Antioxidant activity of new benzo[de]quinolines and lactams: 2DQuantitative structure-activity relationships

Article abstract of DOI:10.2174/157340612802084216

In order to predict the antioxidant activity of 7 polycyclic lactams, a two dimensional quantitative-structure activity relationships (2D-QSAR) study based on a 5-descriptor model was performed. The synthetic compounds built from a condensed lactam scaffold were screened for their abilities to inhibit the autoxidation of pyrogallol, a superoxide anion radical-dependent process. The ketone 2 (8,9-dihydro-7H-benzo[de]pyrrolo[1,2-a]quinoline-7,10(7aH)-dione) exhibited the most potent antioxidant activity in vitro. The oxidation mechanism was proved by the isolation and characterization of alcohol 5 formed in the reaction of ketone 2 with dissolved oxygen in methanol.

Full text of DOI:10.2174/157340612802084216

942
Medicinal Chemistry, 2012, 8, 942-946
Antioxidant Activity of New Benzo[de]quinolines and Lactams: 2D-
Quantitative Structure-Activity Relationships
Alina Ghinet,a,b Amaury Farce,a,c Souhila Oudir,a,b Jean Pommery,a,d Joseph Vamecq,e Jean-Pierre
Hénichart,a,d Benoît Rigoa,b,* and Philippe Gautreta,b
aUniv Lille Nord de France, F-59000 Lille, France
bUCLille, EA 4481 (GRIIOT), Laboratoire de Pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille Cedex, France
cFaculté des Sciences Pharmaceutiques et Biologiques, EA 4481 (GRIIOT), Laboratoire de Chimie Thérapeutique, 3 rue
du Professeur Laguesse, B.P. 83, 59006 Lille Cedex, France
dUnité de Recherche sur la variabilité génétique des défenses de l'organisme face à son environnement chimique, EA
2679, Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Toxicologie, 3 rue du Professeur La-
guesse, B.P. 83, 59006 Lille Cedex, France
eInserm et Département de biochimie et biologie moléculaire, Laboratoire d’Endocrinologie, Métabolisme-Nutrition,
Oncologie, Centre de Biologie et Pathologie, CHRU Lille, 59037 Lille Cedex, France
Abstract: In order to predict the antioxidant activity of 7 polycyclic lactams, a two dimensional quantitative-structure ac-
tivity relationships (2D-QSAR) study based on a 5-descriptor model was performed. The synthetic compounds built from
a condensed lactam scaffold were screened for their abilities to inhibit the autoxidation of pyrogallol, a superoxide anion
radical-dependent process. The ketone 2 (8,9-dihydro-7H-benzo[de]pyrrolo[1,2-a]quinoline-7,10(7aH)-dione) exhibited
the most potent antioxidant activity in vitro. The oxidation mechanism was proved by the isolation and characterization of
alcohol 5 formed in the reaction of ketone 2 with dissolved oxygen in methanol.
Key Words: Lactam, hydroxyketolactam, benzo[de]quinoline, antioxidant agent, 2D-QSAR.
INTRODUCTION
measurements in order to determine (whether) the predictive
value of our previous QSAR model may be extended to the
present compounds.
Several in vivo studies report that protection of cells
against oxidative compounds such as safrole [1,2], paraquat
[3] or kainic acid [4] can be achieved by antioxidant agents
like melatonin [5]. Using the low-density lipoprotein oxida-
tion model, we have previously described a QSAR analysis
of structural analogues of melatonin [6,7], and have subse-
quently characterized the antioxidant activity of aza-
heterocycles from the tryptamine series [8-10], proposing a
model with 5 molecular descriptors [11]. Due to their struc-
tures, lactams 2 and 3 have called our attention as candidates
for new anti-oxidative agents. Indeed, heterocycles 1 were
previously found to react rapidly with oxygen from the air
[12-14]. Comparison of their scaffold with the structures of
known compounds exhibiting antioxidant potency (such as
flavonoids [15], hexahydropyridoindoles [16] or curcumin
derivatives [17]) has led us to further consider the anti-
oxidant activity of lactam 2 (which, in contrast to ketones 1,
has no N-CH2 bond). Because an extensive conjugation can
improve the potential antioxidant activity, we have also de-
signed dienyl lactams 3 and 4 for evaluation in the present
work (Fig. 1). This study includes both in silico and in vitro
MATERIALS AND METHODS
Chemicals
Pyrogallol and vitamin C (used as reference in this pyro-
gallol assay), were purchased from Sigma-Aldrich and were
of analytical grade purity. Naphthyl derivatives 2 and 4 were
synthesized as described recently [18], while dienyl lactams
3 were obtained by dehydration of ketones 1 as previously
reported [19,20]. General chemical structures of compounds
are presented in Fig. (1), and specific substitutions are men-
tioned in Table 1.
7a-Hydroxy-8,9-dihydro-7H-benzo[de]pyrrolo[1,2-
a]quinoline-7,10(7aH)dione (5). Ketone 2 (0.55 g, 2.32
mmol) was added to a solution of sodium methoxide (0.13 g,
2.41 mmol) in methanol (30 mL). The red mixture was
stirred at room temperature for 20 hours, and then acidified
to pH 5 with an aqueous solution of citric acid [13]. The sol-
vent was evaporated, and the residue was dissolved in ethyl
acetate. After getting washed with water then with NaHCO3
solution, the organic phase was dried (MgSO4) then evapo-
rated. The residue obtained after treatment was separated by
chromatography on silica gel, eluting EtOAc/n-heptane 5/5
*Address correspondence to this author at the École des Hautes Études
d’Ingénieur, Lille, France; Tel: +33 328384858; Fax: +33 328384604;
E-mail: benoît.rigo@hei.fr
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

