Antidyslipidemic and antioxidative activities of 8-hydroxyquinoline derived novel keto-enamine Schiffs bases

Article abstract of DOI:10.1016/j.ejmech.2008.08.004

8-Hydroxyquinoline when subjected to Duff reaction resulted in the formation of unexpected 7-methylaminomethylene-8-oxo-7, 8-dihydroquinoline-5-carbaldehyde 2, which existed in the keto-enamine form, in which the aromaticity of the relevant ring was disru

Full text of DOI:10.1016/j.ejmech.2008.08.004

European Journal of Medicinal Chemistry 44 (2009) 1813–1818
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Preliminary communication
Antidyslipidemic and antioxidative activities of 8-hydroxyquinoline derived
novel keto-enamine Schiffs bases
, ,
Koneni V. Sashidhara a 1, Abdhesh Kumar a, Gitika Bhatia b, M.M. Khan b, A.K. Khanna b,
*
J.K. Saxena b
a Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, Uttar Pradesh, India
b Biochemistry Division, Central Drug Research Institute, Lucknow 226 001, Uttar Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2008
Received in revised form 7 August 2008
Accepted 8 August 2008
Available online 22 August 2008
8-Hydroxyquinoline when subjected to Duff reaction resulted in the formation of unexpected 7-meth-
ylaminomethylene-8-oxo-7, 8-dihydroquinoline-5-carbaldehyde 2, which existed in the keto-enamine
form, in which the aromaticity of the relevant ring was disrupted, which upon subsequent treatment
with various primary amines resulted in its nucleophilic substitution of aliphatic methyl amine. These
interesting novel derivatives were evaluated in vitro for their antioxidant and in vivo for their anti-
dyslipidemic and post-heparin lipolytic activities. Compound 6 was found to be most active anti-
dyslipidemic and antioxidative agent in this series, respectively, and thus represent a new class of
promising lead.
Keywords:
Keto-enamine Schiff bases
8-Hydroxyquinoline
Antioxidant
Ó 2008 Elsevier Masson SAS. All rights reserved.
Lipid lowering activity
1. Introduction
The involvement of hydroxyl free radicals (OHꢀ) has been found
to be a major causative factor for peroxidative damage to lipopro-
Atherosclerosis, the principal contributor to the pathogenesis of
myocardial and cerebral infarction, is known to be one of the
leading causes of morbidity and mortality worldwide. Elevated
plasma concentration of cholesterol, especially low-density lipo-
protein (LDL) and triglyceride is recognized as a leading cause in the
development of atherosclerosis and coronary heart disease [1–6].
Several drugs are being used in the treatment of dyslipidemia.
The drugs can intervene by lowering cholesterol (LDL and total
cholesterol) or by lowering triglyceride levels in plasma. Treatment
of hyperlipidemia using statins has been used to lower serum levels
of cholesterol and triglyceride. Statins such as atorvastatin, lova-
statin, fluvastatin, simvastatin and pravastatin are HMG CoA
reductase inhibitors which act by inhibiting cholesterol synthesis
and upregulate LDA receptors in livers. However, common side
effects of Statins are myositis, arthralgias, gastrointestinal upset
and elevated liver function tests. Thus, there is a need for the
therapeutic benefits of several antidyslipidemic drugs while
simultaneously reducing the severe side effects.
teins which is responsible for inhibition and progression of
atherosclerosis in hyperlipidemic subject [7]. Hyperlipidemia may
also induce other abnormalities like oxidation of fatty acids, leading
to the formation of ketone bodies as well as masking liver and
muscle resistance to insulin which initiates the progress of diabetes
in patients [8]. Furthermore, due to hyperglycemia, increase in non-
enzymic glycosylation occurs, accompanied with glucose oxidation
and these reactions being catalyzed by Cu2þ and Fe2þ, resulting in
formation of Oꢀ2 and OHꢀ radicals which further accelerates the risk
of cardiac diseases in dyslipidemic patients [9]. In order to over-
come these ailments, a drug having multifold properties such as
antioxidant, anti-diabetic and lipid lowering activities is in great
demand.
Towards an ongoing drug discovery programme for developing
new antidyslipidemic drugs, wherein we have recently synthesized
a series of Schiff bases from dicarbaldehyde of benzocoumarin as
potential lipid lowering agents [10]. In continuation of our efforts,
we embarked on the synthesis of Schiff bases from 8-hydrox-
yquinoline as potential antidyslipidemic agents.
