecules
COOCH3
HO
H
N
Cl
HO
HO
O
N
N
O
N
O
O
Cl
F
O
O
O
N
O
A
B
C
D
antimicrobial (Koksal et al., 2002), anticonvulsant (Ucar
et al., 1998), antimalarial (Courtois et al., 2004), PPARc
agonist (Blanc-Delmas et al., 2006), etc. The functionali-
zation of the nitrogen atom at the third position of the
benzoxazolone moiety is of interest since the electronic
characteristics of this atom can be decisive for the bio-
logical activity. Several nitrogen heterocycles containing
piperazine moiety have been described as potent chemo-
therapeutic agents. This cyclic amine moiety is also found
in drug candidates displaying antiallergic (John et al.,
1995), antibacterial (Michel et al., 1992), antianxiety,
antiemetic, antimigraine (Christine et al., 1996), and anti-
inflammatory (Dogruer et al., 1998; Gulcan et al., 2003)
activities.
synthesis and cytotoxic studies of the C-2 and N-3
substituted benzoxazole derivatives was under taken
employing simple and straightforward chemical transfor-
mations. The 2-cyclic amine-1,3-benzoxazoles 5a–k,
5-chloro-3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one
8
and 5-chloro-3-[3-(cyclic amine)propyl]-1,3-benzoxazol-
2(3H)-one 9a–f were synthesized. The newly synthesized
compounds were tested for their cytotoxicity toward
human cancer cells.
Chemistry
The facile and practical synthesis of compounds 5, 8, and 9
was achieved using commercially available chemicals with
simple chemistry. As a part of our on going research work
on the synthesis of bio molecules, we have developed
environmentally benign, economical and reusable catalysts
for alkylation (Murty et al., 2003) and sulfonylation (Murty
et al., 2006) of amines using zinc dust as the reaction
medium. In this study, we adapted the same methodology
for alkylation reactions and the details are illustrated as
follows. The 2-chlorobenzoxazole 3 was commercially
available chemical and otherwise prepared from 2-amino-
phenol 1. The 2-aminophenol was treated with carbon
disulfide (CS2) under basic conditions to obtain 2-mer-
capto-1,3-benzoxazole 2 which was then reacted with
phosphorus pentachloride (PCl5) to obtain 3 (Yamada
et al., 1998). The 2-chlorobenzoxazole (3) was treated with
various cyclic amines 4 in acetonitrile at 0°C to afford the
2-cyclic amine substituted benzoxazoles 5a–k as shown in
Scheme 1. No improvement in the yield as well as the
reaction time was observed, when the reaction was carried
Many of the major classes of drugs in current use owe
their overall therapeutic effectiveness, but lack of selec-
tivity for tumor cells over normal cells can lead to severe
side effects (Atkins and Gershell, 2002). Design and syn-
thesis of novel small molecules which can specifically
block some targets in tumor cells are in perspective
direction in modern medicinal chemistry. Therefore, there
is an urgent need to establish a process to assess anticancer
drug action, i.e., safety, efficacy, and mechanism of action.
Many synthetic heterocyclic small molecules with cyto-
toxic activity have been reported and several of them under
gone for the clinical trials (Lesyk et al., 2007).
Results and discussion
Since the benzoxazole skeleton which is responsible for
selective cytotoxicity of UK-1 (Kumar et al., 2002), the
Scheme 1 Reagents and
conditions: (i) CS2, KOH,
EtOH, Reflux; (ii) PCl5, Dry
Toluene; (iii) Acetonitrile,
0°C–room temperature
OH
O
N
O
N
(ii)
(i)
SH
Cl
NH2
1
2
3
O
N
(iii)
+
3
HN
X
N
X
4
5a-k
X = N-Me, N-Et, N-phenyl,N-pyridyl,N-pyrimidyl,N-benzyl, N-(3-chlorophenyl),
CH2 , O.
entry 10: 2-(3-methylpiperazin-1-yl)-1,3-benzoxazole
entry 11: 2-(1,4-Diazepan-1-yl)-1,3-benzoxazole
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Med Chem Res (2011) 20:576–586
out in the presence of zinc dust, and hence the usage of zinc
dust in this reaction is insignificant. The products and the
corresponding yields were listed in Table 1. The conden-
sation of 2-methylpiperazine with 2-chlorobenzoxazole
yielded only mono-substituted product 5j, i.e., the substi-
tution occurred at the less-hindered nitrogen. Similarly,
when one equivalent of homopiperazine was reacted with
2-chlorobenzoxazole, only mono substituted product 5k
was formed.
was retained in the IR spectrum of 8 (t C=O, 1774 cm-1). (2)
The 13C chemical shift value for the carbonyl carbon
(d = 152.6 ppm) of the 5-chorobenzoxazolone 6 was
retained in the 13C spectrum of 8 (d = 154.2 ppm). The
alkylation of 6 with 7 in the presence of zinc dust yielded the
product with less purity in low yield. Hence, the reaction was
carried out under conventional method using a base. Com-
pounds 9a–f were synthesized by means of the following two
methods as shown in the Scheme 2: (i) Compound 8 was
reacted with various cyclic amines 4 using K2CO3 in dry
DMF at 100°C to obtain different 9a–f (Saxena et al.,
2007). (ii) A simple and convenient new synthesis of
9a–f was carried out using zinc dust under neutral con-
ditions. Thus, the synthesis of 9a–f was illustrated by the
use of environmentally benign protocol that involves the
utilization of the recyclable metal, zinc dust as the reac-
tion medium that enables economical, efficient, and high
yield products. The products and the corresponding yields
of the two methods were presented in the Table 1. It was
also investigated for the possibility of zinc dust in
5-Chloro-3-(3-chloropropyl)-1,3-benzoxazol-2(3H)-one
8 and 5-chloro-3-[3-(cyclic amine)propyl]-1,3-benzoxazol-
2(3H)-one 9a–f were synthesized starting from commer-
cially available 5-chlorobenzoxazolone 6 as shown in the
Scheme 2.
