Synthesis, characterization, and antihyperglycemic activity of novel oxazolidine derivatives

Article abstract of DOI:10.1007/s12272-011-0604-3

A number of compounds have been prepared in order to improve pharmacological roles of antihyperglycemic activity. In the present paper, a series of 3-benzyl-2-(4′-substituted phenyl)-4(5H)-(4″-nitrophenyl amino)-1,3-oxazolidines (6a-e) were tested against

Full text of DOI:10.1007/s12272-011-0604-3

Arch Pharm Res Vol 34, No 6, 887-891, 2011
DOI 10.1007/s12272-011-0604-3
Synthesis, Characterization, and Antihyperglycemic Activity
of Novel Oxazolidine Derivatives
Theivendren Panneer Selvam1, Palanirajan Vijayaraj Kumar2, Parthasarathi Ramu3, and Arumugam Siva Kumar4
1Department of Pharmaceutical Chemistry, Srinivas College of Pharmacy, Valachil, Mangalore 574 143, Karnataka, India,
2Faculty of Pharmaceutical Sciences, UCSI (University College Sadaya International) University, Jalan Menara Gading
56000 Cheras, Kuala Lumpur, Malaysia, 3Department of Biotechnology, IITMadras, Chennai 600 036, Tamilnadu, India,
4
and School of Bio Science and Technology, VIT University, Vellore 632 014 Tamilnadu, India
(Received August 24, 2010/Revised November 18, 2010/Accepted November 22, 2010)
A number of compounds have been prepared in order to improve pharmacological roles of anti-
hyperglycemic activity. In the present paper, a series of 3-benzyl-2-(4'-substituted phenyl)-
4(5
antihyperglycemic activity was evaluated by streptozotocin (STZ) and sucrose-loaded (SLM)
models. Compounds 6a, b, c, d, and displayed significant reductions in blood glucose in the
H)-(4''-nitrophenyl amino)-1,3-oxazolidines (6a-e) were tested against hyperglycemia. Their
e
streptozotocin and sucrose loaded rat models. The purity of the synthesized compounds was
characterized by means of IR, 1H-NMR, mass spectral and elemental analysis.
Key words: Oxazolidine, Aromatic aldehydes substitution, Antihyperglycemic activity
that oxazolidines and related oxazolidine are classes
of heterocycles that are of considerable interest because
INTRODUCTION
Diabetes mellitus is a major public health problem of the diverse range of their biological properties, such
in developed as well as developing countries. It is as antihypertensive (Caroon et al., 1983), antide-
ranked seventh among the leading causes of death, pressant (Pinder, 1985), antithyroid (Gardrat and
and is third when its fatal complications are taken Latxague, 1990), leishmanicidal (Sonika and Satyavan,
into account (Trivedi et al., 2004). Recent estimations 1990), antidiabetic (Heong et al., 2007), anti-HIV
of the World Health Organization suggest that more (Sharma et al., 2003), antiarrhythmic (Kostochka et
than 180 million people all over the world suffer from al., 2003), antitumor (Vara Prasad et al., 2006), and
diabetes mellitus (DM). By the year 2030, this number anticonvulsant and antimicrobial (Kim et al., 2008).
may increase more than 2-fold (Diabetes World Health This background information led to the design of 3-
Organization, 2006). DM is a metabolic disorder that benzyl-2-(4'-substituted phenyl)-4(5H)-(4''-nitrophenyl
is associated with three basic pathophysiological amino)-1, 3-oxazolidine derivatives (6a-e).
abnormalities: impaired insulin secretion, excessive
hepatic glucose production, and insulin resistance in
skeletal muscle, liver, and adipose tissue. It is now
clear that aggressive control of hyperglycemia in
patients with diabetes can prevent or delay the onset
MATERIALS AND METHODS
Materials
The synthetic starting material, reagents, and
of complications such as retinopathy, nephropathy, solvents were of analytical reagent grade or of the
and neuropathy (Kumar et al., 2007). We have found highest quality commercially available, and were
purchased from Aldrich Chemical Co., Merck Chemical
Co. and were dried when necessary.