The quinoline nucleus occurs in several natural compounds
(cinchona alkaloids) and pharmacologically active substances dis-
playing a broad range of biological activity [11]. Quinoline moiety is
present in many classes of biologically active compounds. A
number of them have been clinically used as antifungal, antibac-
terial, and antiprotozoic drugs.
* Corresponding author. Fax: þ91 0522 2623405/2623938.
E-mail address: sashidhar123@gmail.com (K.V. Sashidhara).
Presently, Visiting Scientist Under BOYSCAST fellowship (DST) from March 2008
to March 2009 in the Department of Chemistry and Biochemistry, University of
California, Santa Cruz, CA 95064, USA.
1
0223-5234/$ – see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.08.004

1814
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 44 (2009) 1813–1818
It has found to posses antiasthmatic, anti-inflammatory, and
structure. In 1H–1H COSY spectrum, the NH proton (
correlations with the protons present at 3.5 and
more, In the HMBC spectrum, the enamine proton (
range correlations with signals at (CO), (C-2), (C-3), and (N–CH3)
(Scheme 2). The final analysis with all the spectral data confirmed
the structure as 2.
It is important to mention that the unlike 7-hydroxyl-4-methyl-
benzo(h)chromene-2-one and 1-hydroxy-napthalene which when
subjected to Duff reaction furnished their respective dialdehydes
[19] 8-hydroxyquinoline gave only compound 2.
To the best of our knowledge we are first to report this unusual
Duff formylation. It is interesting to note that our efforts to
synthesize the dialdehyde of 8-hydroxyquinoline failed with
changing the, molar ratio, reaction solvent (glacial acetic acid
instead of TFA) and also increasing the reaction temperature, also
we ended up with the same product when the hydrolysis of the
reaction was performed with HCl instead of sulfuric acid. To
compound 2 when treated with different amines resulted in the
respective Schiffs bases quinoline derivatives (3–10) through
nucleophilic substitution [20]. The most plausible mechanism of
this reaction would be nucleophilic attack of the amine at the
enamine moiety of the push–pull system, as this site is the most
electrophilic. The synthesis (Scheme 1) and detailed NMR charac-
terization of the derivatives are given in Table 1.
d
13.41) gave
7.9. Further-
7.9) gave long-
antihypertensive properties as well as antineoplastics [12]. Styr-
ylquinoline derivatives have gained strong attention recently due
to their activity as perspective HIV integrase inhibitors [13–16]. The
compounds containing 8-hydroxyquinoline pharmacophore seem
especially interesting. According to the results reported recently,
some new 8-hydroxyquinoline derivatives possess interesting
antifungal and herbicidal activities [17].
Thus, we found it interesting to evaluate the Schiff base deriv-
atives of 8-hydroxyquinoline for their antioxidant behaviour and
for their antidyslipidemic activity. The structure of our derivatives
combines in addition to the biological active quinoline nucleus,
possesses amine moiety and extended conjugation that is respon-
sible for its highly fluorescent nature and its antioxidant nature.
d
d
d
2. Chemistry
In our efforts to synthesize the quinoline derivatives for
potential leads, we started with Duff formylation [18] to get the
dialdehydes of 8-hydroxyquinoline 2A. But surprisingly we got
compound 2 (Scheme 1) that on careful examination by 2D NMR
spectroscopic experiments such as HSQC and HMBC revealed that
the compound was present in the keto-enamine form at room
temperature. The ESI-Mass spectrum of 2 gave a molecular ion at
m/z 215 [M þ H]þindicated the presence of even number of nitro-
gens. 1H NMR spectrum showed unexpected signals at
d
3.5 and at
9.86 suggesting the presence of N–CH3 group and the free alde-
hyde, respectively. The 13C NMR spectrum apart from other signals
showed two unusual signals at 193.76 (CHO) and 181.91 (CO) and
2.1. Typical procedure for the synthesis of compound 2
d
To a stirred solution of 8-hydroxyquinoline (500 mg, 3.5 mmol)
in TFA (2 ml) was added HMT (970 mg, 6.8 mmol) and the reaction
mixture maintained at 130–140 ꢁC for 2 h and then hydrolysis was
d
this led us to speculate that the product had a keto-enamine
O
H
1. HMTA / TFA
130-140oC, 2 hours
H
2. 10% H2SO4
90oC, 1 hour
N
N
N
O
2
OH
H
1
R-NH2 /EtOH
Catalytic PTSA
R.T., 1-2 min.
