Synthesis of new 2- and 3-hydroxyquinoline-4-carboxylic acid derivatives as potential antioxidants

Article abstract of DOI:10.1515/hc-2013-0163

A new series of 3-aryl-2-hydroxyquinoline-4-carboxylic acids 17a,b, 2-aryl-3-hydroxyquinoline-4-carboxylic acids 12a-d and their derivatives 13-16 and 18-21 were designed, synthesized and evaluated for their antioxidant activity using the ABTS assay method. Compounds 14 and 21a,b showed good antioxidant activity, whereas the remaining compounds displayed mild to moderate activity. All compounds were characterized by physical and spectral data.

Full text of DOI:10.1515/hc-2013-0163

ꢁꢁꢁꢂ
DOI 10.1515/hc-2013-0163ꢀ ꢀHeterocycl. Commun. 2014; 20(2): 81–88
Mohammed A. Massoud, Serry A. El Bialy, Waleed A. Bayoumi* and Walaa M. El Husseiny
Synthesis of new 2- and 3-hydroxyquinoline-
4-carboxylic acid derivatives as potential
antioxidants
Abstract: A new series of 3-aryl-2-hydroxyquinoline- derivatives are 7-chloro-4-hydroxyquinoline (6) and 7-fluoro-
4-carboxylic acids 17a,b, 2-aryl-3-hydroxyquinoline- 4-hydroxyquinoline (7), which have been characterized by
4-carboxylic acids 12a–d and their derivatives 13–16 and their antioxidant effect against free radical initiated peroxi-
18–21 were designed, synthesized and evaluated for their dation [10]. Additional synthetic quinolone derivatives with
antioxidant activity using the ABTS assay method. Com- effective antioxidant activity are TA 270 (8) [11] and quin-
pounds 14 and 21a,b showed good antioxidant activity, oline-3-carbohydrazides (9) [12] (Figure 1). 2-Substituted
whereas the remaining compounds displayed mild to benzimidazoles were recently reported to possess antioxi-
moderate activity. All compounds were characterized by dant activity [13]. Based on the previous data and literature
physical and spectral data.
review, new starting synthons were designed and synthe-
sized: 3-aryl-2-hydroxyquinoline-4-carboxylic acids (17a,b)
Keywords: ABTS assay; antioxidant; benzimidazole; quin- and 2-aryl-3-hydroxyquinoline-4-carboxylic acids (12a-d).
oline-4-carboxylic acid; synthesis.
Hybridization with several pharmacophoric moieties were
achieved in order to explore the effect on enhancing the
antioxidant activity. The following analogs were obtained:
ester derivatives (13a-d, 15 and 18a,b), O-acetyl derivatives
(16a-d) and O-alkyl/aralkyl derivatives (19a-d and 20a,b).
In addition, a heterocyclic hybrid system, in which 2- or
3-hydroxyquinoline ring is hybridized at C4 with 2-benzimi-
dazolyl ring (14 and 21a,b) was designed and synthesized.
The effect of structural modification at C6 of the quinoline
with two lipophilic groups one of which is electron donat-
*Corresponding author: Waleed A. Bayoumi, Faculty of Pharmacy,
Department of Pharmaceutical Organic Chemistry,
Mansoura University, Mansoura 35516, Egypt,
e-mail: waleedbayoumi@mans.edu.eg
Mohammed A. Massoud, Serry A. El Bialy and Walaa M. El Husseiny:
Faculty of Pharmacy, Department of Pharmaceutical Organic
Chemistry, Mansoura University, Mansoura 35516, Egypt
ing and the other is electron withdrawing (-CH3
and -Br
Introduction
respectively) were designed to discover their effect on poten-
tiation of the antioxidant activity. The introduction of the
Quinoline derivatives are an important structural moiety latter group is useful where bromo-substituent as halogen
in a number of chemotherapeutic agents and biologically bonding of the type R−X···Y−R′, where the halogen X acts as
active natural products. Several derivatives of cinchoninic a Lewis acid and Y can be any electron donor moiety (elec-
acid (quinoline-4-carboxylic acid, 1) are important qui- trostatic attraction) has been successfully harnessed for
noline derivatives, including the abandoned analgesic lead identification and optimization. In addition, halogen-
agent cinchophen (2) [1] and brequinar sodium (3) that ated aromatic systems are considered as common scaffolds
has been discovered as an anticancer agent [2] and later in medicinal chemistry [14, 15]. As part of this work, a series
found to have immunosuppressive activity [3]. 3-Hydroxy- of quinoline derivatives were synthesized and evaluated for
2-phenylcinchoninic acid (HPC, 4) has been reported to their antioxidant activity using an improved ABTS decolori-
possess antirheumatic effects [4]. Other derivatives have zation assay [16]. ABTS is 2,2′-azinobis(3-ethylbenzothiazo-
been reported to show antipsychotic [5], antiallergic [6], line-6-sulfonic acid) diammonium salt.
antiarthritic [7] and anxiolytic activities [8]. In addition, a
series of styrylquinoline derivatives that contain a COOH
Results and discussion
group at position 7 and an OH group at position 8 of the
quinoline moiety have been discovered as antiviral agents.
