Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines

Article abstract of DOI:10.1016/j.bmcl.2008.07.029

A series of potential biologically active 2-aryloxy methyl oxazolines 3a-n have been synthesized from substituted hydroxybenzenes 1a-n with good chemical yield. The compounds 3a-n were screened for their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone. The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-inflammatory activity with low ulcerogenic activity than the standard drugs.

Full text of DOI:10.1016/j.bmcl.2008.07.029

Bioorganic & Medicinal Chemistry Letters 18 (2008) 4597–4601
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and anti-inflammatory activity of 2-aryloxy methyl oxazolines
b
c
Shaukath Ara Khanum a, , Noor Fatima Khanum , M. Shashikanth
*
a Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore, Karnataka 570 005, India
b Department of Food Science and Nutrition, Maharani’s Science College for Women, Mysore, Karnataka 570 005, India
c Department of Chemistry, Bharathi College, Bharthinagar, Mandya, 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 potential biologically active 2-aryloxy methyl oxazolines 3a–n have been synthesized from
substituted hydroxybenzenes 1a–n with good chemical yield. The compounds 3a–n were screened for
their anti-inflammatory, ulcerogenic, cyclooxygenase activities and also for their acute toxicity. The
potency of the compounds was compared with that of the standard drugs, aspirin and phenyl butazone.
The outcome indicates that compounds 3b (48.2%), 3h (48.5%) and 3l (46.5%) offered significant anti-
inflammatory activity with low ulcerogenic activity than the standard drugs.
Received 20 December 2007
Revised 15 June 2008
Accepted 10 July 2008
Available online 15 July 2008
Keywords:
Oxazolines
Ó 2008 Elsevier Ltd. All rights reserved.
Anti-inflammatory
Ulcerogenic
Cyclooxygenase
Acute toxicity
Today design and study of new molecules potentially useful in
the control of pain and particularly in the management of oncolog-
ical pain is very important target. It is well known that the mech-
anism of pain transmission is very complex and involves numerous
neuromodulators of pain response.1 Inflammatory responses are
considered to be mediated in part by the prostaglandins (PGs) de-
rived from arachidonic acid by the action of prostaglandin H syn-
thase, which is also referred as cyclooxygenase (COX).2,3 Recent
studies have shown that COX exists in two isoforms COX-1 and
COX-2. Both COX are constitutively expressed in most tissues,
but COX-2, in contrast to COX-1, is the mitogen inducible isoform.
The inducing stimuli for COX-2 include pro-inflammatory cyto-
kines and growth factors, implying a role for COX-2 in both inflam-
mation and control of cell growth.4–6 COX isoforms are almost
identical in structure but have important differences in substrate
and inhibitor selectivity and in their intracellular locations.7 Non-
steroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents
useful in the treatment of inflammation, pain and pyresis although
they exhibit an undesirable gastrotoxicity profile.8,9
mer units, these compounds fulfil fundamental requirements for
an application as carrier molecules in radionuclide therapy.16 Re-
cent studies have shown that highly active sugar oxazolines act
as donor substrates for transglycosylation and exhibit potent
anti-HIV activity.17 Oxazoline analogues have been shown to in-
duce cell growth inhibition, apoptosis, and microtubule disruption
without alkylating beta-tubulin.18 And polyoxazoline-based poly-
mers have shown biological and biomedical application contexts
which include nanoscalar systems such as membranes and nano-
particles, drug and gene delivery applications, as well as stimuli-
responsive systems.19 In addition to pharmaceutical uses it also
possesses synthetic uses, for example it can catalyze the copper-
catalyzed addition of indoles to benzylidene malonates up to
99%.20 Nevertheless, substituted 2-oxazolines are found in several
families of bioactive natural products and can be prepared in an
efficient and general one-pot condensation.21 For instance, new
methodology for the synthesis of various substituted 2-oxazolines
using aldehydes, amino alcohols, and N-bromosuccinimide as an
oxidizing agent is reported.22 Phenoxy acetic acid analogues, pre-
cursor of title compounds also exhibit anti-inflammatory activ-
ity.23 Kunsch et al.24 have investigated anti-inflammatory and
anti-rheumatic activity of phenoxy acetic acid analogues and pro-
vided further support of inhibition of redox-sensitive inflammatory
gene expression which is an attractive approach for the treatment
of chronic inflammatory diseases,
Oxazolines10,11 are known as important heterocyclic com-
pounds and have been investigated widely for pharmaceutical
uses.12 The efficiency of oxazoline analogues as chemotherapeutic
agent especially as analgesic13 and anti-inflammatory14,15 agent is
well documented. Besides, additional functionalities for targeting
can readily be introduced into 2-oxazolines via functional mono-
In continuation of our25 ongoing program to develop environ-
mentally benign microwave irradiation in chemical reaction
enhancement and the initial reports on microwave irradiation26
* Corresponding author. Tel.: +91 9901888755.