H
O
O
H
H
N
H
R
O
OH
2A
N
N
O
H
3-10
R = (3-10)
7 benzyl
3 ethyl
8 2-morpholine ethyl
9 2-morpholine propyl
10 isoheptyl
4 isopropyl
5 t-butyl
6 4-methyl phenyl
Scheme 1.

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 44 (2009) 1813–1818
1815
O
H
and reaction mixture stirred at room temperature for 1–2 min.
Completion of reaction was monitored by TLC, the reaction mixture
was poured in to aqueous NaHCO3 and extracted with chloroform
and dried over anhydrous Na2SO4. The crude product was purified
by column chromatography over silica gel to provide pure enamine
6 in high yield.
H
N
4. Biological activity
N
O
H
4.1. Animals used
Scheme 2. Selected 1H–13C HMBC correlations of 2 in CDCl3.
Rats (Charles Foster strain, male, adult, body weight 200–
225 g) were kept in
a room with controlled temperature
(25–26 ꢁC), humidity (60–80%) and12/12 h light/dark cycle
(light on from 8.00 A.M. to 8.00 P.M.) under hygienic condi-
tions. Animals, which were acclimatized for one week before
starting the experiment, had free access to the normal diet and
water.
done by adding 10% H2SO4 (2 ml) under stirring with reaction
temperature at around 90 ꢁC for 1 h. After completion of reaction
(TLC monitoring) the reaction mixture was poured into NaHCO3
solution and extracted with chloroform, dried over Na2SO4 and
removal of solvent afforded crude compound. The crude product
was purified by column chromatography (MeOH:CHCl3, 5:95) over
silica gel to provide pure enamine 2 in high yield.
4.2. Lipid lowering and post-heparin lipolytic activity
3. General experimental procedure for the synthesis of
compounds 3–10
Rats were divided into 12 Groups control, triton-induced,
triton plus 2–10, and Gemfibrozil (100 mg/kg) treated groups
containing six rats in each group. In this experiment of 18 h,
hyperlipidemia was developed by administration of triton WR-
1339 (Sigma chemical company, St. Louis, MO, USA) at a dose of
To a mixture of compound 2 (2 mmol) and p-toluidine (2 mmol)
was added catalytic amount of PTSA, in absolute ethanol (10 ml)
Table 1
Spectral data of compounds (2–10)
Compound no. ESIMS (Mþ1
)
IR (nmax
)
nNH (KBr cmꢂ1
)
nH–C]O 1H NMR, 300 MHz
(CDCl3): 13.41 (s, 1H, –NH, exchangeable),
Yield (%) MP ꢁ
C
2
215
3441
1649
d
90
215–216
9.86 (s, 1H, –CHO), 9.58 (dd, J ¼ 1.6, 8.4 Hz,
1H, C4–Ar–H), 8.89 (dd, J ¼ 1.6, 4.3 Hz,
1H, C2–Ar–H), 7.98 (d, J ¼ 11.8 Hz, 1H, C11–H),
7.59–7.56 (m, 2H, C3–Ar–H, C6–Ar–H), 3.5
(d, J ¼ 2.4 Hz, 3H, C12–H)
3
4
229
243
3427
3385
1638
1637
(CDCl3):
d
13.49 (d, J ¼ 1.5 Hz, 1H, –NH,
80
85
210–211
237–238
exchangeable), 9.87 (s, 1H, –CHO), 9.60
(d, J ¼ 6.8 Hz, 1H, C4–Ar–H), 8.90 (s, 1H, C2–Ar–H),
8.05 (s, 1H, C11–H), 7.60–7.57 (m, 2H, C3–Ar–H, C6–Ar–H),