5-Chlorobenzoxazolone 6, K2CO3, and 1-bromo-3-chlo-
ropropane 7 were reacted in acetonitrile at ambient temper-
ature to obtain the N-alkylated product 8 (Soyer et al., 2005)
as shown in the Scheme 2. The N-alkylation product 8 was
confirmed by the two observations: (1) The 5-chor-
obenzoxazolone carbonyl stretching (t C=O, 1771 cm-1
)
Table 1 Newly synthesized benzoxazoles 5a–k and benzoxazole-2(3H)-ones 8, 9a–f derivatives
Entry Productsa
Yield(%)b
Entry
Productsa
Yield(%)b
Method A
Method B
O
N
1
70
10
69
CH3
NH
N
N
O
N
N
N
5a
5j
O
N
2
65
75
11
12
74
65
O
N
N
N
N
N
NH
Cl
5b
5k
O
N
3
–
Ph
Cl
N
O
5c
O
8
O
N
4
80
13
67
82
N
N
N
N
Ph
5d
Cl
N
O
O
9a
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Med Chem Res (2011) 20:576–586
579
Table 1 continued
Entry Productsa
Yield(%)b
Entry
14
Productsa
Yield(%)b
Method A
Method B
81
O
N
5
78
72
Ph
N
N
N
5e
Cl
N
O
O
9b
O
N
6
68
15
75
87
O
N
O
N
5f
Cl
N
O
O
9c
7
78
16
77
89
N
O
N
N
N
N
N
N
5g
Cl
N
O
O
9d
8
N
N
85
17
73
84
O
N
N
N
N
N
N
N
5h
Cl
N
O
O
9e
9
82
18
78
89
Cl
Cl
O
N
N
N
N
N
5i
Cl
N
O
O
9f
a
1
All the products were characterized by H NMR, 13C NMR, mass and IR spectroscopy
b
Isolated and optimized yield
123

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Med Chem Res (2011) 20:576–586
Scheme 2 Reagents and
Cl
conditions : (i) K2CO3, CH3CN,
rt; (ii) K2CO3, KI, DMF, 100°C;
(iii) Zn, THF, Reflux
H
N
Cl
Cl
N
(i)
Cl
Br
+
O
O
O
O
7
6
8
X
(ii)
N
Method A
Cl
N
O
O
8
+
HN
X
(iii)
Method B
9a-f
4
X=N-benzyl, N-phenyl, O, N-Pyridyl, N-Pyrimidyl, N-3-chlorophenyl
cancer cells (A549) than cervical cancer (HeLa) and colon
cancer (SW-480) cells except the compound 5c (entry 3)
which showed maximum activity toward cervical cancer
cells (IC50-17.31 lM) followed by lung cancer cells
(IC50-32.35 lM), and is the most potent among the com-
pounds screened. It was very interesting to note that the
compound 5d (entry 4) showed almost equal % of inhibi-
tion to the growth of lung, breast, and colon cancer cells
(IC50-51–54 lM), while almost double the amount was
necessary to induce the same cytotoxic effect in cervical
(IC50-102.02 lM) cancer cells. Similarly, the compound 5b
(entry 2) induced almost equal cytotoxicity in breast
(IC50-54.55 lM) as well as lung (IC50- 52.51 lM) cancer
cells, while it did not show any effect in cervical or colon
cancer cells. The compounds 5g (entry 7) and 9f (entry 18)
were cytotoxic only to breast cancer cells (IC50-52–57 lM)
whereas the compound 5e (entry 5) induced cytotoxicity
only in lung cancer cells (IC50-52.51 lM), while they could
not induce cytotoxicity in any of the other cells studied.
Hence, our preliminary studies indicate that even though
both 5 and 9 series of the compounds showed that good to
moderate activity toward various cancer cells, the 5 series
compounds are comparatively more effective than 9 series.
The specificity of some of the compounds toward certain
types of cancers also looks interesting. However, further
studies are necessary to evaluate the signal transduction
pathways induced by these compounds.
Table 2 Recycle studies of zinc dust for compounds 9a and 9d
Number of uses
1
2
3
4
5
9a
9d
Yield (%)
Yield (%)
82
89
82
87
80
84
76
80
74
77
catalytical or less than stoichiometric quantities. However,
high yields of the products with high purity were obtained
with one equivalent of zinc dust. Reusability of zinc dust
was also studied for 9a and d and the results are illus-
trated in Table 2. The zinc dust was reactivated and used
in subsequent runs. It has shown nearly same activity
after each use. It was found that the new method is more
economic, safe, and efficient. The typical experimental
procedures for compounds 5a (Yoshida et al., 2007), 8
(Soyer et al., 2005), and 9a (Method A (Saxena et al.,
2007) and Method B) were described in the experimental
part. All the synthesized compounds were characterized
by IR, mass, NMR, and elemental analysis.
