Synthesis and evaluation of novel 2,3,5-triaryl-4H,2,3,3a,5,6,6a- hexahydropyrrolo[3,4-d]isoxazole-4,6-diones for advanced glycation end product formation inhibitory activity

Article abstract of DOI:10.1016/j.bmcl.2012.11.080

The synthesis of some biologically interesting pyrrolo-isoxazolidine derivatives was accomplished by the 1,3-dipolar cycloaddition reaction of substituted azomethine N-oxides 1 with substituted N-aryl maleimides 2 leading to the formation of new stereoisomeric 2,3,5-triaryl-4H,2,3,3a,5,6,6a- hexahydropyrrolo[3,4-d]isoxazole-4,6-dione derivatives 3 in excellent yields. The synthesized compounds have been screened for their advanced glycation end (AGE) product formation inhibitory activity on the basis of their ability to inhibit the formation of AGEs in the bovine serum albumin (BSA)-glucose assay. All the synthesized compounds have been found to exhibit significant activity against AGE formation.

Full text of DOI:10.1016/j.bmcl.2012.11.080

Bioorganic & Medicinal Chemistry Letters 23 (2013) 797–801
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of novel 2,3,5-triaryl-4H,2,3,3a,5,6,6a-
hexahydropyrrolo[3,4-d]isoxazole-4,6-diones for advanced glycation
end product formation inhibitory activity
Anjandeep Kaur a, Baldev Singh a, , Amteshwar Singh Jaggi b
⇑
a Department of Chemistry, Punjabi University, Patiala 147002, Punjab, India
b Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala 147002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some biologically interesting pyrrolo-isoxazolidine derivatives was accomplished by the
1,3-dipolar cycloaddition reaction of substituted azomethine N-oxides 1 with substituted N-aryl malei-
mides 2 leading to the formation of new stereoisomeric 2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrol-
o[3,4-d]isoxazole-4,6-dione derivatives 3 in excellent yields. The synthesized compounds have been
screened for their advanced glycation end (AGE) product formation inhibitory activity on the basis of
their ability to inhibit the formation of AGEs in the bovine serum albumin (BSA)-glucose assay. All the
synthesized compounds have been found to exhibit significant activity against AGE formation.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 September 2012
Revised 19 November 2012
Accepted 20 November 2012
Available online 5 December 2012
Keywords:
Nitrone
Isoxazolidines
Cycloaddition
Stereoselective
Antiglycation
Diabetes is an endocrine disorder, which results from an abso-
lute/relative deficiency of insulin or insulin resistance and is charac-
terized by hyperglycemia. As one of the most prevalent metabolic
syndromes word-wide, this disease results in short-term metabolic
changes in lipid and protein metabolism and long-term irreversible
vascular and connective-tissue changes due to which life expec-
tancy of diabetic patients is only two-thirds of that of the normal
population.
Non-enzymatic reaction between reducing sugar and free amino
group of proteins, also known as Maillard reaction is initiated by the
formation of Schiff bases between the sugar carbonyls and the free
amino groups of the proteins, which is followed by isomerization
(Amadori Rearrangements), generating a relatively stable aminoke-
tose derivatives. The rearrangement, oxidation and reduction of
these derivatives which are further capable of acting as protein
cross linking agents, result in the formation of several high molec-
ular weight protein aggregates and other fluorescent entities,
referred as advanced glycation end products (AGEs) such as pentos-
idine, carboxymethyllysine, crossline and pyralline.1,2 Thus AGEs
inactivate proteins or modify their biological activities, leading to
microvascular and macrovascular complications in diabetes melli-
tus and their accumulation on the tissues and organs results in oxi-
dative stress, inflammation and vascular damage which further
trigger a sequence of tissue dysfunction and thus are responsible
for the development of atherosclerosis, retinopathy, cataract,
nephropathy, neuropathy and for increased risk of myocardial
infarction and stroke.3–7 The crosslinked protein, for example,
crosslinked collagen, is postulated to confer pathological conditions
found in patients with diabetes and aging, such as arterial stiffness
and decreased myocardial compliance, resulting from the loss of
collagen elasticity.8,9 Also the enhanced formation of AGEs exists
in the blood and tissues of patients in various pathophysiological
states, such as atherosclerosis, Alzheimer’s disease, end-stage renal
disease (ESRD), rheumatoid arthritis and liver cirrhosis.10,11 Thus,
agents that inhibit the formation of AGEs are purported to have
therapeutic potentials in patients with diabetes and age-related
diseases. Over the last few decades, numerous AGE-inhibitors have
been identified, many of which belongs to natural products like
plant extracts from various vegetative and reproductive parts of
Artocarpus lakoocha,12 Cassia tora,13 Cordia sinensis,14 Hedyotis dif-
fusa15 etc. and various kinds of chilies and spices for example, alli-
gator pepper, ginger, nutmeg etc.16,17 However many of them upon
clinically testing as AGE-inhibitors proved to be therapeutically
inadequate because of their low efficacy.
The valuable and diverse biological activity of molecules con-
taining pyrrolo-isoxazolidines, isoxazolidine, pyrrole and pyrrolid-
inone moieties confers on them a high pharmacological value.
Michael et al reported isoxazolidine ring fused with ring D of steroi-
dal moieties as potential anti-inflammatory agents and such ana-
logues have found clinical status.18 Pyrrolo-isoxazolidine
derivatives also exhibit a wide array of biological activities like
⇑
Corresponding author. Mobile: +91 9988302741.
E-mail address: drbaldev.chem@yahoo.com (B. Singh).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.11.080