3.79–3.71 (m, 2H, C12–H), 1.49 (t, J ¼ 7.0 Hz, 3H, C13–H)
(CDCl3):
d 13.61 (s, 1H, –NH), exchangeable, 9.79 (s, 1H, –CHO),
9.54 (dd, J ¼ 1.0, 8.3 Hz, 1H, C4–Ar–H), 8.84 (s, 1H, C2–Ar–H), 8.06
(d, J ¼ 12.2 Hz, 1H, C11–H), 7.57 (s, 1H, C6–Ar–H), 7.53
(dd, J ¼ 4.2, 8.4 Hz, 1H, C3–Ar–H), 3.91–3.87 (m, 1H, C12–H),
1.45 (d, J ¼ 6.5 Hz, 2H, C13–H, C14–H)
5
257
291
291
314
328
299
3441
3423
3425
3404
3432
3445
1634
1629
1638
1647
1641
1638
(CDCl3):
d
14.09 (s, 1H, –NH, exchangeable), 9.87 (s, 1H, –CHO),
85
80
75
65
65
85
234–235
255–256
Liquid
9.59 (dd, J ¼ 1.5, 8.4 Hz, 1H, C4–Ar–H), 8.89 (d, J ¼ 3.1 Hz, 1H, C2–Ar–H),
8.1 (d, J ¼ 3.2 Hz, 1H, C11–H), 7.65 (s, 1H, C6–Ar–H), 7.57 (dd, J ¼ 4.3, 8.5 Hz,
1H, C3–Ar–H), 1. 56 (s, 9H, C13–H, C14–H, C15–H)
6
(CDCl3): d 15.49 (s, 1H, –NH, exchangeable), 9.91 (s, 1H, –CHO), 9.57
(dd, J ¼ 1.0, 8.34 Hz), 8.92 (d, J ¼ 2.9 Hz, 1H, C4–Ar–H), 8.49 (s, 1H, C11–H), 7.72
(s, 1H, C6–Ar–H), 7.59 (dd, J ¼ 4.2, 8.5 Hz, 1H, C3–Ar–H), 7.28 (s, 4H, C13–Ar–H,
C14–Ar–H, C16–Ar–H, C17–Ar–H), 2.41 (s, 3H, C18–H)
7
(CDCl3):
d
13.93 (d, J ¼ 7.6 Hz, 1H, –NH, exchangeable), 9.87 (s, 1H, –CHO),
9.59 (dd, J ¼ 1.4, 8.4 Hz, 1H, C4–Ar–H), 8.90 (d, J ¼ 2.3 Hz, 1H, C2–Ar–H),
8.03 (s, 1H, C11–H), 7.61–7.58 (m, 2H, C3–Ar–H, C6–Ar–H), 7.46–7.37
(m, 5H, C14–Ar–H, C15–Ar–H, C16–Ar–H, C17–Ar–H, C18–Ar–H), 4.87 (s, 2H, C12–H)
(CDCl3): 13.19 (s, 1H, –NH, exchangeable), 9.75 (s, 1H, –CHO), 9.49
(dd, J ¼ 1.4, 8.4 Hz, 1H, C4–Ar–H), 8.79 (d, J ¼ 3.0 Hz, 1H, C2–Ar–H),
7.94 (s, 1H, C11–H), 7.53 (s, 1H, C6–Ar–H), 7.53–7.47 (m, 1H, C3–Ar–H),
3.70–3.63 (m, 6H), 2.88 (s, 2H), 2.80 (s, 2H), 2.68–2.64 (m, 2H)
8
Liquid
9
(CDCl3):
d
13.39 (s, 1H, –NH, exchangeable), 9.84 (s, 1H, –CHO), 9.56
172–173
Liquid
(dd, J ¼ 1.0, 8.3 Hz, 1H, C4–Ar–H), 8.86 (s, 1H, C2–Ar–H), 8.03 (s, 1H, C11–H),
7.56 (m, 2H, C3–Ar–H, C6–Ar–H), 3.72 (t, J ¼ 4.3 Hz, 6H), 2.47 (t, J ¼ 7.3 Hz, 6H),
1.94 (t, J ¼ 6.0 Hz, 2H)
10
(CDCl3): d 13.68 (s, 1H, –NH, exchangeable), 9.86 (s, 1H, –CHO), 9.58
(dd, J ¼ 1.6, 8.4 Hz, 1H, C4–Ar–H), 8.87 (dd, J ¼ 1.3, 4.1 Hz, 1H, C2–Ar–H)
8.03 (d, J ¼ 12.4 Hz, 1H, C11–H), 7.62 (s, 1H, C6–Ar–H), 7.57 (dd, J ¼ 4.2,
8.4 Hz, 1H, C3–Ar–H), 3.70 (m, 1H, C12–H), 1.76–1.68 (m, 2H, C14–H), 1.49
(s, 2H, C16–H), 1.46 (s, 3H, C16–H), 1.33–1.3 (m, 6H, C15–H, C17–H), 0.90 (t, J ¼ 6.7 Hz, 3H)

1816
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 44 (2009) 1813–1818
40
35
30
25
20
15
10
5
Total cholesterol
Phospholipid
Trigly ceride
0
2
3
4
5
6
7
8
9
10
Gemfibrozil
Compounds
Fig. 1. Showing the lipid lowering activity of different quinoline Schiffs base derivatives (100 mg/kg) in triton treated hyperlipimedic rats. Triton treated group with control and
drug treated group compared with triton group (Units – mg/dl for Tc, Pl, and Tg).