Antiproliferative activity
The synthesized compounds 5a–k, 8, and 9a–f were sub-
jected to cytotoxicity study using cancer cells of various
origins as several reports indicate that benzoxazole deriv-
atives show potent anti-cancer activity (Kumar et al., 2002;
Easmon et al., 2001; Jauhari et al., 2008; Rida et al., 2005).
The cytotoxicity studies of the compounds were deter-
mined against four human cancer cell lines using MTT
assay as described earlier (Smitha et al., 2005), and the
results were presented in the Fig. 2. Among the compounds
(n = 16) evaluated for their cytotoxic potential, about 9–10
entries showed dose-dependent inhibition of cancer cell
proliferation (IC50 values are of \100 lM) and the IC50
values for the compounds are given in Table 3. It is evident
from the results that these compounds are comparatively
more effective on human breast cancer (MCF-7) and lung
Experimental
General procedures
Melting points were determined on a Buchi capillary
melting point apparatus. The 1H NMR (200 and 300 MHz)
and 13C NMR (75 MHz) spectra was recorded on Varian
Gemini and Bruker Avance spectrometers using TMS as an
internal standard. The mass spectra were recorded on a VG
Auto Spec mass spectrometer. Elemental analyses were
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Med Chem Res (2011) 20:576–586
581
over Na2SO4. After concentration, the residue was purified
by flash chromatography to obtain the pure product, and
was crystallized from methanol.
White solid. m.p.: 36–38°C (reported m.p.: 37–38°C;
Yoshida et al., 2007); IR (KBr) m 3057 (=C–H), 2933, 2854
(–C–H), 1639, 1578 (–C=C), 1456 (–C–H ben), 1363 (–C–
1
N), 1285, 1002 (–C–O), 746 (=C–H ben) cm-1. H NMR
(200 MHz, CDCl3) d: 7.22 (t, 2H, J = 7.3 Hz); 7.09 (t, 1H,
J = 7.3 Hz); 6.95 (t, 1H, J = 7.3 Hz); 3.67 (t, 4H,
J = 5.1 Hz); 2.48 (t, 4H, J = 5.1 Hz); 2.30 (s, 3H). 13C
NMR (75 MHz, CDCl3) d: 162.0, 148.7, 142.8, 124.0,
120.8, 116.3, 108.7, 54.0, 45.9, 45.2. EI-MS (m/z): 217
(M?). Anal. calcd. for C12H15N3O (217): C, 66.34; H, 6.96;
N, 19.34. Found: C, 66.36; H, 6.94; N, 19.37.
2-(4-Ethylpiperazin-1-yl)-1,3-benzoxazole (5b) White solid.
m.p.: 78–80°C; IR (KBr) m 3052 (=C–H), 2970 (–C–H),
1638, 1578, 1525 (–C=C), 1459 (–C–H ben), 1399 (–C–N),
1243 (–C–O), 746 (=C–H ben) cm-1. 1H NMR (200 MHz,
CDCl3) d: 7.30 (d, 1H, J = 7.7 Hz); 7.20 (d, 1H,
J = 7.7 Hz); 7.11 (t, 1H, J = 7.7 Hz); 6.96 (t, 1H, J =
7.7 Hz); 3.70 (t, 4H, J = 4.9 Hz); 2.54 (t, 4H, J =
4.9 Hz); 2.45 (q, 2H, J = 7.2 Hz); 1.11 (t, 3H,
J = 7.2 Hz). 13C NMR (75 MHz, CDCl3) d: 162.0, 148.6,
142.9, 123.9, 120.6, 116.1, 108.6, 52.2, 51.9, 45.4, 11.7.
EI-MS (m/z): 231 (M?). Anal. calcd. for C13H17N3O (231):
C, 67.51; H, 7.41; N, 18.17. Found: C, 67.54; H, 7.39; N,
18.15.
2-(4-Benzylpiperazin-1-yl)-1,3-benzoxazole (5c) White
solid. m.p.: 230–231°C; IR (KBr) m 3028 (=C–H), 2917,
2860 (–C–H), 1640, 1578, 1494 (–C=C), 1455 (–C–H ben),
1395 (–C–N), 1245 (–C–O), 739 (=C–H ben) cm-1. NMR
(300 MHz, CDCl3) d: 7.34–7.25 (m, 6H); 7.19 (d, 1H,
J = 7. 8 Hz); 7.11 (t, 1H, J = 7. 8 Hz); 6.96 (t, 1H,
J = 7.8 Hz); 3.70 (t, 4H, J = 4.7 Hz); 3.54 (s, 2H); 2.56 (t,
4H, J = 4.7 Hz). 13C NMR (75 MHz, CDCl3) d: 162.1,
148.7, 143.0, 136.9, 129.2, 128.4, 127.4, 123.9, 120.6,
116.2, 108.7, 62.9, 52.1, 45.4. EI-MS (m/z): 293(M?).
Anal. calcd. for C18H19N3O (293): C, 73.70; H, 6.53; N,
14.32. Found: C, 73.74; H, 6.52; N, 14.33.
Fig. 2 The IC50 values of the compounds 5a–k, 8, and 9a–f
performed on Elemental VARIO EL elemental analyzer. IR
spectra were recorded on Perkin-Elmer Infrared-683.