An example is (E)-8-hydroxy-2-[2-(3,4,5-trihydroxyphenyl)
Chemistry
ethenyl]-7-quinolinecarboxylic acid (5) [9] (Figure 1). Further-
more, substituted quinolones/hydroxyquinolines have been The structural core of quinoline has generally been
investigated for their antioxidant activity. Among important synthesized by various conventional reactions such as
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82ꢀ
ꢀM.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants
O
OH
OH
O
ONa
O
OH
O
OH
F
N
N
F
N
N
1
4
2
3
OH
N
OH
OH
OH
HOOC
N
OH
l
C
F
N
OH
6
5
7
OH
R
O
O
OH
O
O
O
(CH2)7
R = 4-OH
5-OCH3
5-CH3
N
H
3CO
N
N
H
OH
CH3
N
H
H
O
H
OC
3
8
9
Figure 1ꢀBiologically important hydroxyquinolines and quinolinecarboxylic acids.
O
R1
O
O
O
R1
OH
N
H
10a,b
N
R2
R2
13a-d
c
A
O
N
NH
O
11a,b
H
O
i, ii
80–85%
N
14
HO
O
R1
OH
N
N
R2
12a-d
O
O
H
O
R1
R2
H
Entry
N
a
CH3
CH3 CH3
H
O
O
b
c
15
Br
Br
H
R1
OCOCH3
CH3
d
N
R2
16a-d
Scheme 1ꢀReagents and conditions: (i) KOH, C2H5OH, H2O, reflux, 24 h; (ii) HOAc; (iii) CH3OH, H2SO4, reflux, 72 h; (iv) o-phenylenediamine,
140°C, 1–2 h; (v) 8-hydroxyquinoline, H2SO4, DMF, reflux, 72 h; (vi) HOAc/Ac2O, reflux, 48 h.
Skraup, Doebner-Von Miller, Friedlander, Pfitzinger, quinoline synthesis often do not allow for adequate diver-
Conrad-Limpach and Combes. These classical syntheses sity and substitution on the quinoline ring system. Among
are well known and still used frequently for the prepara- the synthetic strategies which could be conceived for
tion of quinoline backbone. However, these methods for the synthesis of quinoline derivatives, the Pfitzinger
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M.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidantsꢀ
ꢀ83
O
O
O
H
O
O
R1
i
R1
ii
R1
O
80–83%
90–91%
N
N
OH
H
N
OH
R2
Entry
a
R1
10a,b
18a,b
17a,b
CH3
CH3
iii
r
B
C
H
3
iv
b
c
88–92%
82–87%
CH3 CH2Ph
r
d
B
CH2Ph
H
O
O
O
O
N
NH
R1
R1
R1
O
R2
O
N
O
N
N
OH
O
19a-d
20a,b
21a,b
Scheme 2ꢀReagents and conditions: (i) phenylacetic acid, NaOAc, 200°C, 3 h; (ii) CH3OH, H2SO4, reflux, 6 h; (iii) RX, CH3CN, K2CO3, reflux,
24 h; (iv) BrCH2COOC2H5, DMF, K2CO3, reflux, 24 h; (v) o-phenylenediamine, 140°C, 1–2 h.
reaction offers a very convenient synthetic entry to the heating of the respective substrates 12a–d with a mixture
quinoline-4-carboxylic acid derivatives from isatins and a of acetic anhydride and acetic acid (Scheme 1). Synthesis
ketone.
of 2-hydroxyquinoline-4-carboxylic acid derivatives 17a,b
Synthesis of the substituted quinoline-4-carboxylic was achieved through reaction of isatin derivatives 10a,b
acid derivatives 12a–d, which are the starting compounds and phenyl acetic acid via fusion in presence of sodium
of Scheme 1, was achieved through Pfitzinger reaction by acetate as a catalyst (Scheme 2) [20]. The conversion of
heating isatins 10a,b [17] with compounds 11a,b [18] in an 17a,b into their methyl esters 18a,b was achieved through
aqueous/alcoholic KOH solution. The conversion of com- esterification following the same procedure already men-
pounds 12a–d into their esters 13a–d was accomplished tioned for the esters 13a–d. Alkylation and aralkylation of
by using Fischer esterification [19], that is, heating 12a-d compounds 18a,b at the 2-hydroxy group affording 19a,b
in methanol in the presence of sulfuric acid as a catalyst was achieved through Williamson ether synthesis [21]. In
and a dehydrating agent. Benzimidazole derivative 14 a similar way, alkylation of the 2-hydroxyl group of com-
was obtained by conventional condensation of 12b with pounds 17a,b with ethyl bromoacetate in DMF using K2CO3
o-phenylenediamine under solvent-free condition. Esteri- as a catalyst to afford esters 20a,b [22, 23]. In addition,
fication of 12b with 8-hydroxyquinoline afforded the ester treatment of the carboxylic acids 17a,b with o-phenylen-
15. O-Acetylated compounds 16a–d were obtained by ediamine furnished the respective benzimidazoles 21a,b
Table 1ꢀResults of ABTS antioxidant assay.