400 mg/kg. b.w. intraperitoneally to animals of all the groups
except the control. These derivatives were macerated with gum
acacia (0.2% w/v), suspended in water and fed simultaneously
with triton with a dose of 100 mg/kg p.o. to the animals of treated
group and the diet being withdrawn. Animals of control and triton
group without treatment with quinoline compounds were given
same amount of gum acacia suspension (vehicle). After 18 h of
treatment the animals were anaesthetized with thiopentone
solution (50 mg/kg b.w.) prepared in normal saline and then
1.0 ml blood was withdrawn from retro-orbital sinus using glass
capillary in EDTA coated Eppendorf tube (3.0 mg/ml blood). The
blood was centrifuged (at 2500 g) at 4 ꢁC for 10 min and plasma
was separated. Plasma was diluted with normal saline (ratio of
1:3) and used for analysis of total cholesterol (Tc), triglycerides
(Tg) and phospholipids (Pl) by standard enzymatic methods [21]
and post-heparin lipolytic activity (PHLA) were assayed (Wing
and Robinson, 1968) using spectrophotometer and Beckmann
auto-analyzer and standard kits purchased from Beckmann
Coulter International, USA.
4.4. Statistical evaluation
Data were analyzed using Student’s t-test. The hyperlipidemic
groups were compared with control drug treated groups. Simi-
larly the generations of oxygen free radicals with different ben-
zocoumarin derivatives were compared with that of their
formation without compounds. P < 0.05 was considered to be
significant.
5. Results and discussion
5.1. Effect of quinoline derivatives on hyperlipidemia and its post-
heparin lipolytic activity
Administration of Triton WR-1339 in rats induced marked
hyperlipidemia as evidenced by increase in the plasma level of Tc
(3.19-fold) Pl (2.76-fold) and Tg (3.12-fold) as compared to control.
Triton treated (induced) rats caused inhibition of plasma PHLA
(post-heparin lipolytic activity) (28%) as compared to control.
Treatment of hyperlipidemic rats with quinoline derivatives at the
dose of 100 mg/kg p.o. reversed the plasma levels of lipid with
varying extents. Triton WR-1339 acts as surfactant, suppresses the
action of lipase and blocks the uptake of lipoproteins from
the circulation by extrahepatic tissues resulting an increase in the
levels of circulating lipid [25]. These test samples inhibited
cholesterol biosynthesis and potentiated the activity of lipolytic
4.3. Antioxidant activity (generation of free radicals)
Superoxide anions were generated enzymatically [22] by
xanthine (160 mM), xanthine oxidase (0.04 U) and nitroblue
tetrazolium (320
mM) in the absence or presence of compounds
(100 g/ml) in 100 mM phosphate buffer (pH 8.2). Fractions were
m
sonicated well in phosphate buffer before use. The reaction
mixtures were incubated at 37 ꢁC and after 30 min the reaction
was stopped by adding 0.5 ml glacial acetic acid. The amount of
formazone formed was measured at 560 nm on a spectrophotom-
eter. Percentage inhibition was calculated taking absorption coef-
ficient of formazone as 7.2 ꢃ 103 M/cm. In another set of
experiment, an effect of compounds on generation of hydroxyl
radicals (OHꢀ) was also studied by non-enzymic reactants [23].
Briefly OHꢀ was generated in a non-enzymic system comprised of
deoxy ribose (2.8 mM), FeSO4$7H2O (2 mM), sodium ascorbate
(2.0 mM) and H2O2 (2.8 mM) in 50 mM KH2PO4 buffer, pH 7.4 to
a final volume of 2.5 ml. The above reaction mixtures in the
30
Post heparin lipolytic activity
25
20
15
10
5
0
Gemfibrozil
10
2
3
4
5
6
7
8
9
absence or presence of compounds (100 mg/ml) were incubated at
37 ꢁC for 90 min. Reference samples and reagent blanks were also
run simultaneously. Malondialdehyde (MDA) content in both
experimental and reference samples were estimated spectropho-
tometrically by thiobarbituric acid method as mentioned above
[24].