Correspondence to: Theivendren Panneer Selvam, Department
The melting points were taken in open capillary
of Pharmaceutical Chemistry, Srinivas College of Pharmacy,
tubes and were uncorrected. IR spectra were recorded
Valachil, Mangalore 574 143, Karnataka, India
with KBr pellets (ABB Bomem FT-IR spectrometer
MB 104 ABB Limited Bangaluru). Proton (1H) NMR
Tel: 91-748-3067724, Fax: 91-824-2442766
E-mail: tpsphc@gmail.com
887

888
T. P. Selvam et al.
spectra (Bruker 400 NMR spectrometer Mumbai) were
recorded with TMS as internal references. Mass
General procedures
The synthetic strategy leading to the target
spectral data were recorded with a quadrupol mass compounds is illustrated in Scheme 1. The 3-benzyl-2-
spectrometer (Shimadzu GC MS QP 5000), and (4'-substituted phenyl)-4(5 )-(4''-nitrophenyl amino)-
H
microanalyses were performed using a vario EL V300 1,3-oxazolidine derivatives were synthesized by a
elemental analyzer (Elemental Analysensysteme GmbH previously reported method (Zarghi et al., 2007).
Chennai). The purity of the compounds was assessed Accordingly, benzylamine
by TLC on pre-coated SiO2 gel (HF254, 200 mesh) equimolar amount of substituted benzaldehyde
aluminium plates (E. Merck) using ethyl acetate: hydroxy acetic acid in dry toluene under reflux for
benzene (1:3) and visualized in a UV chamber. The IR, 24-48 h to give 3-benzyl-2-(4’-substituted phenyl)-1,3-
1H-NMR, mass spectral data and elemental analyses oxazolidine-4(5
)-one . This was further treated with
thionyl chloride and DMF to attain the chloro
1
was treated with an
2
and
3
H
4
were consistent with the assigned structures.
Scheme 1.

Antihyperglycemic Oxazolidine Derivatives
889
derivative
chloro-1,3-oxazolidine which was then coupled with
nitro anilines in DMF at 80oC and quenched in ice- bending), 3313 (N-H stretching); H-NMR (CDCl3):
5
3-benzyl-2-(4'-substituted phenyl)-4(5
H
p
)- Paleyellow solid, yield 77%; m.p. 170-123°C; IR (cm-1):
-
3027 (Ar-CH), 1413 (C=C), 1570 (N=O), 1334 (N-H
1
δ
water to acquire the product. The product was 6.62-7.18 (m, 13H, Ar-H), 6.29 (s, 2H, -CH), 3.69 (s,
separated by filtration, vaccum dried, and recrystallized 3H, -CH3), 7.21 (s, 1H, N-H), 3.49-3.63 (m, 4H, 2 ×
from warm ethanol to yield the 3-benzyl-2-(4'- CH2); EI-MS (m/z): [M]+ 389; (Calcd for C23H23N3O3;
substituted phenyl)-4(5H)-(4''-nitrophenyl amino)-1,3- 389.45). Anal (%). Calcd for C23H23N3O3: C, 70.93; H,
oxazolidines 6a-e
.
5.95; N, 10.79. Found: C, 70.95; H, 5.91; N, 10.83.