798
A. Kaur et al. / Bioorg. Med. Chem. Lett. 23 (2013) 797–801
anti-HIV,19 anti-bacterial,20,21 anti-fungal,22 anti-cancer,23 anti-
tuberculosis,24,25 and have also been present as basic moiety in
broad spectrum antibiotics like negamycin and 3-epinegamycin.26
Nicolaou et al and Negoro et al have reported substituted pyrrol-
1-ylacetic acids and tetrahydropyrrolo[1,2-a]pyrazine derivatives
to be active for inhibition of aldose reductase, the enzyme respon-
sible for diabetic complications.27,28 Ilyin et al found a series of
novel heterocyclic combinatorial libraries containing 4H-thieno
[3,2-b]pyrrole, thieno[20,30:4,5]-pyrrolo[1,2-d][1,2,4]triazine and
thieno [20,30:4,5]pyrrolo[1,2-a]pyrazine heterocyclic moieties to
be antidiabetic in nature.29 Uniflorine and Alexine which are poly-
hydroxylated pyrrolizidine alkaloids, synthesized by 1,3-dipolar
cycloaddition of nitrone and alkene has also been found to be anti-
diabetic in nature.30,31 The isoxazolyl-serine and isoxazole based
peroxisome proliferator activated receptor agonists have antidia-
betic properties and show robust insulin sensitizing and hypolipi-
demic activities in clinical trials.32,33 The other isoxazole and
isoxazolidine-3,5-dione derivatives have been used as antidiabetic
agents.34,35
Scheme 2. Schematic diagram describing the steps in the synthesis of maleimides
from differently substituted aniline derivatives.
Thus the pyrrolo-isoxazolidine moieties serve as versatile syn-
thetic intermediates with immense biological activities including
a potential to inhibit advanced glycation end product formation.
Therefore, the present study was designed to synthesize variously
ortho-substituted nitrones and their cycloproducts pyrrolo-isoxaz-
olidines and to evaluate these compounds for their advanced gly-
cation end-product formation inhibitory activity. This is the first
report on AGE-inhibitory activity exhibited by pyrrolo-isoxazoli-
dine moieties which due to their high efficacy may open new ave-
nues for the development of therapeutics targeted against protein
glycation in hyperglycemic conditions.
As can be seen from the results recorded (Table 1 inSupplemen-
tary data), in all examples examined, a smooth reaction proceeds
to give isoxazolidines (3a–h) exclusively in moderate to good
yields via regioselective cycloaddition of azomethine N-oxides
and maleimides. The starting compounds, azomethine N-oxides 1
(Scheme 1) and maleimides 2 (Scheme 2) were synthesized by fol-
lowing the similar procedure as reported in literature.36,37 Equimo-
lar quantities of 1 and 2 in sodium dried toluene under refluxing
conditions gave a mixture of diastereoisomers (Scheme 3) of
2,3,5-triaryl-4H,2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-
4,6-dione derivatives 3a–h, which were separated through column
chromatography into two diastereomers 3–A and 3–B using hex-
ane:ethyl acetate mixture in ratio of 9:1 as eluent.38 The stereo-
chemical assignment of the these diastereomers was made on
the basis 1H NMR, 1H NMR COSY and 1H NMR NOESY spectral data
which revealed the coupling patterns for both the diastereomers
that allowed for the differentiation between the two molecules
Scheme 3. Schematic diagram describing the synthesis of cis and trans isomers
from differently substituted diaryl nitrones and maleimides.
In their I.R. spectra these derivatives exhibit a strong absorption
band (m
max) in the range 1712–1717 cmꢀ1 and a shoulder band in
the range 1746–1792 cmꢀ1 due to imide carbonyl groups. How-
ever, in the 1H NMR spectra cis-3-(2-chlorophenyl)-2,5-bis(phe-
nyl)-4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3a–A) displays a doublet of doublet at d 4.06 (1H, H3a) due to cou-
pling with both H3 and H6a (J = 9.00 Hz and 7.84 Hz), a doublet at d
4.90 (1H, H3) due to coupling with proton H3a (J = 9.08 Hz), a an-
other doublet at d 5.28 (1H, H6a) due to coupling with H3a
(J = 7.80 Hz), multiplet signal at d 6.60–7.65 (14H, Ar–H). While
the 1H NMR spectrum of trans-3-(2-chlorophenyl)-2,5-bis(phe-
nyl)-4H-2,3,3a,5,6,6a-hexahydropyrrolo[3,4-d]isoxazole-4,6-dione
(3a–B) displays a partially resolved doublet of doublet at d 4.05
(1H, H3a) due to coupling with H6a (J = 7.40 Hz) and minor coupling
with H3, a doublet at d 5.05 (1H, H6a) due to coupling with H3a
(J = 7.48 Hz), a singlet at d 6.11 (1H, H3) and multiplet signal at d
6.53–7.77 (equivalent to 14H, Ar–H).
using their obtained spectra. The isomers showing C3–H and C6a
–
H as doublets and C3a–H as doublet of doublet on coupling with
both protons C3–H and C6a–H were assigned as cis geometry and
the isomers showing C3–H as singlet, C3a–H and C6a–H as doublets
in their 1H NMR spectra were assigned as trans geometry.
In 1H NMR COSY spectra of cis isomer3a–A (Fig. 1), the presence
of off diagonal cross peaks from protons H3a/H3 at d 4.06/4.90 and
H3a/H6a at d 4.06/5.28 indicate the syn-geometry of all the three
protons, while the absence of cross peaks from protons H6a/H3 at
d 5.05/6.11 and existence of very minor cross peaks from protons
Scheme 1. Schematic diagram describing the synthesis of differently substituted
nitrones.