E-mail address: shaukathara@yahoo.co.in (S.A. Khanum).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.029

4598
S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4597–4601
has inspired us to synthesize some newer oxazoline analogues
using microwave technique since these systems possess well doc-
umented anti-inflammatory activity.
except control group. All animals were sacrificed 5 h after the com-
pletion of dosing. With the aid of a microscope the stomach and
small intestine of the rats were examined to find incidence of
hyperemia, shedding of epithelium, petechial, frank hemorrhages
and erosion or discrete ulceration with or without perforation.
The presence of any of these criteria was considered to be an evi-
dence of ulcerogenic activity.30
Acute toxicity study. ALD50 of the compounds was determined in
albino rats (body weight 200–230 g). The test compounds were in-
jected intra peritoneally at different dose levels in groups of 10 ani-
mals. After 24 h of drug administration, percent mortality in each
group was observed from the data obtained ALD50 was calculated
by adopting previous method.31
The synthetic sequence is outlined in Scheme 1. A mixture of
1a–n, chloro acetic acid in acetone and anhydrous potassium car-
bonate was refluxed for 8 h, cooled, and the solvent was removed
under reduced pressure. The residual mass was triturated with
ice water to remove potassium carbonate, extracted with ether
and the ether layer was washed with 10% sodium hydroxide solu-
tion followed by distilled water. The ether layer was dried over
anhydrous sodium sulfate and evaporated to dryness to get crude
solid, which on recrystallization with ethanol gave pure substi-
tuted aryloxy ethanoic acids (2a–n).
A mixture of 2a–n and ethanolamine was subjected to micro-
wave irradiation operating at its 20% power for 5–10 min. The
reaction mixture was extracted into ether, washed with distilled
water and dried over anhydrous sodium sulfate. After evaporation
of ether layer, the crude solid was recrystallized with ethanol to af-
ford, 2-aryloxy methyl oxazolines (3a–n). The compounds 2a–n27
and 3a–n28 were characterized by IR, 1H NMR and mass
spectrophotometer.
All the animal experiments with Albino rats were carried out at
Farooqia College of Pharmacy, Mysore, and permission for conduct-
ing these animal experiments was obtained from institutional
Animals Ethics Committee (1848/06–07).
Cyclooxygenase activity. The in vitro test on microsomal fraction
of mucosal preparation of rabbit distal colon was carried out in or-
der to search out the plausible mechanism of the compounds. By
adopting previous procedure32 the preparation was carried out.
About 2–3 g of stripped, colonic mucosa was minced and homoge-
nized in 3 volumes of tris buffer 0.1 M, pH 8.0, and the homoge-
nized was centrifuged. The precipitate was suspended in tris
buffer 0.1 M, pH 8.0, and recentrifuged. For enzyme assay cycloox-
ygenase activity, the microsomal pellet was used immediately. By
measuring the rate of conversion of arachidonic acid to PGE2,
cyclooxygenase activity was assayed. About 50 ml of microsomal
fractions was incubated with test agents for 10 min at 37 °C in
Anti-inflammatory activity. Anti-inflammatory activity was per-
formed by paw oedema inhibition test adopting Winter et al.,
method.29 Groups of five rats (body weight 200–230 g) were given
a dose of a test compound. After 30 min, 0.2 ml of 1% carrageenan
suspension in 0.9% sodium chloride solution was injected subcuta-
neously, into planter aponeurosis of the hind paw and the paw vol-
ume was measured by a water plethysmometer socrel and then
measured again after a time span of 3 h. The mean increase of
paw volume at each time interval was compared with that of con-
trol group (five rats treated with carrageenan, but not with test
compounds) at the same time intervals. The percentage inhibition
values were calculated using the formula:
% inhibition = (1 À vt/vc) Â 100, where vt and vc are the mean
relative changes in the volume of paw oedema in the test com-
pounds and control, respectively.