Tested
compound
ꢁ
Sampleꢁ
absorbance
(mean)
% Inhibition
ꢁ
Tested
compound
ꢁ
Sample
absorbance
(mean)
ꢁ % Inhibition
Control
ꢃ
0.512ꢃ
0.051ꢃ
0.474ꢃ
0.491ꢃ
0.473ꢃ
0.466ꢃ
0.512ꢃ
0.394ꢃ
0.504ꢃ
0.504ꢃ
0.048ꢃ
0.466ꢃ
0.458ꢃ
0.473ꢃ
0.00
90.04ꢀ ꢀ0.31
7.51ꢀ ꢀ0.02
4.09ꢀ ꢀ0.02
7.60ꢀ ꢀ0.29
8.97ꢀ ꢀ0.40
0.00ꢀ ꢀ0.00
23.02ꢀ ꢀ0.55
1.65ꢀ ꢀ0.08
1.65ꢀ ꢀ0.18
96.00ꢀ ꢀ0.52
8.97ꢀ ꢀ0.45
10.63ꢀ ꢀ0.57
7.20ꢀ ꢀ0.19
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
16c
16d
17a
17b
18a
18b
19a
19b
19c
19d
20a
20b
21a
21b
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
0.473
0.466
0.504
0.490
0.491
0.436
0.446
0.458
0.290
0.335
0.266
0.114
0.050
0.049
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
7.20ꢀ ꢀ0.29
8.97ꢀ ꢀ0.41
1.65ꢀ ꢀ0.19
4.29ꢀ ꢀ0.24
4.19ꢀ ꢀ0.13
Ascorbic acid ꢃ
12a
12b
12c
12d
13a
13b
13c
13d
14
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ 14.82ꢀ ꢀ0.29
ꢃ 12.87ꢀ ꢀ0.39
ꢃ 10.63ꢀ ꢀ0.35
ꢃ 43.41ꢀ ꢀ0.24
ꢃ 34.53ꢀ ꢀ0.47
ꢃ 48.09ꢀ ꢀ0.45
ꢃ 77.65ꢀ ꢀ0.87
ꢃ 93.00ꢀ ꢀ0.64
ꢃ 94.00ꢀ ꢀ0.55
15
16a
16b
Data are expressed as meanꢀ ꢀSEM, nꢀ= ꢀ3; SEM is standard error of the mean.
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84ꢀ ꢀM.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants
obtained in DMSO-d6 on a Bruker Avance 400 spectrometer at
Georgia State University, Atlanta, GA, USA. Elemental analysis data
were obtained at the Micro Analytical Center, Cairo University, Egypt.
MS analyses were performed on a JOEL JMS-600H spectrometer in
Cairo University. Reaction times were determined using a TLC tech-
nique on silica gel plates 60 F245 E. Merk, and the spots were visual-
(Scheme 2). The synthesis of new target 2- or 3-hydroxy-
quinoline derivatives hybridized and conjugated with
1H-benzimidazol-2-yl moiety at C4 (14 and 21a,b) of the
expected antioxidant activity is one of the unique points of
this work. Compounds 14 and 21a,b are the first examples
of this class. The heterocyclic hybridized systems of non- ized by UV irradiation at 366 nm or 245 nm. Synthesis of isatins 10a,b
and acetates of α-hydroxyketones 11a,b is described elsewhere [17,
hydroxylated quinolone derivatives have been previously
obtained by using several synthetic methods [24–28].
29]. 3-Hydroxy-6-methyl-2-phenylquinoline-4-carboxylic acid (12a)
and 6-bromo-3-hydroxy-2-phenylquinoline-4-carboxylic acid (12c)
were synthesized as previously reported [30].
ABTS antioxidant assay
The synthesized compounds were evaluated for their anti- Synthesis of 2-aryl-3-hydroxy-6-substituted
oxidant activity using an improved ABTS decolorization
quinoline-4-carboxylic acids (12a–d)
assay [16]. The assay that uses ABTS, 2,2′-azinobis(3-eth-
ylbenzothiazoline-6-sulfonic acid) diammonium salt, is a
A mixture of acetoxy ketone 11a,b (5 mmol), 5-substituted isatin
radical cation decolorization test. This spectrophotometric
10a,b (5 mmol) and KOH (1.28 g, 23 mmol) in 50% aqueous ethanol
method is widely used for the assessment of antioxidant
activity of various substances. The test is applicable for
both lipophilic and hydrophilic compounds. The colored
(20 mL) was heated under reflux for 24 h. Then, the reaction mix-
ture was diluted with aqueous ethanol (20 mL, 30%) and neutralized
with 50% acetic acid. The resultant precipitate was filtered, dried and
crystallized from ethanol.