Compounds
Fig. 2. Showing the post-heparin lipolytic activity of different quinoline Schiffs base
derivatives (100 mg/kg) in triton treated hyperlipimedic rats. Triton treated group with
control and drug treated group compared with triton group (Unit – nmol free fatty acid
formed/h/ml of plasma).

K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 44 (2009) 1813–1818
1817
90
80
70
60
50
40
30
20
10
0
Superoxide anions
Hydroxylions
Microsomal lipid peroxidation
Standard
drug
2
3
4
5
6
7
8
9
10
Compounds
Fig. 3. Showing the effect of quinoline Schiffs base derivatives (100 and 200
mg/ml) on Superoxide ion (n mole formazone formed/min), hydroxyl ion (n mole MDA formed/h) and
lipid peroxidation in microsomes (n mole MDA formed/mg protein). (Standard drug for superoxide anions-Alloperinol (20
peroxidation- tocopherol (100 g/ml) was used).
mg/ml), hydroxyl ions-Manitol and for microsomal lipid
a
m
enzymes to early clearance of lipids from circulation in triton-
induced hyperlipidemia. Compounds 2 and 6 showed significant
decrease in plasma levels of Tc, Pl and Tg by 26, 25, 24%; and 23,
18, 25%, respectively. While compounds 3–5, 8–10 showed mild
lipid lowering activity. These data compared with standard drug
Gemfibrozil at the similar dose of 100 mg/kg showed decrease in
plasma levels of Tc, Pl, Tg by 36, 34, 38%, respectively, (Fig. 1). The
data in Fig. 2 shows that in triton-induced hyperlipidemica in rats
inhibited the post-heparin lipolytic activity (28%) and in case of
triton plus drug treated rats suppressed the PHLA activity up to 5–
20%, respectively, and in case of standard drug showed 27%
activity.
uncommon method of treating compound 2 with various primary
amines and evaluated for their antidyslipidemic activity and
antioxidative activity. It was found that most of the new analogs
were exhibiting significant to moderate activity. Further work, to
develop the active compound, as a potential lead is currently
underway as these compounds are devoid of cytotoxicity in
normal cells, namely vero cell line and primary osteoblast cells.
Also, efforts are underway to assess its mode of action and its in
vivo efficacy.
Acknowledgements
Authors are grateful to the Director, CDRI, Lucknow, India for
constant encouragement. We also thank the RSIC for spectral data.
A.K. is thankful to CSIR, New Delhi for financial support. This is CDRI
publication number 7457.
5.2. Effect of quinoline derivatives on oxygen free radical generation
in vitro
The scavenging potential of quinoline derivatives at 100 and
200 m
g/ml against formation of Oꢀ2 and OHꢀ in non-enzymic systems
Appendix. Supplementary material
was studied (Fig. 3). Further, the effect of compounds on lipid
peroxidation in microsomes was also studied. Compounds 4 and 6
(200 mg/ml) was most potent and showed significant decrease in
Spectral data of all the compounds associated with this article is
available as supplementary data.
superoxide anions inhibition by 47 and 44%, hydroxyl radicals
inhibition by 38 and 36% and 35 and 41% inhibition in microsomal
lipid peroxidation, respectively. The standard drug Alloperinol at
Supplementary material associated with this article can also be
found in the online version, at doi: 10.1016/j.ejmech.2008.08.004.
20
m
g/ml showed 84% inhibition in superoxide anions. Manitol and
g/ml showed 50 and 47% inhibition
References
a
-tocopherol at a dose of 100
m
of hydroxyl ions and microsomal lipid peroxidation, respectively.
While compounds 2, 3, 5 and 7 showed moderate activity,
compared to 8–10. The properties of these derivatives as antioxi-
dant and scavenger of oxygen free radicals appear to be mediated
through radical addition/by electron transfer/or by hydrogen
abstraction from compound, like carotenoids wherein by virtue of
extended conjugation the compound has the ability to delocalize
unpaired electrons.
A closer look at the biological results of the above compounds
reveals that compound 6 formed from nucleophilic substitution of
2 with p-toluidine was active both in antidyslipidemic and anti-
oxidant assays. The results indicate that Schiff bases formed from
substituted primary aromatic amine might act as a lead for
further optimization and development showing this dual activity.
It will be thus interesting to prepare new analogs of 6 for lead
optimization.