3-benzyl-2-phenyl-1, 3-oxazolidine-4(5
Yellow solid, yield 82%; m.p. 172-174°C; IR (cm-1):
3096 (Ar-CH), 1728 (C=O), 1468 (C=C); 1H-NMR Pale solid, yield 71%; m.p. 181-183°C; IR (cm-1): 3027
(CDCl3): 6.96-7.54 (m, 10H, Ar-H), 6.67 (s, 1H, -CH), (Ar-CH), 1413 (C=C), 1546 (N=O), 1334 (N-H bending),
4.12-4.62 (m, 4H, 2 × CH2); EI-MS (m/z): [M]+ 253; 3313 (N-H stretching); H-NMR (CDCl3):
H)-one (4)
3-benzyl-2-(4'-nitro phenyl)-4(5
nyl amino)-1,3-oxazolidine (6d)
H)-(4''-nitrophe-
δ
1
δ
6.79-7.33
(Calcd for C16H15NO2; 253.3). Anal (%). Calcd for (m, 13H, Ar-H), 6.21 (s, 2H, -CH), 7.27 (s, 1H, N-H),
C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.46; 3.46-3.78 (m, 4H, 2 × CH2); EI-MS (m/z): [M]+ 420;
H, 5.61; N, 5.36.
(Calcd for C22H20N4O5; 420.42). Anal (%). Calcd for
C22H20N4O5: C, 62.85; H, 4,79; N, 13.33. Found: C,
62.87; H, 4.75; N, 13.37.
3-benzyl-2-(4'-substituted phenyl)-4(5
H)-chloro
-1,3-oxazolidine (5)
Pale Yellow solid, yield 71%; m.p. 146-148°C; IR (cm-1) :
3084 (Ar-CH), 827 (C-Cl), 1412 (C=C); 1H-NMR
3-benzyl-2-(4'-chloro phenyl)-4(5
nyl amino)-1,3-oxazolidine (6e)
H)-(4''-nitrophe-
(CDCl3):
δ
6.18-7.42 (m, 10H, Ar-H), 4.98-5.27 (s, Brown solid, yield 81%; m.p. 184-186°C; IR (cm-1):
2H, -CH), 3.46-4.22 (m, 4H, 2 × CH2); EI-MS (m/z): 3026 (Ar-CH), 1524 (C=C), 1532 (N=O), 1316 (N-H
[M]+ 273; (Calcd for C16H16ClNO; 273.09). Anal (%). bending), 3319 (N-H stretching), 749 (C-Cl); H-NMR
1
Calcd for C16H16ClNO: C, 70.20; H, 5.89; N, 5.12. (CDCl3):
Found: C, 70.41; H, 5.96; N, 5.72.
δ
6.71-7.37 (m, 13H, Ar-H), 6.34 (s, 2H, -CH),
7.31 (s, 1H, N-H), 3.48-3.81 (m, 4H, 2 × CH2); EI-MS
m/z): [M]+ 409; (Calcd for C22H20ClN3O3; 409.87).
(
Anal (%). Calcd for C22H20ClN3O3: C, 64.47; H, 4.92; N,
10.25. Found: C, 64.43; H, 4.99; N, 10.29.
3-benzyl-2-(4'-hydroxy phenyl)-4(5H)-(4''-nitro-
phenyl amino)-1,3-oxazolidine (6a)
Pale yellow solid, yield 76%; m.p. 156-158°C; IR (cm-1):
3464 (O-H), 3027 (Ar-CH), 1494 (C=C), 1564 (N=O),
Antihyperglycemic activity
Streptozotocin (STZ) model
1
1306 (N-H bending), 3396 (N-H stretching); H-NMR
(CDCl3):
δ
9.87 (s, 1H, Ar-OH), 6.76-7.27 (m, 13H, Ar-
A solution of streptozotocin (60 mg/kg) in 100 mM
H), 6.31 (s, 2H, -CH), 7.21 (s, 1H, N-H), 3.44-3.67 (m, citrate buffer, pH 4.5, was prepared and a calculated
4H, 2 × CH2); EI-MS (m/z): [M]+ 391; (Calcd for amount of the fresh solution was dosed to overnight
C22H21N3O4; 391.42). Anal (%). Calcd for C22H21N3O4: fasted rats (60 mg/kg) intraperitoneally. Blood sugar
C, 67.51; H, 5.41; N, 10.74. Found: C, 67.57; H, 5.44; levels were measured after 48 h by a glucometer.
N, 10.79.