Ulcerogenic activity. Groups of 10 rats (body weight 200–230 g),
fasted for 24 h were treated with an oral dose of test compounds,
30
5 mM
l
l Tris–HCl, pH 8.0, containing 2 mM reduced glutathione,
L
-tryptophan, 1 M hematin. The substrate 20 M arachi-
l
l
donic acid with tracer amount of [1-14C] arachidonic acid was then
added and the reaction proceeded for 5 min at 37 °C. The reaction
was stopped by addition of 0.2 ml of ether/methanol/citric acid
0.2 M (30:4:1 v/v), which was precooled at À25 °C PGE2, was ex-
tracted twice into the same mixture. The solvent was removed un-
der nitrogen stream and radiolabelled arachidonic acid was
separated and from this radiolabelled PGE3 was separated by HPLC
with 2 nmol unlabelled PGE2as an interval standard. PG chromato-
graphic profile was obtained by isocratic elution with 150 mM
orthophosphoric acid in water, pH 3.5, containing 30% acetonitrile,
a flow rate of 1 ml/min monitoring the UV absorption at 214 nm.
Radioactivity that co-eluted with authentic PGE2 was quantified
by liquid scintillation spectrometry. Test samples were compared
to paired control incubations. The percentage of inhibition was cal-
culated as follows.
5
2
4
N
O
1
3
OCH2COOH
OH
R1
R1
O
HO(CH2)2NH
R1
R2
.ClCH2COOH
K2CO3/Acetone
Micro wave
R2
R2
R3
R3
R3
1a-n
2a-n
3a-n
a: R1=R2=H, R3=OCH3
c: R1=Br, R2=R3=H
e: R1=Cl, R2=R3=H
g: R1=R3=H, R2=CH3
i: R1=R2=H, R3=F
b: R1=R2=H, R3=Cl
d: R1= CH3, R2=R3=H
f:: R1=H, R2=CH3, R3=Cl
h: R1=R2=H, R3=Br
j: R1=NO2, R2= R3=H
l: R1=R3=CH3, R3=H
n: R1=R3=H, R2=NO2
k: R1=R2=H, R3=NO2
m: R1=F, R2=R3=H
Scheme 1.

S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4597–4601
4599
cpm control À cpm test=cpm control  100
ortho and para position in phenoxy moiety have exhibited nearest
anti-inflammatory activity. Compounds 3i with a fluoro group at
para position, 3k with a nitro group at para position, 3m a fluoro
group at ortho position, 3a with a methoxy group at para position
and 3j, with a nitro group at ortho position, in phenoxy moiety has
elicited oedema inhibition in the range 30.2–35.5%. The remaining
compounds 3c with a bromo group at ortho position, 3n a nitro
group at meta position and 3d, with a methyl group at ortho posi-
tion in phenoxy moiety have exhibited oedema inhibition in the
range 29.1–29.5%.
The characteristic feature of the title compounds is the presence of
oxazoline ring. All the compounds 3a–n have shown good anti-
inflammatory activity in the range 22.2–48.5% at a dose of 40 mg/
kg po.
Among 3a–n, the compound 3h with a bromo group at para po-
sition in phenoxy moiety elicited maximum inhibition of oedema
(48.5%), whereas compound 3e with a chloro group at ortho posi-
tion in phenoxy moiety elicited minimum inhibition of oedema
(22.2%). Compound 3b with chloro group at para position in phen-
oxy moiety has shown second highest anti-inflammatory activity
(48.2%). Besides compounds 3g (44.6%) with a methyl group at
meta position, 3f (45.4%) with a methyl group at meta and a chloro
group at para position and 3l (46.5%), with two methyl group at
Compounds 3h, 3b and 3l were studied in detail at three graded
doses and have shown dose dependent activity. Anti-inflammatory
activity of compounds 3a–n and their comparison with standard
drugs, aspirin and phenylbutazone are given in Table 1.