Chemistry
2-(4-Phenylpiperazin-1-yl)-1,3-benzoxazole (5d) White
solid. m.p.: 147–148°C (reported m.p.: 150–151°C; Yam-
ada et al., 1998); IR (KBr) m 3045 (=C–H), 2980, 2914
(–C–H), 1629, 1575, 1497(–C=C), 1455 (–C–H ben), 1237
Typical procedure for the preparation
of 2-(4-methylpiperazin-1-yl)-1,3-benzoxazole
(Yoshida et al., 2007) (5a)
(–C–O), 735 (=C–H ben) cm-1 1H NMR (300 MHz,
.
CDCl3) d: 7.33 (d, 1H, J = 7.6 Hz); 7.26 (d, 1H,
J = 7.6 Hz); 7.23 (d, 2H, J = 6.8 Hz); 7.14 (t, 1H, J =
6.8 Hz); 6.99 (t, 1H, J = 7.6 Hz); 6.92 (d, 2H, J = 6.8 Hz);
6.88 (t, 1H, J = 7.6 Hz); 3.85 (t, 4H, J = 5.3 Hz); 3.29
(t, 4H, J = 5.3 Hz). 13C NMR (75 MHz, CDCl3) d: 161.8,
150.8, 148.6, 142.6, 129.2, 124.1, 120.9, 120.8, 116.9, 116.3,
The 2-chlorobenzoxazole (2.6 mmol, 400 mg) was added
to a solution of 1-methyl piperazine (2.6 mmol, 260 mg) in
dry acetonitrile (30 ml) at 0°C. The mixture was stirred at
0°C–room temperature for 30 min, quenched in ice water
(30 ml), extracted with ethyl acetate (3 9 20 ml) and dried
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Med Chem Res (2011) 20:576–586
Table 3 IC50 values on different cell lines for the compounds 5a–k, 8, and 9a–f
Compound
IC50 values (lM)
HeLa
MCF-7
A549
SW-480
Entry-2 (5b)
Entry-3 (5c)
Entry-4 (5d)
Entry-5 (5e)
Entry-6 (5f)
Entry-7 (5g)
Entry-8 (5h)
Entry-9 (5i)
Entry-11 (5k)
Entry-12 (8)
Entry-13 (9a)
Entry-14 (9b)
Entry-15 (9c)
Entry-16 (9d)
Entry-17 (9e)
Entry-18 (9f)
Curcumin
212.93 19.18
17.31 6.09
102.02 14.97
NA
54.55 3.65
46.21 4.83
52.21 5.99
72.54 5.99
77.36 6.0
52.21 4.82
84.52 3.66
132.49 12.0
241.44 14.48
279.91 23.83
NA
52.51 6.66
32.35 17.6
51.59 5.94
52.51 20.07
77.60 20.98
216.82 32.12
233.61 18.53
89.37 9.21
229.41 5.94
98.58 24.37
201.77 17.61
278.14 38.49
143.01 10.95
94.38 17.61
85.99 27.74
74.32 18.43
24.59 5.12
NA
214.68 21.65
54.11 8.31
NA
NA
226.67 16.67
NA
NA
NA
159.40 14.63
145.07 9.02
116.41 11.99
NA
NA
109.51 19.18
216.67 23.41
NA
248.32 16.67
NA
136.18 15.44
109.51 11.69
NA
281.07 10.82
NA
90.08 14.34
NA
144.48 8.34
87.01 12.50
57.37 19.16
21.39 4.99
216.67 23.4
109.51 11.7
17.31 3.7
NA
212.34 19.01
18.13 4.99
NA not active
108.8, 49.2, 45.5. EI-MS (m/z): 279 (M?). Anal. calcd. for
C17H17N3O (279): C, 73.10; H, 6.13; N, 15.04. Found: C,
73.08; H, 6.12; N, 15.05.
2-[4-(Pyridin-2-yl)piperazin-1-yl]-1,3-benzoxazole (5g) White
solid. m.p.: 186–188°C; IR (KBr) m 3053 (=C–H), 2993,
2917 (–C–H), 1635, 1576, 1480 (–C=C), 1459 (–C–H ben),
1
1435 (–C–N), 1242 (–C–O), 744 (=C–H ben) cm-1. H
NMR (200 MHz, CDCl3) d: 8.19–8.15 (m, 1H); 7.51–7.44
(m, 1H); 7.33 (d, 1H, J = 7.7 Hz); 7.23 (d, 1H, J =
7.7 Hz); 7.13 (dt, 1H, J = 6.6, 1.1 Hz); 6.99 (dt, 1H,
J = 6.6, 1.3 Hz); 6.68–6.61 (m, 2H); 3.88–3.77 (m, 4H);
3.74–3.67 (m, 4H). 13C NMR (75 MHz, CDCl3) d: 161.9,
158.2, 148.7, 146.8, 142.8, 138.4, 124.0, 120.9, 116.4,
113.8, 108.8, 107.8, 45.2, 44.9. EI-MS (m/z): 280 (M?).