·+
ABTSꢀꢀ radical cation, generated by oxidation of ABTS, is
quantified spectrophotometrically. The results of the anti-
oxidant screening are shown in Table 1.
3-Hydroxy-6-methyl-2-(4-methylphenyl)quinoline-4-carboxylic
acid (12b)ꢀYellow crystals; mp 194–195°C; yield 82%; 1H NMR: δ
2.31 (s, 3H, CH3), 2.52 (s, 3H, CH3), 7.33–7.40 (2H, m, Ar-H), 7.64 (d,
J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.05 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.10–8.21
(m, 2H, Ar-H), 8.48 (s, 1H, Quin-5-H), 9.11 (s, 1H, OH, D2O exchange-
able), COOH proton seems to be exchanged by the solvent; MS: m/z
294 (M++1, 10%), 293 (M+, 43%). Anal. Calcd for C18H15NO3 (293.32): C,
73.71; H, 5.15; N, 4.78. Found: C, 73.73; H, 5.10; N, 4.77.
Conclusions
The results summarized in Table 1 reveal that 2- or 3-hydroxy-
quinoline derivatives 14 and 21a,b carrying benzimidazole
moiety exhibit high antioxidant activity that is slightly
higher than the antioxidant property of ascorbic acid. In
addition, the esters 19c and 20a,b show mild antioxidant
activity. The remaining compounds are weak antioxidants.
The exhibited promising antioxidant activity in
compound 14 may be attributed to its behavior as a biden-
6-Bromo-3-hydroxy-2-(4-methylphenyl)quinoline-4-carboxylic
1
acid (12d)ꢀYellow crystals; mp 180–182°C; yield 80%; H NMR: δ
2.37 (s, 3H, CH3), 7.30–7.42 (2H, m, Ar-H), 7.71 (d, J ꢀ= ꢀ 8 Hz, 1H, Ar-H
Quin-7-H), 8.18–8.26 (m, 2H, Ar-H), 8.35 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H),
8.56 (s, 1H, Quin-5-H), 9.65 (s, 1H, OH, D2O exchangeable), COOH pro-
ton seems to be exchanged by the solvent; MS: m/z 360 (M++2, 8%),
358 (M+, 8%). Anal. Calcd for C17H12BrNO3 (358.19): C, 57.00; H, 3.38; N,
tate chelator (-OH at C3 and –NH of benzimidazole) for 3.91. Found: C, 57.03; H, 3.40; N, 3.92.
(Fe2+, Cu2+, Zn2+), thus preventing metal oxidation catalysis,
while the high antioxidant activity in 21a,b may be potenti-
General procedure for synthesis of methyl
ated by benzimidazole ring. However, those 2- or 3-hydroxy-
quinoline-benzimidazole hybrids may be regarded as lead
compounds in combating oxidative stress. Further struc-
tural modification at C4 is needed for studying the effect of
other functional groups on antioxidant activity.
2-aryl-3-hydroxy-6-substituted quinoline-
4-carboxylates (13a–d)
A few drops of concentrated sulfuric acid were added to a solution of
compound 12a–d in methanol (25 mL) and the reaction mixture was
heated under reflux for 72 h. Afer cooling, the mixture was poured
into ice water and the resultant solid was filtered, washed with water,
dried and crystallized from ethanol.
Experimental
Methylꢀ3-hydroxy-6-methyl-2-phenylquinoline-4-carboxylate
1
(13a)ꢀWhite crystals; mp 118–120°C; yield 79%; H NMR: δ 2.30 (s,
Chemistry
3H, Ar-CH3), 3.40 (s, 3H, COOCH3), 7.10–7.22 (m, 3H, Ar-H), 7.32–7.43 (m,
Melting points were recorded using a Fisher-Johns melting point 2H, Ar-H), 7.34 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.90 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-
1
apparatus and were uncorrected. H NMR spectra (400 MHz) were 8-H), 8.00 (s, 1H, Quin-5-H), 11.22 (s, 1H, OH, D2O exchangeable); MS:
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ꢀ85
m/z 294 (M++1, 9%), 293 (M+, 40%). Anal. Calcd for C18H15NO3 (293.32):
C, 73.71; H, 5.15; N, 4.78. Found: C, 73.72; H, 5.12; N, 4.79.
crystallized from 95% ethanol: white crystals; mp 285–287°C; yield
1
71%; H NMR: δ 2.32 (s, 3H, CH3), 2.51 (s, 3H, CH3), 7.10–7.25 (m, 3H,
Ar-H), 7.33–7.64 (m, 3H, Ar-H), 8.05 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.10–
8.21 (m, 2H, Ar-H), 8.25–8.31 (m, 2H, Ar-H), 8.48 (s, 1H, Quin-5-H),
8.60 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 9.00 (s, 1H, OH, D2O exchangeable);
MS: m/z 421 (M++1, 0.1%), 420 (M+, 0.03%). Anal. Calcd for C27H20N2O3
(420.46): C, 77.13; H, 4.79; N, 6.66. Found: C, 77.14; H, 4.81; N, 6.69.