Table 1
Antiinflammatroy, ulcerogenic, cyclooxygenase and toxicity data of compounds 3a–n
Compound
Dose
(mg/kg po)
Anti-inflammatory
activity % oedema
inhibition relative
to control
Dose
(mg/kg po)
Ulcerogenic
Activity
Cyclooxygenase activity
assay inhibitory action
of some selected compound %
ED50
(mg/kg
po)
ALD50
(mg/kg
po)
% of animal
with hyperemia
% of anima
with ulcer
inhibition 10
lM
3a
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
20
40
80
16.6
33.2
64.1
30.3
48.2
94.1
20.1
29.1
62.8
3.1
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
100
200
400
30
50
70
90
30
60
90
70
90
100
40
60
100
20
40
60
50
70
100
50
70
90
60
80
100
25
40
50
30
55
90
50
70
100
25
50
75
40
60
80
20
35
55
30
60
90
30
60
90
—
05
10
15
10
20
12
10
20
40
10
20
40
40
30
80
20
30
40
15
20
25
05
10
15
50
25
75
20
25
45
10
15
20
15
25
18
10
15
20
45
30
80
80
90
90
30
60
90
—
70
77.2
51.2
62.5
78.3
77.5
60.2
76.2
65.5
75.5
70.1
60.5
57.3
76.2
75.5
98.3
—
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
—
3b
ni
3c
40
20
ni
3d
29.5
55.3
13.7
22.2
45.5
22.2
45.4
77.1
16.6
44.6
64.1
35.5
48.5
60.1
18.5
30.2
40.5
20.5
35.5
50.5
29.2
30.4
77.1
31.4
46.5
85.5
20.6
30.5
60.1
15.5
29.4
46.5
30.4
35.5
59.6
31.3
35.5
57.2
—
3e
3f
87
70
60
ni
3g
3h
3i
3j
30
85
ni
3k
3l
3m
65
ni
3n
Aspirin
65
60
ni
Phenyl butazone
Control
—
—
—
60
90
nia, no inhibition.

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S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4597–4601
(s, 1H, COOH, D2O exchangeable); EI–MS: m/z 186.5 (M+, 60), 142.5 (100),
Ulcerogenic activity. Compounds 3a–n exhibited low ulcer pro-
127.5 (71), 111.5 (18). Anal. Calcd for C8H7ClO3 (186.5): C, 51.50; H, 3.78; Cl,
19.00. Found: C, 51.33; H, 3.61; Cl, 19.15%. 2c: Mp 147–149 °C; IR (Nujol): 1735
(acid C@O), 3410–3510 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.45 (s, 2H, OCH2),
7.1–7.6 (m, 4H, Ar–H), 9.4 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 231
(M+, 58), 233 (M+, 53), 187 (100), 189 (98), 172 (68), 174, (66), 156 (20), 158
(18). Anal. Calcd for C8H7BrO3 (231): C, 41.59; H, 3.05; Br, 34.58. Found: C,
41.51; H, 3.17; Br, 34.50%. 2d: Mp 155–157 °C; IR (Nujol): 1733 (acid C@O),
3450–3540 cmÀ1 (acid OH); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 4.44 (s, 2H,
OCH2), 6.9–7.55 (m, 4H, Ar–H), 9.2 (s, 1H, COOH, D2O exchangeable); EI–MS:
m/z 166 (M+, 58), 122 (100), 107 (69), 91 (16). Anal. Calcd for C9H10O3 (166): C,
65.05; H, 6.07. Found: C, 65.15; H, 6.16%. 2e: Mp 151–153 °C; IR (Nujol): 1735
(acid C@O), 3410–3510 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.42 (s, 2H, OCH2),
6.8–7.6 (m, 4H, Ar–H), 9.3 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 186.5
(M+, 59), 142.5 (100), 127.5 (70), 111.5 (17). Anal. Calcd for C8H7ClO3 (186.5):
C, 51.50; H, 3.78; Cl, 19.00. Found: C, 51.58; H, 3.58; Cl, 19.18%. 2f: Mp 158–
160 °C; IR (Nujol): 1750 (acid C@O), 3430–3510 cmÀ1 (acid OH); 1H NMR
(CDCl3): d 2.5 (s, 3H, CH3), 4.21 (s, 2H, OCH2), 6.8–7.5 (m, 3H, Ar–H), 9.1 (s, 1H,
COOH, D2O exchangeable); EI–MS: m/z 200.5 (M+, 59), 141.5 (100), 156.5 (68),
125.5 (15). Anal. Calcd for C9H9ClO3 (200.5): C, 53.88; H, 4.52; Cl, 17.67. Found:
C, 53.72; H, 4.42; Cl, 17.53%. 2g: Mp 135–137 °C; IR (Nujol): 1715 (acid C@O),
3420–3530 cmÀ1 (acid OH); 1H NMR (CDCl3): d 2.25 (s, 3H, CH3), 4.35 (s, 2H,
OCH2), 6.95–7.6 (m, 4H, Ar–H), 9.3 (s, 1H, COOH, D2O exchangeable); EI–MS:
m/z 166 (M+, 59), 122 (100), 107 (69), 91 (17). Anal. Calcd for C9H10O3 (166): C,
65.05; H, 6.07. Found: C, 65.20; H, 6.25%. 2h: Mp 141–143 °C; IR (Nujol): 1740
(acid C@O), 3420–3520 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.3 (s, 2H, OCH2),
6.7–6.9–7.3 (m, 4H, Ar–H), 9.5 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z
231 (M+, 57), 233 (M+, 52), 187 (100), 189 (98), 172 (67), 174, (66), 156 (19),
158 (18). Anal. Calcd for C8H7BrO3 (231): C, 41.59; H, 3.05; Br, 34.58. Found: C,
41.14; H, 3.15; Br, 34.49%. 2i: Mp 150–152 °C; IR (Nujol): 1755 (acid C@O),
3450–3540 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.21 (s, 2H, OCH2), 6.9 (m, 4H,
Ar–H), 9.35 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 170 (M+, 60), 126
(100), 111 (67), 98 (19). Anal. Calcd for C8H7FO3 (170): C, 56.14; H, 4.15; F,
11.17. Found: C, 56.32; H, 4.22; F, 11.23%. 2j: Mp 125–127 °C; IR (Nujol): 1725
(acid C@O), 3435–3565 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.15 (s, 2H, OCH2),
6.9–7.5 (m, 4H, Ar–H), 9.35 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 197
(M+, 57), 153 (100), 138 (65), 122 (14). Anal. Calcd for C8H7NO5 (197): C, 14.74;
H, 3.58; N, 7.10. Found: C, 14.65; H, 3.45; N, 7.22%. 2k: Mp 149–151 °C; IR
(Nujol): 1745 (acid C@O), 3465–3560 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.2 (s,
2H, OCH2), 6.8–7.2 (m, 4H, Ar–H),, 9.4 (s, 1H, COOH, D2O exchangeable); EI–
MS: m/z 197 (M+, 58), 153 (100), 138 (66), 122 (15). Anal. Calcd for C8H7NO5
(197): C, 14.74; H, 3.58; N, 7.10. Found: C, 14.55; H, 3.42; N, 7.25%. 2l: Mp 163–
165 °C; IR (Nujol): 1743 (acid C@O), 3465–3550 cmÀ1 (acid OH); 1H NMR
(CDCl3): d 2.2 (s, 6H, 2CH3), 4.1 (s, 2H, OCH2), 6.9–7.6 (m, 3H, Ar–H), 9.25 (s, 1H,
COOH, D2O exchangeable); EI–MS: m/z 180 (M+, 59), 136 (100), 120 (68), 105
(17). Anal. Calcd for C10H12O3 (180): C, 66.65; H, 6.71. Found: C, 66.73; H,
6.79%. 2m: Mp 129–131 °C; IR (Nujol): 1725 (acid C@O), 3450–3545 cmÀ1
(acid OH); 1H NMR (CDCl3): d 4.2 (s, 2H, OCH2), 6.8–7.4 (m, 4H, Ar–H), 9.35 (s,
1H, COOH, D2O exchangeable); EI–MS: m/z 170 (M+, 60), 126 (100), 111 (68),
98 (18). Anal. Calcd for C8H7FO3 (170): C, 56.14; H, 4.15; F, 11.17. Found: C,
56.37; H, 4.25; F, 11.25%. 2n: Mp 168–170 °C; IR (Nujol): 1750 (acid C@O),
3465–3565 cmÀ1 (acid OH); 1H NMR (CDCl3): d 4.32 (s, 2H, OCH2), 6.9–7.55 (m,
4H, Ar–H), 9.42 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 197 (M+, 56), 153
(100), 138 (63), 122 (13). Anal. Calcd for C8H7NO5 (197): C, 14.74; H, 3.58; N,
7.10. Found: C, 14.61; H, 3.47; N, 7.25%.
duction activity compared to standard drug, aspirin and phenylbu-
tazone (10–30%) at 200 mg/kg po. Compounds 3a and 3h with a
methoxy and a bromo group, respectively, at para position in phen-
oxy moiety have shown low ulcer production activity at 200 mg/kg
po. Compounds 3e with ortho chloro group, 3f with meta methyl
and para chloro groups and 3n with meta nitro group in phenoxy
moiety elicited maximum ulcer production activity.