Anal. calcd. for C16H16N4O (280): C, 68.55; H, 5.75; N,
19.99. Found: C, 68.59; H, 5.78; N, 19.96.
2-(Piperidin-1-yl)-1,3-benzoxazole (5e) Brown solid. m.p.:
71–72°C; IR (KBr) m 3057 (=C–H), 2936, 2854 (–C–H),
1638, 1577, 1525 (–C=C), 1455 (–C–H ben), 1394 (–C–N),
1221 (–C–O), 744 (=C–H ben) cm-1. 1H NMR (300 MHz,
CDCl3) d: 7.33 (d, 1H, J = 7.9 Hz); 7.23 (d, 1H, J =
7.9 Hz); 7.14 (t, 1H, J = 7.9 Hz); 6.99 (t, 1H, J =
7.9 Hz); 3.70 (s, 4H); 1.74 (s, 6H). 13C NMR (75 MHz,
CDCl3) d: 161.9, 148.4, 142.2, 124.1, 120.7, 115.8, 108.7,
46.8, 25.2, 23.9. EI-MS (m/z): 202 (M?). Anal. calcd. for
C12H14N2O (202): C, 71.26; H, 6.98; N, 13.85. Found: C,
71.29; H, 7.00; N, 13.82.
2-[4-(Pyrimidin-2-yl)piperazin-1-yl]-1,3-benzoxazole (5h)
White solid. m.p.: 183–185°C; IR (KBr) m 2911, 2860 (–C–H),
1651, 1581, 1490 (–C=C), 1451 (–C–H ben), 1393 (–C–N),
1
1251 (–C–O), 733 (=C–H ben) cm-1. H NMR (200 MHz,
CDCl3) d: 8.30 (d, 2H, J = 5.0 Hz); 7.33 (d, 1H, J = 7.6 Hz);
7.23 (d, 1H, J = 7.6 Hz); 7.13 (t, 1H, J = 7.6 Hz); 6.99 (t,
1H, J = 7.6 Hz); 6.51 (t, 1H, J = 5.0 Hz); 4.04–3.94 (m, 4H);
3.81–3.72 (m, 4H). 13C NMR (75 MHz, CDCl3) d: 166.6,
161.4, 157.8, 148.6, 144.4, 124.3, 121.1, 116.3, 110.6, 108.9,
45.5, 43.2. EI-MS (m/z): 281 (M?). Anal. calcd. for
C15H15N5O (281): C, 64.04; H, 5.37; N, 24.89. Found: C,
64.08; H, 5.41; N, 24.94.
2-(Morpholin-4-yl)-1,3-benzoxazole (5f) Brown solid.
m.p.: 205–206°C; IR (KBr) m 3057 (=C–H), 2966, 2863
(–C–H), 1637, 1578, 1525 (–C=C), 1454 (–C–H ben), 1398
1
(–C–N), 1242, 1105 (–C–O), 745 (=C–H ben) cm-1. H
NMR (200 MHz, CDCl3) d: 7.32 (d, 1H, J = 7.9 Hz); 7.21
(d, 1H, J = 7.9 Hz); 7.13 (t, 1H, J = 7.9 Hz); 6.98 (t, 1H,
J = 7.9 Hz); 3.77 (t, 4H, J = 4.5 Hz); 3.64 (t, 4H,
J = 4.5 Hz). 13C NMR (75 MHz, CDCl3) d: 161.2, 148.2,
141.1, 124.3, 121.3, 116.0, 108.9, 66.0, 45.8. EI-MS (m/z):
204 (M?). Anal. calcd. for C11H12N2O2 (204): C, 64.69; H,
5.92; N, 13.72. Found: C, 64.65; H, 5.94; N, 13.69.
2-[4-(3-Chlorophenyl)piperazin-1-yl]-1,3-benzoxazole
(5i) White solid. m.p.: 134–136°C; IR (KBr) m 3015
123

Med Chem Res (2011) 20:576–586
583
(=C–H), 2913 (–C–H), 1625, 1593, 1478 (–C=C), 1397
1
solid was filtered, washed with cold water, and crystallized
from ethanol to give the pure product.
(–C–N), 1253 (–C–O), 695 (=C–H ben) cm-1. H NMR
(200 MHz, CDCl3) d: 7.33 (d, 1H, J = 6.8 Hz); 7.23 (d, 1H,
J = 7.6 Hz); 7.17 (d, 1H, J = 7.6 Hz); 7.13 (t, 1H, J =
7.6 Hz); 7.00 (t, 1H, J = 7.6 Hz); 6.90 (t, 1H, J = 2.3 Hz);
6.85 (d, 1H, J = 7.6 Hz); 6.79 (d, 1H, J = 7.6 Hz); 3.84 (t,
4H, J = 5.3 Hz); 3.31 (t, 4H, J = 5.3 Hz,). 13C NMR
(75 MHz, CDCl3) d: 161.9, 151.9, 150.9, 142.8, 135.0, 130.1,
124.1, 120.9, 120.3, 116.6, 116.4, 114.7, 108.8, 48.6, 45.3. EI-
MS (m/z): 313 (M?). Anal. calcd. for C17H16ClN3O (313): C,
65.07; H, 5.14; N, 13.39. Found: C, 65.09; H, 5.14; N, 13.36.
White solid. m.p.: 82–84°C; IR (KBr) m 3063 (=C–H),
2933 (–C–H), 1774 (–C=O), 1611, 1485 (–C=C), 1369
(–C–N), 1247, 1061 (–C–O), 829, 721 (=C–H ben) cm-1
.