Methyl 3-hydroxy-6-methyl-2-(4-methylphenyl)quinoline-4-car-
boxylate (13b)ꢀWhite crystals; mp 158–160°C; yield 77%; 1H NMR: δ
2.31 (s, 3H, Ar-CH3), 2.50 (s, 3H, Ar-CH3), 4.23 (s, 3H, COOCH3), 7.03–
7.15 (m, 2H, Ar-H), 7.22 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.52–8.62 (m, 2H,
Ar-H), 7.87 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.20 (s, 1H, Quin-5-H), 10.90 (s,
1H, OH, D2O exchangeable); MS: m/z 308 (M++1, 22%), 307 (M+, 55%).
Anal. Calcd for C19H17NO3 (307.34): C, 74.25; H, 5.58; N, 4.56. Found: C,
74.28; H, 5.60; N, 4.58.
Synthesis of 3-acetoxy-2-aryl-6-substituted-
quinoline-4-carboxylic acids (16a–d)
A mixture of compound 12a–d (10 mmol), glacial acetic acid (10 mL)
and acetic anhydride (10 mL) was heated under reflux for 48 h. Afer
cooling, the mixture was poured into ice water and the resultant solid
was filtered, washed with water, dried and crystallized from dichlo-
romethane.
Methylꢀ6-bromo-3-hydroxy-2-phenylquinoline-4-carboxylate
1
(13c)ꢀWhite crystals; mp 135–136°C; yield 79%; H NMR: δ 4.32 (s,
3H, COOCH3), 7.20–7.31 (m, 3H, Ar-H), 7.42–7.53 (m, 2H, Ar-H), 7.83
(d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.20 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.33 (s,
1H, Quin-5-H), 11.20 (s, 1H, OH, D2O exchangeable); MS: m/z 360
(M++2%), 358 (M+, 24%). Anal. Calcd for C17H12BrNO3 (358.19): C, 57.00;
H, 3.38; N, 3.91. Found: C, 57.02; H, 3.39; N, 3.93.
3-Acetoxy-6-methyl-2-phenylquinoline-4-carboxylicꢀacid
(16a)ꢀWhite crystals; mp 206–208°C; yield 85%; 1H NMR: δ 2.12 (s, 3H,
Ar-CH3), 2.65 (s, 3H, OCOCH3), 7.41–7.52 (m, 3H, Ar-H), 7.54–7.66 (m, 2H,
Ar-H), 7.71 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.05 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H),
8.37 (s, 1H, Quin-5-H), COOH proton seems to be exchanged by the sol-
vent; MS: m/z 322 (M++1, 10%), 321 (M+, 41%). Anal. Calcd for C19H15NO4
(321.33): C, 71.02; H, 4.71; N, 4.36. Found: C, 71.10; H, 4.73; N, 4.33.
Methyl 6-bromo-3-hydroxy-2-(4-methylphenyl)quinoline-4-car-
boxylate (13d)ꢀWhite crystals; mp 144–146°C; yield 75%; 1H NMR: δ
2.42 (s, 3H, Ar-CH3), 4.13 (s, 3H, COOCH3), 7.22–7.30 (m, 2H, Ar-H), 7.88
(d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.92–8.13 (m, 2H, Ar-H), 8.12 (d, J ꢀ= ꢀ 8 Hz,
1H, Quin-8-H), 8.23 (s, 1H, Quin-5-H), 11.20 (s, 1H, OH, D2O exchange-
able); 13C NMR (DMSO-d6, 100 MHz): δ 20.9, 53.1, 117.1, 121.3, 125.5,
125.6, 128.5, 129.4, 129.9, 131.5, 134.0, 138.8, 140.4, 149.0, 152.7, 167.1;
MS: m/z 374 (M++2, 18%), 372 (M+, 19%). Anal. Calcd for C18H14BrNO3
(372.21): C, 58.08; H, 3.79; N, 3.76. Found: C, 58.11; H, 3.81; N, 3.77.