Cyclooxygenase activity. Compounds 3a, 3c, 3d, 3f, 3g, 3h, 3j, 3k
and 3m showed good cyclooxygenase activity indicating that these
compounds reduce inflammatory response by inhibition of Prosta-
glandins. The other compounds which did not inhibit the cycloox-
ygenase activity, therefore, seems to act through some other
mechanism rather than inhibiting prostaglandin synthesis.
ALD50 studies. The toxicity study of these compounds indicates
their good safety margin.
From the result of pharmacological activity, we can conclude
that integration of oxazoline ring into the phenoxy moiety is fruit-
ful as the compounds 3h and 3b were found to show potent anti-
inflammatory activity. In addition compound 3h also show de-
creased ulcer production activity. Compounds 3b, 3e, 3i, 3l and
3n were found to have no suppressive effect on cyclooxygenase,
which is the prime mechanism of anti-inflammatory activity.
Acknowledgement
The authors express their sincere gratitude to the University of
Mysore, Mysore for providing laboratory facilities.
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8. Palomer, A.; Perez, J. J.; Navea, S.; Llorens, O.; Pascual, J.; Garcia, M. L.; Mauleon,
D. M. J. Med. Chem. 2000, 43, 2280.
9. Palomer, A.; Pascual, J.; Cabre, M.; Borras, L.; Gonzalez, G.; Aparici, M.;
Carabaza, A.; Cabre, F.; Garcia, M. L.; Mauleon, D. Bioorg. Med. Chem. Lett. 2002,
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28. 3a: Mp 120–122 °C; IR (Nujol): 1670 cmÀ1 (C@N); 1H NMR (CDCl3): d 3.4 (t,
J = 7 Hz, 2H, NCH2), 3.78 (s, 3H, OCH3), 4.35 (t, J = 7 Hz, 2H, OCH2), 4.68 (s, 2H,
OCH2), 6.78–7.4 (m, 4H, Ar–H); EI–MS: m/z 207 (M+, 72), 179 (52), 163 (35),
123 (100), 107 (25). Anal. Calcd for C11H13NO3 (207): C, 63.76; H, 6.32; N, 6.76.
Found C, 63.61; H, 6.22; N, 6.64%. 3b: Mp 130–132 °C; IR (Nujol): 1680 cmÀ1
(C@N); 1H NMR (CDCl3): d 3.45 (t, J = 7 Hz, 2H, NCH2), 4.41 (t, J = 7 Hz, 2H,
OCH2), 4.7 (s, 2H, OCH2), 6.9–7.4 (m, 4H, Ar–H); EI–MS: m/z 211.5 (M+, 71),
183.5 (52), 167.5 (34), 127.5 (100), 111.5 (24). Anal. Calcd for C10H10ClNO2
(211.5): C, 56.75; H, 4.76; Cl, 16.75; N, 6.62. Found: C, 56.81; H, 4.81; Cl, 16.85;
N, 6.71%. 3c: Mp 98–100 °C; IR (Nujol): 1690 cmÀ1 (C@N); 1H NMR (CDCl3): d
3.5 (t, J = 7 Hz, 2H, NCH2), 4.45 (t, J = 7 Hz, 2H, OCH2), 4.72 (s, 2H, OCH2), 6.9–
7.5 (m, 7H, Ar–H); EI–MS: m/z 256 (M+, 70), 258 (M+, 68), 345 (55), 228 (52),
230 (50), 212 (34), 214 (32), 172 (100), 174 (97), 156 (26), 158 (25). Anal. Calcd
for C10H10BrNO2 (256): C, 46.90; H, 3.94; Br, 31.20; N, 5.47. Found: C, 46.83; H,
11. Gant, T. G.; Mayers, A. I. Tetrahedron 1994, 50, 2297.
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20. Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Org. Lett. 2006, 8, 6099.
21. Fan, L.; Lobkovsky, E.; Ganem, B. Org. Lett. 2007, 9, 2015.
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24. Kunsch, C.; Luchoomun, J.; Chen, X. L.; Dodd, G. L.; Karu, K. S.; Meng, C. Q.;
Marino, E. M.; Olliff, L. K.; Piper, J. D.; Qiu, F. H.; Sikorski, J. A.; Somers, P. K.;
Suen, K. L.; Thomas, S.; Whalen, A. M.; Wasserman, M. A.; Sundell, C. L. J.
Pharmacol. Exp. Ther. 2005, 313, 492.