[1] D. Steinberg, S. Parthasarathy, T.E. Carew, J.L. Khoo, Witztum, N. Engl. J. Med.
320 (1989) 915–924.
[2] M.S. Brown, J.L. Goldstein, Annu. Rev. Biochem. 52 (1983) 223–261.
[3] (a) R. Ross, Nature 362 (1993) 801–809;
(b) T. Inoue, Atherosclerosis 160 (2002) 369–376.
[4] J.J. Badimon, V. Fuster, J.H. Chesebro, L. Badimon, Circulation 87 (1993) 3–16.
[5] J.L. Witzum, D.J. Steinberg, Clin. Invest. 88 (1991) 1785–1792.
[6] M. Aviram, Atherosclerosis 98 (1993) 1–9.
[7] S. Parthasarathy, D. Steinbert, J.L. Swiztum, Annu. Rev. Med. 43 (1992) 219–225.
[8] C.D.A. Stehouwer, J. Lambert, A.J.M. Donker, V.W.M. Van Hinsbergh, Car-
diovasc. Res. 43 (1997) 55–68.
[9] T. Asahina, A. Kashiwagi, Y. Nishio, Diabetes 44 (1995) 520–526.
[10] K.V. Sashidhara, J.N. Rosaiah, G. Bhatia, J.K. Saxena, Eur. J. Med. Chem., in press,
doi: 10.1016/j.ejmech.2007.10.029.
[11] S. Anzali, G. Barnickel, B. Cezanne, M. Krug, D. Filimonov, V. Poroikov, J. Med.
Chem. 44 (2001) 2432–2437.
[12] H.J. Roth, H. Fenner, Arzneistoffe, third ed. Deutscher Apotheker Verlag,
Stuttgart, 2000, pp. 51–114.
[13] K. Mekouar, J.F. Mouscadet, D. Desmaele, F. Subra, H. Leh, D. Savoure, C. Auclair,
J. d’Angelo, J. Med. Chem. 41 (1998) 2846–2857.
[14] F. Zouhiri, M. Danet, C. Bernard, M. Normand-Bayle, J.F. Mouscadet, H. Leh,
C.M. Thomas, G. Mbemba, J. d’Angelo, D. Desmaele, Tetrahedron Lett. 46
(2005) 2201–2205.
In conclusion, a series of novel Schiffs bases derivatives from
8-hydroxyquinoline have been synthesized following an

1818
K.V. Sashidhara et al. / European Journal of Medicinal Chemistry 44 (2009) 1813–1818
[15] Y. Pommier, A.A. Johnson, C. Marchand, Nat. Rev. Drug Discov. 4 (2005) 236–
248.
[16] J. Polanski, F. Zouhiri, L. Jeanson, D. Desmaele, J. d’Angelo, J. Mouscadet,
R. Gieleciak, J. Gasteiger, M.L. Bret, J. Med. Chem. 45 (2002) 4647–4654.
[17] J. Jampilek, M. Dolezal, J. Kunes, V. Buchta, K. Kralova, J. Med. Chem. 1 (2005)
591–599.
[18] F.L. Jay, N.J. Eric, G. Yun, H. Yaping, N. Xiaoyi, M.Z. Charles, J. Org. Chem. 59
(1994) 1939–1942.
[19] K.V. Sashidhara, J.N. Rosaiah, T. Narender, Tetrahedron Lett. 48 (2007) 1699–1702.
[20] K.V. Sashidhara, J.N. Rosaiah, Tetrahedron Lett. 48 (2007) 3285–3287.
[21] (a) R. Deeg, J. Ziegehorn, Clin. Chem. 29 (1983) 1798–1802;
(b) G. Buccolo, H. David, Clin. Chem. 19 (1973) 476–482;
(c) D.B. Zilversmit, A.K. Davis, B.S. Memphis, J.L. Tenn, Clin. Med. 35 (1950)
155–160.
[22] A. Bindoli, M. Valente, L. Cavallini, Pharmacol. Res. Commun.17 (1985) 831–840.
[23] B. Halliwell, J.M.C. Gutteridge, O. Arouma, Anal. Biochem. 165 (1987) 215–219.
[24] H. Okhawa, N. Ohishi, K. Yagi, Anal. Biochem. 95 (1978) 351–358.
[25] P.E. Schurr, J.R. Schultz, T.M. Parkinson, Lipids 7 (1972) 68–74.