3-Acetoxy-6-methyl-2-(4-methylphenyl)quinoline-4-carboxylic
acid (16b)ꢀWhite crystals; mp 205–207°C; yield 82%; 1H NMR: δ 2.11
(s, 3H, Ar-CH3), 2.40 (s, 3H, Ar-CH3), 2.63 (s, 3H, OCOCH3), 7.22–7.34
(m, 2H, Ar-H), 7.50 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.81–7.92 (m, 2H, Ar-H),
8.16 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.32 (s, 1H, Quin-5-H), COOH proton
seems to be exchanged by the solvent; MS: m/z 336 (M++1, 14%), 335
(M+, 45%). Anal. Calcd for C20H17NO4 (335.35): C, 71.63; H, 5.11; N, 4.18.
Found: C, 71.66; H, 5.16; N, 4.21.
Synthesis of 4-(1H-benz[d]imidazol-2-yl)-
6-methyl-2-(4-methylphenyl)quinolin-3-ol (14)
A mixture of compound 12b (2.93 g, 10 mmol) and o-phenylenedi-
amine (1.08 g, 10 mmol) was thoroughly ground with a pestle in a
mortar at room temperature in an open atmosphere until the overall
mixture turned into a melt. The melted mixture was then heated in a
sand bath at 140°C for 1–2 h. The progress of the reactions was moni-
tored by TLC. Afer completion, the melt was cooled, poured over ice
water, and the solid material was filtered, washed, dried and crystal-
lized from dichloromethane: buff crystals; mp ꢀ> ꢀ300°C; yield 77%; 1H
NMR: δ 2.33 (s, 3H, CH3), 2.50 (s, 3H, CH3), 7.30–7.38 (2H, m, Ar-H), 7.60
(d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.15 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.19–8.25
(m, 2H, Ar-H), 8.28–8.35 (m, 4H, Ar-H), 8.50 (s, 1H, Quin-5-H), 8.98 (s,
1H, OH, D2O exchangeable), NH proton seems to be exchanged by the
solvent; MS: m/z 365 (M+, 26%). Anal. Calcd for C24H19N3O (365.43): C,
78.88; H, 5.24; N, 11.50. Found: C, 78.90; H, 5.27; N: 11.54.
3-Acetoxy-6-bromo-2-phenylquinoline-4-carboxylicꢀacid
1
(16c)ꢀWhite crystals; mp 195–197°C; yield 86%; H NMR: δ 2.60 (s,
3H, CH3), 7.05–7.18 (m, 3H, Ar-H), 7.22–7.34 (m, 2H, Ar-H), 7.84 (d, J ꢀ= ꢀ 8
Hz, 1H, Quin-7-H), 8.09 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.25 (s, 1H, Quin-
5-H), COOH proton seems to be exchanged by the solvent; MS: m/z
388 (M++2, 22%), 386 (M+, 23%). Anal. Calcd for C18H12BrNO4 (386.20):
C, 55.98; H, 3.13; N, 3.63. Found: C, 55.99; H, 3.16; N, 3.67.
3-Acetoxy-6-bromo-2-(4-methylphenyl)quinoline-4-carboxylic
acid (16d)ꢀWhite crystals; mp 198–200°C; yield 85%; 1H NMR: δ
2.12 (s, 3H, Ar-CH3), 2.62 (s, 3H, OCOCH3), 7.30–7.42 (m, 2H, Ar-H),
7.75 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.88–7.97 (m, 2H, Ar-H), 8.10 (d, J ꢀ= ꢀ 8
Hz, 1H, Quin-8-H), 8.19 (s, 1H, Quin-5-H), COOH proton seems to be
exchanged by the solvent; MS: m/z 402 (M++2, 25%), 400 (M+, 26%).
Anal. Calcd for C19H14BrNO4 (400.22): C, 57.02; H, 3.53; N, 3.50. Found:
C, 57.05; H, 3.55; N, 3.53.
Synthesis of quinolin-8-yl 3-hydroxy-
6-methyl-2-(4-methylphenyl)quinolin-
4-carboxylate (15)
Synthesis of 2-hydroxy-3-phenyl-6-substi-
tuted quinoline-4-carboxylic acids (17a,b)
Sulfuric acid (1 mL) was added to a suspension of compound 12b (2.93
g, 10 mmol) and 8-hydroxyquinoline (1.45 g, 10 mmol) in DMF (25 mL). A mixture of 5-methyl or 5-bromoisatin (15 mmol), phenylacetic acid
The reaction mixture was heated under reflux for 6 h. Afer cooling, (3.57 g, 26.25 mmol) and sodium acetate (0.3 g) was heated at 200°C
the precipitated solid was filtered, washed with ethanol, dried and for 3 h. Afer cooling, sodium hydroxide solution (20 mL, 30%) was
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86ꢀ ꢀM.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants
added. The mixture was filtered and the filtrate was acidified with
hydrochloric acid. The precipitated solid was filtered, washed with
water, dried and crystallized from 95% ethanol.