3.81; Br, 31.11; N, 5.39%. 3d: Mp 104–106 °C; IR (Nujol): 1675 cmÀ1 (C@N); 1
H
NMR (CDCl3): d 2.23 (s, 3H, CH3), 3.4 (t, J = 7 Hz, 2H, NCH2), 4.4 (t, J = 7 Hz, 2H,
OCH2), 4.65 (s, 2H, OCH2), 6.8–7.5 (m, 4H, Ar–H); EI–MS: m/z 191 (M+, 70), 163
(52), 147 (36), 107 (100), 91 (27). Anal. Calcd for C11H13NO2 (191): C, 69.09; H,
6.85; N, 7.32. Found: C, 69.15; H, 6.93; N, 7.41%. 3e: Mp 134–136 °C; IR (Nujol):
1680 cmÀ1 (C@N); 1H NMR (CDCl3): d 3.45 (t, J = 7 Hz, 2H, NCH2), 4.41 (t,
J = 7 Hz, 2H, OCH2), 4.7 (s, 2H, OCH2), 6.9–7.5 (m, 4H, Ar–H), EI–MS: m/z 211.5
(M+, 70), 183.5 (51), 167.5 (33), 127.5 (100), 111.5 (23). Anal. Calcd for
C
10H10ClNO2 (211.5): C, 56.75; H, 4.76; Cl, 16.75; N, 6.62. Found: C, 56.77; H,
25. Khanum, S. A.; Venu, T. D.; Shashikanth, S.; Firdouse, A. Bioorg. Chem. Lett. 2005,
14, 5351.
4.76; Cl, 16.79; N, 6.72%. 3f: Mp 138–140 °C; IR (Nujol): 1680 cmÀ1 (C@N); 1
H
NMR (CDCl3): d 2.25 (s, 3H, CH3), 3.45 (t, J = 7 Hz, 2H, NCH2), 4.41 (t, J = 7 Hz,
2H, OCH2), 4.7 (s, 2H, OCH2), 6.9–7.5 (m, 3H, Ar–H), EI–MS: m/z 225.5 (M+, 69),
197.5 (51), 181.5 (33), 141.5 (100), 125.5 (22). Anal. Calcd for C11H12ClNO2
(225.5): C, 58.54; H, 5.36; Cl, 15.71; N, 6.21. Found: C, 58.41; H, 5.26; Cl, 15.66;
N, 6.15%. 3g: Mp 108–110 °C; IR (Nujol): 1670 cmÀ1 (C@N); 1H NMR (CDCl3): d
2.25 (s, 3H, CH3), 3.45 (t, J = 7 Hz, 2H, NCH2), 4.45 (t, J = 7 Hz, 2H, OCH2), 4.6 (s,
2H, OCH2), 6.9–7.6 (m, 4H, Ar–H); EI–MS: m/z 191 (M+, 69), 163 (51), 147 (35),
26. Varma, R. S.; Dahiya, R.; Saini, R. K. Tetrahedron Lett. 1997, 38, 8819.
27. 2a: Mp 140–142 °C; IR (Nujol): 1738 (acid C@O), 3470–3575 cmÀ1 (acid OH);
1H NMR (CDCl3): d 3.8 (s, 3H, OCH3), 4.88 (s, 2H, OCH2), 6.7–7.1 (m, 4H, Ar–H),
9.1 (s, 1H, COOH, D2O exchangeable); EI–MS: m/z 182 (M+, 60), 138 (100), 123
(70), 107 (21). Anal. Calcd for C9H10O4(182): C, 59.34; H, 5.53. Found: C, 59.25;
H, 5.42%. 2b: Mp 137–139 °C; IR (Nujol): 1730 (acid C@O), 3400–3500 cmÀ1
(acid OH); 1H NMR (CDCl3): d 4.46 (s, 2H, OCH2), 6.65–7.05 (m, 4H, Ar–H), 9.5

S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 18 (2008) 4597–4601
4601
107 (100), 91 (25). Anal. Calcd for C11H13NO2 (191): C, 69.09; H, 6.85; N, 7.32.