Animals showing blood glucose levels of 200-400 mg/
dL were selected for antidiabetic screening. The
diabetic animals were divided into groups of six
animals each. The rats in the experimental group
3-benzyl-2-(4'-methoxy phenyl)-4(5H)-(4''-nitro-
phenyl amino)-1,3-oxazolidine (6b)
White solid, yield 89%; m.p. 184-186°C; IR (cm-1): 3026 were administered a suspension of the desired test
(Ar-CH), 1524 (C=C), 1567 (N=O), 1316 (N-H bending), sample (prepared in 1% gum acacia) orally (100 mg/kg
1
3319 (N-H stretching); H-NMR (CDCl3):
δ 6.72-7.23 body weight). The control group animals were also fed
(m, 13H, Ar-H), 6.36 (s, 2H, -CH), 3.78 (s, 3H, -OCH3), 1% gum acacia. Blood glucose levels were measured at
7.15 (s, 1H, N-H), 3.54-3.72 (m, 4H, 2 × CH2); EI-MS 1, 2, 3, 4, 5, 6, 7 and 24 h intervals. The % decrease in
(
m/z): [M]+ 405; (Calcd for C23H23N3O4; 405.45). Anal blood glucose from 1 to 24 h for the test samples was
(%). Calcd for C23H23N3O4; C, 68.13; H, 5.72; N, 10.36; calculated according to the area under curve (AUC)
Found: C, 68.19; H, 5.76; N, 10.31.
method. The average reduction in AUC in the
experimental group compared to the control group
provided % antihyperglycemic activity.
3-benzyl-2-(4'-methyl phenyl)-4(5
H)-(4''-nitrophe-
nyl amino)-1,3-oxazolidine (6c)

890
T. P. Selvam et al.
sentative compounds 6a-e showed missing chloro
Sucrose-loaded (SLM) model
Overnight fasted male Sprague-Dawley rats were group bands. This clearly suggests that the chloro
used for the sucrose-loaded experiment. Blood was group of was converted into secondary NH. The
5
collected initially and thereafter test compounds were proton magnetic resonance spectra of oxazolidine and
given to the test group consisting of five rats by oral its corresponding derivatives were recorded in CDCl3.
gavage at a dose of 100 mg/kg of body weight. After For 6a-e, the NH signal of the 3-benzyl-2-(4'-substituted
half an hour post-test treatment, a sucrose load of 10 phenyl)-4(5H)-(4''-nitrophenyl amino)-1,3-oxazolidine
gm/kg of body weight was given to each rat. Blood was moiety appeared at 7.26 (s), 7.15 (s), 7.21 (s), 7.27 (s),
collected at 30, 60, 90, and 120 min post sucrose load. 7.34 (s), ppm, respectively. The position and presence
1
The % decrease in blood glucose level was calculated of the NH signal in the H-NMR spectra of the final
according to the AUC method.
RESULTS AND DISCUSSION
Chemistry
compounds confirms the secondary NH proton in the
oxazolidine moiety. This clearly indicates that the
oxazolidine-4(5H)-one moiety was involved in 4(5H)-
chloro-1,3-oxazolidine as well as (4''-nitrophenyl
amino)-1,3-oxazolidine formation. All these observed
The synthesized series of heterocycles, 6a-e, by the facts clearly demonstrate that the 4th position of the
reaction of
5 with appropriate p-nitro anilines in the keto group in the oxazolidine ring was converted into
presence of DMF are presented in Scheme 1. The IR, a secondary amino group as indicated in Scheme 1
1H-NMR, mass spectroscopy, and elemental analysis and confirms the proposed structures (6a-e) Fig. 1.
results for the new compounds are in accordance with
the assigned structures. The IR spectra of compound
showed stretching bands of a keto group at 1728 cm−1.