Methylꢀ2-methoxy-6-methyl-3-phenylquinoline-4-carboxylate
1
(19a)ꢀYellow crystals; mp 262–264°C; yield 92%; H NMR: δ 2.33 (s,
3H, CH3), 3.40 (s, 3H, COOCH3), 3.80 (s, 3H, OCH3), 7.10–7.18 (m, 3H,
Ar-H),7.28–7.36 (m, 2H, Ar-H), 7.60 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.77 (d,
J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 7.92 (s, 1H, Quin-5-H); MS: m/z 308 (M++1,
10%), 307 (M+, 11%). Anal. Calcd for C19H17NO3 (307.34): C, 74.25; H,
5.58; N, 4.56. Found: C, 74.28; H, 5.60; N, 4.59.
2-Hydroxy-6-methyl-3-phenylquinoline-4-carboxylicꢀacid
(17a)ꢀWhite crystals; mp ꢀ> ꢀ300°C; yield 80%; 1H NMR: δ 2.31 (s,
3H, CH3), 7.25–7.34 (m, 3H, Ar-H),7.40–7.47 (m, 2H, Ar-H), 7.53 (d, J ꢀ= ꢀ
8 Hz, 1H, Quin-7-H), 7.66 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.08 (s, 1H, Quin-
5-H), 12.11 (s, 1H, OH, D2O exchangeable), COOH proton seems to be
exchanged by the solvent; MS: m/z 280 (M++1, 20%), 279 (M+, 75%).
Anal. Calcd for C17H13NO3 (279.29): C, 73.11; H, 4.69; N, 5.02. Found: C,
73.13; H, 4.72; N, 5.05.
Methylꢀ6-bromo-2-methoxy-3-phenylquinoline-4-carboxylate
1
(19b)ꢀYellow crystals; mp 250–251°C; yield 90%; H NMR: δ 3.43 (s,
3H, COOCH3), 3.82 (s, 3H, OCH3), 7.13–7.22 (m, 3H, Ar-H), 7.31–7.42 (m,
2H, Ar-H), 7.63 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.84 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-
8-H), 7.97 (s, 1H, Quin-5-H); MS: m/z 374 (M++2, 29%), 372 (M+, 30%).
Anal. Calcd for C18H14BrNO3 (372.21): C, 58.08; H, 3.79; N, 3.76. Found:
C, 58.09; H, 3.81; N: 3.79.
6-Bromo-2-hydroxy-3-phenylquinoline-4-carboxylicꢀacid
(17b)ꢀWhite crystals; mp ꢀ> ꢀ300°C; yield 83%; 1H NMR: δ 7.28–7.38 (m,
3H, Ar-H),7.40–7.52 (m, 2H, Ar-H), 7.70 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.73
(d, J ꢀ= ꢀ 8 Hz, Quin-8-H), 8.11 (s, 1H, Quin-5-H), 12.31 (s, 1H, OH, D2O
exchangeable), COOH proton seems to be exchanged by the solvent;
13C NMR (DMSO-d6, 100 MHz): δ 113.6, 117.1, 117.5, 126.9, 127.4, 127.9,
129.3, 130.0, 133.0, 133.9, 137.4, 140.63, 160.2, 166.6; MS: m/z 346 (M++2,
16%), 344 (M+, 16%). Anal. Calcd for C16H10BrNO3 (344.16): C, 55.84; H,
2.93; N, 4.07. Found: C, 55.87; H, 2.95; N, 4.10.
Methyl 2-benzyloxy-6-methyl-3-phenylquinoline-4-carboxylate
1
(19c)ꢀYellow crystals; mp 270–272°C; yield 89%; H NMR: δ 2.31 (s,
3H, CH3), 3.31 (s, 3H, COOCH3), 5.62 (s, 2H, CH2), 7.26–7.57 (m, 10H,
Ar-H), 7.93 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.21 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H),
8.30 (s, 1H, Quin-5-H); MS: m/z 384 (M++1, 10%), 383 (M+, 15%). Anal.
Calcd for C25H21NO3 (383.44): C, 78.31; H, 5.52; N, 3.65. Found: C, 78.33;
H, 5.54; N, 3.68.
Methyl 2-benzyloxy-6-bromo-3-phenylquinoline-4-carboxylate
(19d)ꢀYellow crystals; mp 248–250°C; yield 88%; 1H NMR: δ 3.33
(s, 3H, COOCH3), 5.62 (s, 2H, CH2), 7.27–7.45 (m, 10H, Ar-H), 7.67 (d,
J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.78 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.25 (s, 1H,
Quin-5-H); MS: m/z 450 (M++2, 30%), 448 (M+, 31%). Anal. Calcd for
C24H18BrNO3 (448.31): C, 64.30; H, 4.05; N, 3.12. Found: C, 64.32; H,
4.07; N, 3.15.