1H NMR (200 MHz, CDCl3) d: 7.17–7.03 (m, 3H); 3.99 (t,
2H, J = 7.0 Hz); 3.62 (t, 2H, J = 5.5 Hz); 2.28 (q, 2H,
J = 7.0 Hz). 13C NMR (75 MHz, CDCl3) d: 154.2, 141.1,
132.1, 129.5, 122.4, 109.9, 108.6, 41.6, 39.7, 30.3. EI-MS
(m/z): 246 (M?). Anal. calcd. for C10H9Cl2NO2 (246): C,
48.81; H, 3.69; N, 5.69. Found: C, 48.84; H, 3.71; N, 5.65.
2-(3-Methylpiperazin-1-yl)-1,3-benzoxazole (5j) Brown
solid. m.p.: 51–52°C; IR (KBr) m 3321 (–N–H), 3057 (=C–
H), 2958, 2856 (–C–H), 1638, 1578 (–C=C), 1458 (–C–H
ben), 1400 (–C–N), 1246 (–C–O), 805, 744 (=C–H ben)
Typical procedure for the preparation of the 5-chloro-3-[3-
(4-benzylpiperazin-1-yl)propyl]-1,3-benzoxazol-2(3H)-one
(9a)
cm-1
.
1H NMR (200 MHz, CDCl3) d: 7.30 (d, 1H,
Method A (Saxena et al., 2007) A mixture of N-ben-
zylpiperizine (2.0 mmol) and K2CO3 (3.0 mmol) in dry
DMF (5 ml) was stirred for 10 min under N2 atmosphere.
5-Chloro-3-(3-chloropropyl)-2,3-dihydro-1,3-benzoxazol-
2-one (8) (2.0 mmol) in dry DMF (2 ml)and catalytic KI
(0.1 mmol) were added to the above mixture, and was
heated at 100°C for 4 h. After the reaction completed
(TLC), the reaction mixture was cooled and then poured
into cold water. The separated solid was filtered, washed
with cold water, and crystallized from ethanol to give the
pure product.
J = 7.6 Hz); 7.19 (d, 1H, J = 7.6 Hz); 7.11 (t, 1H,
J = 7.6 Hz); 6.95 (t, 1H, J = 7.6 Hz); 4.11 (d, 2H,
J = 11.3 Hz); 3.07 (t, 2H, J = 9.0 Hz); 2.91 (t, 2H,
J = 9.0 Hz); 2.71 (t, 1H, J = 8.3 Hz); 1.80 (s, 1H); 1.11
(d, 3H, J = 8.3 Hz). 13C NMR (75 MHz, CDCl3) d: 161.5,
148.5, 142.8, 123.6, 120.3, 116.0, 108.3, 51.7, 50.0, 44.9,
44.5, 18.5. EI-MS (m/z): 217 (M?). Anal. calcd. for
C12H15N3O (217): C, 66.34; H, 6.96; N, 19.34. Found: C,
66.36; H, 6.99; N, 19.29.
2-(1,4-Diazepan-1-yl)-1,3-benzoxazole (5k) Brown solid.
m.p.: 195–198°C; IR (KBr) m 3399 (–N–H), 3050 (=C–H),
2934 (–C–H), 1639, 1578 (–C=C), 1459 (–C–H ben), 1402
Method B A mixture of N-benzylpiperizine (2.0 mmol)
and activated zinc dust (2.0 mmol) in dry tetrahydro furan
(THF) (5 ml) was stirred for 5 min under N2 atmosphere.
5-Chloro-3-(3-chloropropyl)-2,3-dihydro-1,3-benzoxazol-
2-one (8) (2.0 mmol) in dry THF (3 ml) and catalytic
amount of tetrabutyl ammonium iodide (TBAI) (0.2 mmol)
were added to the above mixture, and was refluxed for 3 h.
After the reaction was completed (TLC), ethyl acetate was
added to the reaction mixture, the zinc dust was filtered off,
washed with ethyl acetate. The combined organic layer was
washed with water, brine, and dried over Na2SO4. The
organic layer was concentrated and the residue was purified
by flash chromatography, and the product was crystallized
from ethanol to obtain the pure product.
1
(–C–N), 1244 (–C–O), 744 (=C–H ben) cm-1. H NMR
(200 MHz, CDCl3) d: 7.31 (d, 1H, J = 7.6 Hz); 7.23 (d,
1H, J = 7.6 Hz); 7.13 (t, 1H, J = 7. 6 Hz); 6.98 (t, 1H,
J = 7.6 Hz); 3.96 (s, 2H); 3.76 (t, 4H, J = 6.0 Hz); 3.07 (t,
1H, J = 5.2 Hz); 2.91 (t, 1H, J = 5.2 Hz); 2.27(q, 1H,
J = 6.0 Hz); 1.97 (q, 1H, J = 6.0 Hz). 13C NMR
(75 MHz, CDCl3) d: 161.6, 148.9, 143.1, 124.0, 120.6,
116.2, 108.7, 49.5, 49.1, 48.4, 47.4, 26.7. EI-MS (m/z): 217
(M?). Anal. calcd. for C12H15N3O (217): C, 66.34; H, 6.96;
N, 19.34. Found: C, 66.31; H, 6.97; N, 19.32.