In
, stretching bands of a chloro group at 749 cm−1 is strated antihyperglycemic activity in the STZ and
evidence for the conversion of oxazolidinone. For the SLM models, For these compounds, 3-benzyl-2-(4'-
title compounds 6a-e stretching and bending NH hydroxy phenyl)-4(5 )-(4''-nitrophenyl amino)-1,3-
bands appeared at 3300-3400 cm−1 and 1300-1350 cm−1 oxazolidine (6a) and 3-benzyl-2-(4'-nitro phenyl)-4(5
respectively. The recorded IR spectrum of repre- -(4''-nitrophenyl amino)-1,3-oxazolidine (6d) reduced
4
Antihyperglycemic activity
Among the screened compounds, 6a-e demon-
5
5
H
H)
Fig. 1. Schematic structure for the synthesized oxazolidine derivatives

Antihyperglycemic Oxazolidine Derivatives
891
Table I. In vivo antihyperglycemic activity of various
oxazolidines derivatives (6a–e) in streptozotocin (STZ)
and sucrose-loaded (SLM) rat models
Diabetes. World Health Organization. Information Bulletin
No.312 (2006).
Gardrat, C., Latxague, L., and Picard, J. P., A new synthesis
of DL-5-vinyl oxazolidine-2-thione, a natural antithyroid
factor. J. Heterocycl. Chem., 27, 811-812 (1990).
Heong, S. O., Hoh, G. H., and Seung, H. C., Solid phase
synthesis of 1, 3-oxazolidine derivatives, Tetrahedron
Lett., 41, 5069-5072 (2007).
Kim, S. J., Jung, M.-H., Yoo, K. H., Cho, J.-H., and Oh, C.-H.,
Synthesis and antibacterial activities of novel oxazolidi-
nones having cyclic sulfonamide moieties. Bioorg. Med.
Chem. Lett., 18, 5815-5818 (2008).
Kostochka, L. M., Lezina, V. P., and Kostochka, M. L.,
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% Blood sugar lowering activity
(100 mg/kg)
Compounds
6a
6b
6c
STZ model
SLM model
52.0
19.6
13.4
48.5
10.9
19.7
31.2
72.0
NIL
33.2
66.4
43.6
13.5
39.4
6d
6e
Metformin
Glybenclamide
blood glucose to 52% and 72%, and 48.5% and 66.4%,
in the STZ and SLM models, respectively. The other
active compound 3-benzyl-2-(4'-mehoxy phenyl)-4(5H)-
5-carboxylic acid derivatives as PPARγ activators. Bioorg.
Med. Chem. Letts., 17, 4613-4618 (2007).
(4''-nitrophenyl amino)-1,3-oxazolidine (6b) displayed
moderate antihyperglycemic activity in the STZ model
(19.6%) and was inactive in the SLM model, this is
possibly due to its slower transformation than the
other highly active metabolites (6a, 6d, 6e, and 6c).
The compound with a chloro substituent at position 4´
in the phenyl ring (6e) displayed signicant blood
glucose lowering activity (43.6%) in the SLM model
while only a 10.9% reduction in blood glucose in the
STZ model. Compound 6c reduced blood glucose by
13.4% in the STZ model while later demonstrated
signicant activity (33.2%) in the SLM model. The
Pinder, R. M., A2 adrenoceptor antagonists as anti-depres-
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Indian J. Chem., 29B, 855-858 (1990).
Trivedi, N. A., Mazumdar, B., Bhatt, J. D., and Hemavathi,
K. G., Effect of Shilajit on blood glucose and lipid profile in
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373-376 (2004).
Vara Prasad, J. V. N., Boyer, F. E., Chupak, L., Dermyer, M.,
Ding, Q., Gavardinas, K., Hagen, S. E., Huband, M. D.,
Jiao, W., Kaneko, T., Maiti, S. N., Melnick, M., Romero, K.,
Patterson, M., and Wu, X., Synthesis and structure-activ-
ity studies of novel benzocycloheptanone oxazolidinone
antibacterial agents. Bioorg. Med. Chem. Lett., 16, 5392-
5397 (2006).
transformation order of screened compounds was 6a
>
6d 6e 6c 6b. Metformin and glybenclamide were
>
>
>
used as standard antidiabetic drugs in both models.
All values are presented in Table I.
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