A. Kaur et al. / Bioorg. Med. Chem. Lett. 23 (2013) 797–801
799
Figure 3. 400 MHz 1H NMR NOESY spectrum of 3a–A in CDCl3.
Figure 1. 400 MHz 1H NMR COSY spectrum of 3a–A in CDCl3.
H3a/H3 at d 4.05/6.11 in 1H NMR COSY spectra of trans isomer 3a–B
(Fig. 2) indicates the anti-geometry of proton H3 to the protons H3a
and H6a. But the presence of cross peaks from the protons H3a/H6a
in both the isomers shows the same planarity of these protons in
these isomers. In the 1H NMR NOESY spectra of cis isomer 3a–A
(Figs. 3 and 4) there exists correlation cross peaks from protons
H3a/H3 at d 4.06/4.90 and protons H3a/H6a at d 4.06/5.28 but no cor-
relation of H3a with the proton of C-phenyl ring which signifies the
‘anti’ geometry of H3 and C-phenyl ring and ‘syn’ nature of protons
H3, H3a and H6a protons. Cross peaks were also observed from pro-
tons H3/(H-20, H-60) at d 4.06/7.11. While in case of trans isomer
3a–B (Figs. 5 and 6) cross peaks from protons H3a/H6a at d 4.05/
5.05 and from protons H3a/H-600 at d 4.05/7.75 evident the ‘syn’
geometry of H3a H6a and C-phenyl ring and the ‘anti’ geometry of
,
Figure 4. Structure of compound 3a–A and NOE correlation.
H3 proton with H3a proton and C-phenyl ring. Besides this the cross
peaks were also exhibited from protons H3/(H-20, H-60) at d 6.11/
7.20. Cross peaks between protons H6a and H3a in both the isomers
proves their ‘syn’ geometry. In all the reactions studied the cis and
trans isomers were obtained approximately in 20:80 ratio indicat-
ing the steric interactions in endo-type transition state due to the
o-substitution and more stability of the exo-type transition state.
Figure 5. 400 MHz 1H NMR NOESY spectrum of 3a–B in CDCl3.
All the synthesized compounds 3a–h were subjected to in vitro
bioassay to Advanced Glycation End Product formation inhibitory
activity by following the similar procedure as reported in litera-
ture.39 The potential of the compounds 3a–h to inhibit AGEs-for-
mation is summarized in Table 1. All the synthesized compounds
Figure 2. 400 MHz 1H NMR COSY spectrum of 3a–B in CDCl3.