Typical procedure for the preparation of the 5-chloro-3-
(3-chloropropyl)-1,3-benzoxazol-2(3H)-one (8) (Soyer et al.,
2005)
Brown solid. m.p.: 103–105°C; IR (KBr) m 2939
(–C–H), 1782 (–C=O), 1612, 1488 (–C=C), 1370 (–C–N),
1248, 1010 (–C–O), 804, 744 (=C–H ben) cm-1. 1H NMR
(300 MHz, CDCl3) d: 7.31–7.16 (m, 5H); 7.13 (d, 1H,
J = 2.3 Hz); 7.09–6.98 (m, 2H); 3.86 (t, 2H, J = 6.8 Hz);
3.49 (s, 2H); 2.55–2.29 (m, 10H); 1.91 (q, 2H, J =
6.8 Hz). 13C NMR (75 MHz, CDCl3) d: 154.4, 141.0,
137.9, 132.7, 129.2, 129.1, 128.2, 126.9, 121.9, 110.6,
109.2, 63.0, 54.5, 53.0, 40.3, 24.5. EI-MS (m/z): 386 (M?).
Anal. calcd. for C21H24ClN3O2 (386): C, 65.36; H, 6.27; N,
10.89. Found: C, 65.34; H, 6.28; N, 10.91.
A mixture of 5-chlorobenzoxazolone (3.0 mmol) and
K2CO3 (4.5 mmol) in dry acetonitrile (15 ml) was stirred
for 10 min under N2 atmosphere. 3-Chloro-1-bromopro-
pane (3.2 mmol) was added through syringe to the above
mixture and stirred for 8 h. After the reaction completed
(thin layer chromatography, TLC) cold water was added to
the reaction mixture and stirred for 30 min. The separated
123

584
Med Chem Res (2011) 20:576–586
5-Chloro-3-[3-(4-phenylpiperazin-1-yl)propyl]-1,3-ben-
zoxazol-2(3H)-one (9b) Brown solid. m.p.: 128–129°C;
IR (KBr) m 3056(=C–H), 2940 (–C–H), 1783 (–C=O),
1598, 1489 (–C=C), 1355 (–C–N), 1241, 1058 (–C–O),
calcd. for C18H20ClN5O2 (374): C, 57.83; H, 5.39; N,
18.73. Found: C, 57.80; H, 5.43; N, 18.76.
5-Chloro-3-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}-1,3-
benzoxazol-2(3H)-one (9f) Brown solid. m.p.: 138–140°C;
IR (KBr) m 2947, 2824 (–C–H), 1781 (–C=O), 1594, 1487
(–C=C), 1372 (–C–N), 1246, 1061 (–C–O), 770 (=C–H
1
834, 751 (=C–H ben) cm-1. H NMR (200 MHz, CDCl3)
d: 7.30–6.98 (m, 5H); 6.92–6.75 (m, 3H); 3.91 (t, 2H,
J = 6.3 Hz); 3.14 (t, 4H, J = 5.5 Hz); 2.52 (t, 4H,
J = 5.5 Hz); 2.42 (t, 2H, J = 6.3 Hz); 1.97 (q, 2H,
J = 6.3 Hz). 13C NMR (75 MHz, CDCl3) d: 154.3, 151.1,
141.0, 132.6, 129.1, 129.0, 122.0, 119.7, 116.7, 110.7,
109.1, 54.6, 52.0, 49.0, 40.3, 24.4. EI-MS (m/z): 372 (M?).
Anal. calcd. for C20H22ClN3O2 (372): C, 64.60; H, 5.96; N,
11.33. Found: C, 64.63; H, 5.92; N, 11.34.
1
ben) cm-1. H NMR (300 MHz, CDCl3) d: 7.17–7.01 (m,
4H); 6.86–6.68 (m, 3H); 3.91 (t, 2H, J = 6.2 Hz); 3.14 (t,
4H, J = 5.0 Hz); 2.50 (t, 4H, J = 4.9 Hz); 2.42 (t, 2H,
J = 6.4 Hz); 1.96 (q, 2H, J = 6.2 Hz). 13C NMR
(75 MHz, CDCl3) d: 152.2, 141.1, 135.0, 132.6, 130.0,
129.3, 122.1, 120.0, 119.3, 115.7, 113.8, 110.7, 109.0,
54.6, 52.9, 48.5, 40.3, 24.4. EI-MS (m/z): 406 (M?). Anal.
calcd. for C20H21Cl2N3O2 (406): C, 59.12; H, 5.21; N,
10.34. Found: C, 59.15; H, 5.22; N, 10.32.
5-Chloro-3-[3-(morpholin-4-yl)propyl]-1,3-benzoxazol-
2(3H)-one (9c) Brown solid. m.p.: 97–99°C; IR (KBr) m
2953, 2855 (–C–H), 1782 (–C=O), 1613, 1488 (–C=C),
1370 (–C–N), 1251, 1117 (–C–O), 805, 750 (=C–H ben)
Evaluation of cytotoxicity of the compounds toward
cancer cells
1
cm-1. H NMR (300 MHz, CDCl3) d: 7.13–7.01 (m, 3H);
3.89 (t, 2H, J = 6.4 Hz); 3.63 (t, 4H, J = 4.5 Hz);
2.40–2.29 (m, 6H); 1.93 (q, 2H, J = 6.4 Hz). 13C NMR
(75 MHz, CDCl3) d: 154.6, 153.1, 141.2, 129.4, 122.1,
110.8, 109.0, 66.9, 55.0, 53.4, 40.3, 24.0. EI-MS (m/z): 297
(M?). Anal. calcd. for C14H17ClN2O3 (297): C, 56.66; H,
5.77; N, 9.44. Found: C, 56.62; H, 5.78; N, 9.47.