Found: C, 69.19; H, 6.96; N, 7.45%. 3h: Mp 91–93 °C; IR (Nujol): 1670 cmÀ1
(C@N); 1H NMR (CDCl3): d 3.4 (t, J = 7 Hz, 2H, NCH2), 4.3 (t, J = 7 Hz, 2H, OCH2),
4.65 (s, 2H, OCH2), 6.8–7.3 (m, 4H, Ar–H); EI–MS: m/z 256 (M+, 69), 258 (M+,
67), 345 (54), 228 (51), 230 (50), 212 (33), 214 (31), 172 (100), 174 (98), 156
(25), 158 (23). Anal. Calcd for C10H10BrNO2 (256): C, 46.90; H, 3.94; Br, 31.20;
N, 5.47. Found: C, 46.80; H, 3.82; Br, 31.15; N, 5.36%. 3i: Mp 126–128 °C; IR
(Nujol): 1675 cmÀ1 (C@N); 1H NMR (CDCl3): d 3.5 (t, J = 7 Hz, 2H, NCH2), 4.5 (t,
J = 7 Hz, 2H, OCH2), 4.8 (s, 2H, OCH2), 6.9–7.45 (m, 4H, Ar–H), EI–MS: m/z 195
(M+, 66), 167 (49), 151(31), 111 (100), 95 (20). Anal. Calcd for C10H10FNO2
(195): C, 61.53; H, 5.16; F, 9.73; N, 7.18. Found: C, 61.61; H, 5.26; F, 9.71; N,
7.25%. 3j Mp 135–137 °C; IR (Nujol): 1675 cmÀ1 (C@N); 1H NMR (CDCl3): d 3.6
(t, J = 7 Hz, 2H, NCH2), 4.55 (t, J = 7 Hz, 2H, OCH2), 4.75 (s, 2H, OCH2), 6.9–7.45
(m, 4H, Ar–H); EI–MS: m/z 222 (M+, 67), 194 (49), 178 (30), 138 (100), 122 (20).
Anal. Calcd for C10H10N2O4 (222): C,54.05; H, 4.54; N, 12.61. Found: C, 54.18; H,
4.63; N, 12.69%. 3k: Mp 115–117 °C; IR (Nujol): 1680 cmÀ1 (C@N); 1H NMR
(CDCl3): d 3.45 (t, J = 7 Hz, 2H, NCH2), 4.75 (t, J = 7 Hz, 2H, OCH2), 4.85 (s, 2H,
OCH2), 6.85–7.4 (m, 4H, Ar–H); EI–MS: m/z 222 (M+, 68), 194 (50), 178 (31),
138 (100), 122 (21). Anal. Calcd for C10H10N2O4 (222): C, 54.05; H, 4.54; N,
12.61. Found: C, 54.19; H, 4.65; N, 12.67%. 3l: Mp 121–123 °C; IR (Nujol):
1690 cmÀ1 (C@N); 1H NMR (CDCl3): d 2.23 (s, 6H, 2CH3), 3.35 (t, J = 7 Hz, 2H,
NCH2), 4.45 (t, J = 7 Hz, 2H, OCH2), 4.7 (s, 2H, OCH2), 6.8–7.5 (m, 3H, Ar–H); EI–
MS: m/z 205 (M+, 68), 177 (51), 161 (34), 121 (100), 105 (25). Anal. Calcd for
C
12H15NO2 (205): C, 70.22; H, 7.37; N, 6.82. Found: C, 70.15; H, 7.26; N, 6.77%.
3m: Mp 129–131 °C; IR (Nujol): 1635 cmÀ1 (C@N); 1H NMR (CDCl3): d 3.52 (t,
J = 7 Hz, 2H, NCH2), 4.52 (t, J = 7 Hz, 2H, OCH2), 4.75 (s, 2H, OCH2), 6.8–7.45 (m,
4H, Ar–H), EI–MS: m/z 195 (M+, 67), 167 (14), 151(32), 111 (100), 95 (21). Anal.
Calcd for C10H10FNO2 (195): C, 61.53; H, 5.16; F, 9.73; N, 7.18. Found: C, 61.65;
H, 5.24; F, 9.73; N, 7.27%. 3n: Mp 139–141 °C; IR (Nujol): 1625 cmÀ1 (C@N); 1
H
NMR (CDCl3): d 3.4 (t, J = 7 Hz, 2H, NCH2), 4.5 (t, J = 7 Hz, 2H, OCH2), 4.7 (s, 2H,
OCH2), 6.8–7.4 (m, 4H, Ar–H), EI–MS: m/z 222 (M+, 68), 194 (14), 178 (31), 138
(100), 122 (19). Anal. Calcd for C10H10N2O4 (222): C, 54.05; H, 4.54; N, 12.61.
Found: C, 54.19; H, 4.64; N, 12.67%.
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