Antioxidant Activity of New Benzo[de]quinolines and Lactams
Medicinal Chemistry, 2012, Vol. 8, No. 5 943
O
O
O
OH
HO
HO
O
OH
O
HO
OH
O
O
O
O
3
OH
Flavone
Curcumin
Vitamin C
Vitamin E
N
O
O
O
O
O
O
N
N
N
N
R1
R
N
H
R2
R3
Hexahydropyridoindole
1
2
3
4
Fig. (1). Chemical structures of some reference antioxidants, and of lactams 1 to 4.
to generate pure product 5 as a yellow solid in 64% yield;
ꢁ2: 2nd order connectivity index (topological de-
scriptor);
mp (EtOAc/n-heptane) 175-178 °C; TLC Rf (EtOAc/n-
heptane 5/5) = 0.32; H NMR (CDCl3, 400 MHz) ꢀ 2.41
1
IC5: 5th order information content index (topologi-
(ddd, J = 14.1, 9.4, 2.4 Hz, 1H, CH2CH2COH), 2.59 (ddd, J
= 17.1, 9.7, 2.4 Hz, 1H, CH2CH2COH), 2.82 (dt, J = 14.1,
9.7 Hz, 1H, CH2CH2COH), 2.97 (dt, J = 17.1, 9.4 Hz, 1H,
CH2CH2COH), 3.34 (s, 1H, CH2CH2COH), 7.61 (t, J = 7.9
Hz, 1H, ArH), 7.67 (t, J = 7.8 Hz, 1H, ArH), 7.76 (dd, J =
8.4, 0.9 Hz, 1H, ArH), 8.17 (dd, J = 8.4, 1.4 Hz, 1H, ArH),
8.35 (dd, J = 7.8, 1.4 Hz, 1H, ArH), 8.57 (dd, J = 7.8, 0.9
Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz) ꢀ 27.2 (CH2),
29.8 (CH2), 88.7 (C), 119.7 (CH), 123.1 (C), 124.4 (C),
125.1 (CH), 126.3 (CH), 127.3 (CH), 128.1 (CH), 129.2 (C),
133.1 (C), 135.7 (CH), 174.5 (C), 189.2 (C). Anal. Calcd. for
C15H11O3N: C 71.14, H 4.38, N 5.53; found: C 71.49, H
4.63, N, 5.75.
cal descriptor);
ICR: radial centric information index (molecular
descriptor);
nCT: total number of aliphatic tertiary carbon
(functional group descriptor);
nCO: total number of aliphatic ketones (functional
group descriptor);
Experimental Antioxidant Evaluations
The antioxidant potential of synthetic and reference
products was determined by UV-visible spectroscopy. We
choose to perform the measurement at pH 7.4 in order to be
near the physiological conditions; determination of the initial
rates of the superoxide-dependent [23] autoxidation of pyro-
gallol (25 mM) in the presence of different compounds, us-
ing a slight modification of a described procedure [23]. Inhi-
bition studies were carried out as follows: a solution of a
potential inhibitor (50 ꢂL) in dimethylsulfoxide (1 to 100
mM) was added to a solution of pyrogallol (0.75 mM) in 50
mM Tris buffer. The literature wavelength value utilized to
monitorize the oxidized pyrogallol was confirmed to be 420
nm (Fig. 2). Supplementary assays were conducted in the
presence of EDTA in order to eliminate the possibility of the
presence of metallic ions in the media.
Benzo[cd]indol-2(1H)-one (6). By-product from synthe-
sis of compound 5: yellow solid with the same physical pro-
perties as described in the literature [21]; 8% yield; TLC Rf
(EtOAc/n-heptane 5/5) = 0.51; 1H NMR (CDCl3, 400 MHz)
ꢀ 6.98 (d, J = 7.0 Hz, 1H, ArH), 7.47 (dd, J = 8.6, 7.0 Hz,
1H, ArH), 7.58 (d, J = 8.6 Hz, 1H, ArH), 7.75 (dd, J = 8.6,
7.0 Hz, 1H, ArH), 7.92 (s large, 1H, NH), 8.07 (d, J = 8.6
Hz, 1H, ArH), 8.10 (d, J = 7.0 Hz, 1H, ArH). 13C NMR
(CDCl3, 100 MHz) ꢀ 106.3 (CH), 120.3 (CH), 124.4 (CH),
126.4 (C), 126.6 (C), 128.6 (CH), 128.7 (CH), 129.5 (C),
131.2 (CH), 136.9 (C), 169.6 (C).
Selection of the Descriptors
The calculation of the topological, the molecular, and the
functional group descriptors was carried out with Dragon 2.1
program [22] following the methodology described in a pre-
vious study [11]. The resulting descriptor values were intro-
duced in Equation 1, (a QSAR equation previously validated
for 19 hexahydropyridoindoles and 12 flavonoids), to predict
the antioxidant power of compounds 2, 3 and 4. For hetero-
cycles which do not possess an aliphatic ketone group or an
aliphatic tertiary carbon atom, the values for the nCT and
nCO descriptor were null, leading to utilization of a model
with only 3 descriptors.
RESULTS AND DISCUSSION
In silico Studies
In order to validate the pertinence of syntheses and bio-
logical evaluations of new products, we have first deter-
mined the antioxidant potency of 11 compounds in silico
(Table 1). The prediction of these antioxidant potencies was
based on the cumulated scores of new chemicals using the
same 5 topological and functional descriptors as those used
in a previous QSAR study [11]; however, for reasons de-
tailed in the Discussion, it proved to be necessary to correct
the constant value from the original 2.698 to 1.698 (Equation
2), yielding a ranking which was closely related to the in
vitro experimental responses.
Equation 1: pIC50 = 2.698 + 0.093ꢁ2 – 0.183 ICR +
0.400 IC5 + 0.405 nCT – 0.675 nCO
pIC50: log(1/IC50);