Maintenance of the cells
The human cancer cells of various origin (HeLa: Cervix,
MCF-7: Breast, A549: Lung, SW 480: Colon) were pro-
cured from National Centre for Cell sciences, Pune and
maintained in DMEM containing 10% FBS with antibiotics
and antimycotics at 37°C in a CO2 incubator.
5-Chloro-3-{3-[4-(pyridin-2-yl)piperazin-1-yl]propyl}-1,3-
benzoxazol-2(3H)-one (9d) White solid. m.p.: 132–133°C;
IR (KBr) m 2944, 2826 (–C–H), 1780 (–C=O), 1594, 1487
(–C=C), 1370 (–C–N), 1250, 1060 (–C–O), 774 (=C–H ben)
MTT assay
cm-1 1H NMR (300 MHz, CDCl3) d: 8.12 (dd, 1H,
.
This assay helps to measure the toxicity induced by the
compounds on the cells. Active mitochondrial dehydro-
genases of living cells convert the water soluble yellow
tetrazolium salt to an insoluble purple formazan. This can
be solubilized by 20% SDS dissolved in 50% dimethyl
formamide and the intensity of color developed is an
indicator of percentage of viable cells present. The assay
was conducted as described earlier (Smitha et al., 2005).
Briefly, cells (5 9 103/well) were plated in 96-well
plates and kept overnight at 37°C. Next day, the cells were
incubated with and without various concentrations of the
compounds (5, 10, 25, and 50 lM). Curcumin was used as
the positive control. At the end of the incubation, medium
was removed and fresh medium containing 20% MTT
solution (5 mg/ml in PBS) was added to each well. After
2 h, 0.1 ml of the extraction buffer (20% SDS and 50%
DMF) was added, and the optical density was measured at
570 nm using a 96-well multiscanner auto reader after 4 h
and compared with that of the untreated control. The per-
centage of inhibition of cell viability was determined with
reference to the untreated control. The data were subjected
to linear regression analysis and the regression lines were
J = 3.8, 1.5 Hz); 7.41 (dt, 1H, J = 7.6, 1.5 Hz); 7.14 (d,
1H, J = 1.5 Hz); 7.11–7.00 (m, 2H); 6.58 (dt, 2H, J = 7.6,
2.3); 3.91 (t, 2H, J = 6.8 Hz); 3.49 (t, 4H, J = 5.3 Hz);
2.46 (t, 4H, J = 5.3 Hz); 2.40 (t, 2H, J = 6.0 Hz); 1.96 (q,
2H, J = 6.0 Hz). 13C NMR (75 MHz, CDCl3) d: 159.4,
154.5, 148.0, 140.7, 137.4, 132.8, 129.2, 122.0, 113.3, 110.5,
108.9, 107.0, 54.8, 53.0, 44.9, 40.2, 24.6. EI-MS (m/z): 373
(M?). Anal. calcd. for C19H21ClN4O2 (373): C, 61.21; H,
5.68; N, 15.03. Found: C, 61.23; H, 5.65; N, 15.01.
5-Chloro-3-{3-[4-(pyrimidin-2-yl)piperazin-1-yl]propyl}-1,3-
benzoxazol-2(3H)-one (9e) White solid. m.p.: 125–126°C;
IR (KBr) m 2927, 2853 (–C–H), 1781 (–C=O), 1585,
1488 (–C=C), 1362 (–C–N), 1252, 1061 (–C–O), 801, 750
(=C–H ben) cm-1. 1H NMR (500 MHz, CDCl3) d: 8.24 (d,
2H, J = 4.9 Hz); 7.14 (d, 1H, J = 2.0 Hz); 7.11–7.03 (m,
2H); 6.43 (t, 1H, J = 4.9 Hz); 3.93 (t, 2H, J = 6.8 Hz);
3.78 (t, 4H, J = 4.9 Hz); 2.45–2.38 (m, 6H); 1.98 (q, 2H,
J = 6.8 Hz). 13C NMR (75 MHz, CDCl3) d: 161.6, 157.4,
154.8, 150.8, 132.9, 129.4, 122.1, 110.7, 109.8, 109.1,
54.8, 53.0, 43.4, 40.3, 24.3. EI-MS (m/z): 374 (M?). Anal.
123

Med Chem Res (2011) 20:576–586
585
Dogruer DS, Unlu S, Sahin MF, Yqilada E (1998) Anti-nociceptive
and anti-inflammatory activity of some (2-benzoxazolone-3-yl
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plotted for the best straight-line fit. The IC50 concentrations
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Conclusions
In conclusion, various 5a–k, 8, and 9a–f derivatives were
synthesized using simple chemical transformations and
commercially available chemicals. The N-alkylation of 6
with 7 was occurred under conventional basic conditions
and the same reaction was not facile in the presence of zinc
dust. The alkylation of 8 on cyclic amines 4 was achieved
using zinc dust under neutral conditions. The zinc–THF
combination provided an efficient and convenient method
for the N-alkylation of cyclic amines 4. This method offers
advantages like good yields and cleaner products. The
benefits of this method are the easy handling, commercially
availability, inexpensiveness, and reusability of the reagent
zinc dust. The antiproliferative activity studies of the newly
synthesized compounds were examined and majority of the
compounds from the two series were found to exhibit good
to moderate activity. This study provides a good starting
point to develop unsymmetrical benzoxazoles as novel
anticancer agents. Further lead optimization is ongoing.
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