800
A. Kaur et al. / Bioorg. Med. Chem. Lett. 23 (2013) 797–801
Figure 6. Structure of compound 3a–B and NOE correlation.
Figure 7. Graphical representation of IC50 (lM) values of o-Cl substitution on C-
phenyl ring of pyrrolo-isoxazolidine derivatives with the standard drug
aminoguanidine.
have shown considerable advanced glycation end product forma-
tion inhibitory activity as the fluorescence of AGEs was shown to
be remarkably inhibited by the all the synthesized compounds.
Among the variously synthesized pyrrolo-isoxazolidines the com-
pounds 3a–A, 3a–B, 3b–A, 3c–A, 3c–B, 3d–A, 3e–A, 3f–A, 3g–A
and 3h–A were more potent than the standard drug aminoguani-
As evident from the results, among all the synthesized com-
pounds, the cis isomers (3–A) were find out to be more active than
the trans isomers (3–B). The compounds having o-Cl substituent on
C-phenyl ring (3a–A) were more active than the corresponding
compounds having o-OH group on C-phenyl moiety (3e–A). It sug-
gests that the compounds with stronger electron withdrawing
group (EWG) (–Cl) at ortho position of C-phenyl ring are more ac-
tive than compounds with weaker EWG that is, –OH group. Among
all the synthesized compounds the compound with p-CH3 substitu-
ent on the N-phenyl ring of the succinimide moiety (3b–A) was
most active, followed by the compound with no substitution on
this ring (3a–A). The compounds with p-OCH3 group exhibited
moderate and the compounds with p-COOH group were find out
to be least active anti-glycating agents. However the compounds
with EWGs (–OCH3 and –COOH) on the N-phenyl ring of the suc-
cinimide moiety (3c, 3d, 3g and 3h) were less active than the cor-
responding compounds with no substitution (3a and 3e) or
substitution with electron donating group p-CH3 (3b and 3f) on
this ring. Furthermore, among –OCH3 and –COOH substituted com-
pounds, the compounds with –COOH group (stronger electron
withdrawing) on the N-phenyl ring were comparatively less potent
dine. The most active compounds 3a–A (IC50 = 7.40 1.3
3b–A (IC50 = 7.18 1.4 M) and 3c–A (IC50 = 8.63 1.6 M) were
sixfolds more active than the standard drug aminoguanidine
(IC50 = 40.54 2.0 M). The compounds 3a–B, 3b–B, 3c–B, 3d–A,
3e–A, 3g–A and 3h–A (IC50 value ranging from 18.76 1.8 to
33.05 2.1 M) also exhibited significant inhibitory activity com-
lM),
l
l
l
l
parable to the standard drug. However the compounds 3d–B, 3e–
B, 3f–B, 3g–B and 3h–B exhibited lower anti-glycation activity
than the standard drug (IC50 value ranging from 63.90 2.2 to
126.67 2.3 lM). The graphical representation of this data has also
been shown in the form of bar graphs in Figures 7 and 8.
Table 1
Advanced glycation end-product formation inhibitory activity of pyrrolo-isoxazoli-
dine derivatives (3)
X
O
N
N
O
O
Y
Compounds
X
Y
IC50 (lM)
3a-A
3a-B
3b-A
3b-B
3c-A
3c-B
3d-A
3d-B
3e-A
3e-B
3f-A
3f-B
3g-A
3g-B
3h-A
3h-B
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
—
H
H
7.40 1.30
30.91 2.20
7.18 1.45
23.92 1.92
8.63 1.61
24.17 1.80
33.05 2.11
126.67 2.31
25.90 1.60
64.77 2.30
18.76 1.82
75.00 2.00
26.60 2.11
90.10 1.80
24.40 1.91
63.90 2.21
40.54 2.0
CH3
CH3
OCH3
OCH3
COOH
COOH
H
H
CH3
CH3
OCH3
OCH3
COOH
COOH
—
Figure 8. Graphical representation of IC50 (lM) values of o-OH substitution on C-
phenyl ring of pyrrolo-isoxazolidine derivatives with the standard drug
Aminoguanidine
aminoguanidine.

A. Kaur et al. / Bioorg. Med. Chem. Lett. 23 (2013) 797–801
801
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than the corresponding compounds with –OCH3 (weaker electron
withdrawing) group.
Thus we concluded that novel pyrrolo-isoxazole derivatives
exhibited significant anti AGE product formation activity. The
activity was mainly influenced by stereochemistry of the com-
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succinimide moiety. It is concluded that hexahydropyrrolo-isoxa-
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