944 Medicinal Chemistry, 2012, Vol. 8, No. 5
Ghinet et al.
OH
O
Biological screening on pyrogallol autoxidation
HO
OH
HO
O
O2
0,1
3i
0,09
0,08
0,07
0,06
0,05
0,04
0,03
0,02
0,01
0
PG
Vitamin C
PG
Oxidized PG
3d
3g
2
2
3e
3a
3c
3f
1,75
1,5
1,25
1
0
0,05 0,1 0,15 0,2 0,25 0,3 0,35 0,4 0,45 0,5
oxidized PG
PG
time (min)
O
Fig. (3). Autoxidation of pyrogallol (2.5 10-4 M) in the absence
(magenta) and in the presence of some compounds (5.10-4 M) in 50
mM Tris buffer.
0,75
0,5
0,25
0
O
OH
OH
OH
OH
Table 2. IC50 Values of the Selected Compounds in the Pyrogal-
lol Autoxidation Test
200
300
400
Wavelength (nm)
500
600
Compounds
IC50 (10-4 M)
Vitamin C
0.7
5.8
7.2
Fig. (2). Absorption spectra of pyrogallol in distilled water (magenta) and
oxidized pyrogallol (blue) in Tris buffer.
2
3f
Equation 2: pIC50 = 1.698 + 0.093ꢀ2 – 0.183 ICR +
0.400 IC5 + 0.405 nCT – 0.675 nCO
for IC50 determination, and results reported in Table 2 em-
phasize that lactam 2 possesses an interesting antioxidant
activity, lower than for vitamin C but comparable to the one
of flavonoids which is in the 4.15 range [11].
In vitro Studies
The extent of the inhibition of spontaneous pyrrogallol
autoxidation rates accounts for the superoxide radical anion-
scavenging potency and antioxidant activity of compounds
[24]; as illustrated by the initial rates curves for pyrogallol
autoxidation reported in Fig. (3), in this set of compounds,
lactams 2 and 3f showed a high activity. They were chosen
Although the initial QSAR model was developed for
products built around a hexahydropyridoindole or flavonoid
scaffold [11], this model proved to be rather general and we
have now showed that it can provide the virtual ranking of
Table 1. Descriptors Values, and Predicted Antioxidant Activities (pIC50) of Lactam Derivatives 2-4 and of Reference Vitamin C
ꢀ
2
Compounds
R1
R2
R3
ICR
IC5
nCT
nCO
pIC50
2
8.0
7.0
6.0
6.0
7.0
6.0
6.0
6.0
7.0
6.0
8.0
4.0
1.0
1.0
2.0
1.0
2.0
1.0
2.0
1.0
2.0
2.0
2.0
1.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
1.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
4.9
4.8
4.5
4.7
4.6
4.7
4.5
4.7
4.6
4.5
4.4
3.9
4
3a
H
H
H
H
H
H
H
H
Ph
H
Cl
Cl
H
Cl
H
3b
3c
Cl
3d
H
3e
H
Me
H
3f
Me
H
3g
OMe
Br
H
3h
3i
H
H
Vitamin C

Antioxidant Activity of New Benzo[de]quinolines and Lactams
Medicinal Chemistry, 2012, Vol. 8, No. 5 945
OH
O
OH
O
O
O
O
N
O
N
O
O
O
N
2
5
Fig. (4). Potential mechanistic pathway explaining the antioxidation power of ketone 2.
OH
O
O
O
O
O
N
N
HN
(i)
+
2
5 64%
6
8%
O2
MeOH
MeONa
NaO2C
O
NaO2C
O
O2H
O
O2
O
O
O
O
O
NH
O
N
N
N
N
CO2H
CO2Na
MeONa
7
8
Fig. (5). Proved oxidation of ketone 2 with dissolved oxygen in methanol. Reagents and conditions: (i) MeONa 1.05 equiv, MeOH, rt, 20h.
antioxidant properties of chemicals from other families. The
activities of compounds in Table 1 were predicted using
Equation 1, in order to give a rough idea of their relative
ranking. Interestingly, despite the heavily different condi-
tions of testing, the ranking of these products was fairly
good. However, as the mechanism in itself was conserved,
we feel rather confident that the only required modification
in our previous modes was the adjustment of the constant
term in Equation 1. Indeed, this is related to the external fac-
tors, as opposed to the descriptors, which account for the
intrinsic properties of compounds themselves. Modifying
this factor from the original 2.698 to 1.698 offers a good
predictive power for the new tested compounds, and ranks
them cleanly according to their in vitro values; this modifica-
tion leads to Equation 2, and to pIC50 reported in Table 1.
This makes the model an interesting tool in further investiga-
tion in these chemical series, and it should help with the se-
lection and recognition of the most worthy structures.
Moreover, while the biological test was different from that
employed in previous studies (autoxidation of pyrogallol
versus LDL copper-induced peroxidation), the QSAR Equa-
tion 2 predicted also an activity for vitamin C used as refer-
ence compound in the in vitro experiments. It is also note-
worthy that due to the structural dissimilarity between lac-
tams 2-4 and vitamin C, the antioxidative power of this one
was poorly predicted by the QSAR model. The prediction of
the reference compound was therefore brought back to an
acceptable level of error, due to the minor discrepancies in
experimentation.
Chemical Studies
It was already described that other ketolactams reacted
with oxygen dissolved in methanol to furnish hydroperoxide
intermediates [12-14] (Fig. 4). Thus, we checked the reactiv-
ity of ketone 2 with oxygen from air by stirring it in the
standard conditions (MeONa/MeOH) utilized for other ke-
tolactams [13] (Fig. 5). Accordingly, alcohol 5 was isolated
in 64% yield, accompanied by 8% of known [21] lactam by-
product 6, issued from rearrangement of intermediate hy-
droperoxide 7, opening of the resulting succinimide 8 then
cyclization to the lactam scaffold of compound 6 (Fig. 5);
isolation of these two products proves that ketone 2 indeed
can react with dissolved oxygen.
CONCLUSIONS
In conclusion, the antioxidant activity of 7 polycyclic lac-
tams was predicted by using a slightly modified known two
dimensional quantitative-structure activity relationships (2D-
QSAR). This model, based on 5-descriptor parameters, was
initially validated to predict the activity of hexahydropyrido-
indoles and flavanoids. The studied compounds present a
condensed lactam scaffold and were screened for their abili-
ties to inhibit the autoxidation of pyrogallol. The ketone 2
(8,9-dihydro-7H-benzo[de]pyrrolo[1,2-a]quinoline-7,
10(7aH)-dione) exhibited the most potent antioxidant activ-
ity in vitro. The oxidation mechanism was proved by the
isolation and characterization of alcohol 5 formed in the re-
action of ketone 2 with dissolved oxygen in methanol.

946 Medicinal Chemistry, 2012, Vol. 8, No. 5
Ghinet et al.
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CONFLICT OF INTEREST
The author(s) confirm that this article content has no con-
flicts of interest.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge the Conseil Régional
Nord-Pas-de-Calais for the A. G.’s and S. O.’s PhD scholar-
ships, the ARC (Association pour la Recherche sur le Can-
cer) (project no 4941) and the PRES (Pôle de Recherche et
d’Enseignement Supérieur, Université Lille Nord de France)
for financial support and the National Cancer Institute for the
biological evaluation of lactam 2 in order to predict its activ-
ity against cancer.
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[24]
Received: July 13, 2011
Revised: April 18, 2012
Accepted: April 24, 2012