Methyl 2-hydroxy-3-phenyl-6-substituted-
quinoline-4-carboxylates (18a,b)
Concentrated H2SO4 (1 mL) was added to a suspension of compound
17a,b (10 mmol) in methanol (25 mL). The reaction mixture was heated
under reflux for 6 h. Afer cooling, the precipitated solid was filtered,
washed with methanol, dried and crystallized from methanol.
Methyl 2-hydroxy-6-methyl-3-phenylquinoline-4-carboxylate
1
(18a)ꢀWhite crystals; yield 90%; mp 263–265°C; H NMR: δ 2.30 (s,
Synthesis of 6-substituted-
3H, Ar-CH3), 3.31 (s, 3H, COOCH3), 7.21–7.29 (m, 3H, Ar-H),7.33–7.42 (m,
2H, Ar-H), 7.98 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.01 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-
8-H), 8.20 (s, 1H, Quin-5-H), 12.12 (s, 1H, OH, D2O exchangeable); 13C
NMR (DMSO-d6, 100 MHz): δ 20.4, 52.4, 115.4, 124.5, 127.7, 128.1, 129.2,
130.1, 131.6, 132.2, 134.2, 135.1, 136.4, 140.2, 160.2, 166.5. MS: m/z 294
(M++1, 9%), 293 (M+, 43%). Anal. Calcd for C18H15NO3 (293.32): C, 73.71;
H, 5.15; N, 4.78. Found: C, 73.73; H, 5.13; N, 4.80.
2-{[(ethoxycarbonyl)methyl]oxy}-3-phe-
nylquinoline-4-carboxylic acids (20a,b)
A mixture of compound 17a,b (10 mmol), K2CO3 (1.38 g, 10 mmol)
and ethyl bromoacetate (1.67 g, 10 mmol) in DMF (20 mL) was heated
under reflux for 24 h. Afer cooling, the mixture was poured on ice
water and the resultant solid was filtered, washed with water, dried
and crystallized from water.
Methyl
6-bromo-2-hydroxy-3-phenylquinoline-4-carboxylate
1
(18b)ꢀWhite crystals; mp 247–248°C; yield 91%; H NMR: δ 3.52 (s,
3H, CH3), δ 3.52 (s, 3H, CH3), 7.21–7.32 (m, 3H, Ar-H),7.30–7.42 (m, 2H,
Ar-H), 7.59 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 7.76 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H),
8.00 (s, 1H, Quin-5-H), 12.31 (s, 1H, OH, D2O exchangeable); MS: m/z
360 (M++2, 40%), 358 (M+, 41%). Anal. Calcd for C17H12BrNO3 (358.19):
C, 57.00; H, 3.38; N, 3.91. Found: C, 57.03; H, 3.41; N, 3.92.
2-{[(Ethoxycarbonyl)methyl]oxy}-6-methyl-3-phenylquinoline-
4-carboxylic acid (20a)ꢀBuff crystals; mp 210–211°C; yield 87%; 1H
NMR: δ 1.22 (t, 3H, CH3), 2.34 (s, 3H, Ar-CH3), 4.21 (q, 2H, CH2), 4.72 (s,
2H, CH2), 7.18–7.27 (m, 3H, Ar-H), 7.30–7.38 (m, 2H, Ar-H), 7.40 (d, J ꢀ= ꢀ 8
Hz, 1H, Quin-7-H), 8.43 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.00 (s, 1H, Quin-
5-H), COOH proton seems to be exchanged by the solvent; 13C NMR
(DMSO-d6, 100 MHz): δ 14.4, 21.0, 61.6, 62.1, 115.8, 116.0, 125.4, 128.3,
128.7, 129.8, 131.0, 132.0, 132.8, 134.4, 136.9, 139.8, 160.6, 166.2, 167.6;
MS: m/z 366 (M++1, 19%), 365 (M+, 34%). Anal. Calcd for C21H19NO5
(365.38): C, 69.03; H, 5.24; N, 3.83. Found: C, 69.05; H, 5.25; N, 3.85.
Synthesis of methyl 2,6-disubstituted-
3-phenylquinoline-4-carboxylates (19a–d)
A mixture of compound 18a,b (10 mmol), alkyl or aralkyl halide (15
mmol) and K2CO3 (1.38 g, 10 mmol) in acetonitrile was heated under
reflux for 24 h. Afer cooling, the solid product was filtered, washed
with water, dried and crystallized from absolute ethanol.
6-Bromo-2-{[(ethoxycarbonyl)methyl]oxy}-3-phenylquinoline-
4-carboxylic acid (20b)ꢀBuff crystals; mp 191–192°C; yield 88%; 1H
NMR: δ 1.25 (t, 3H, CH3), 4.24 (q, 2H, CH2), 4.75 (s, 2H, CH2), 7.19–7.24
(m, 3H, Ar-H), 7.33–7.40 (m, 2H, Ar-H), 7.45 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H),
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M.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidantsꢀ
ꢀ87
be exchanged by the solvent; MS: m/z 418 (M++2, 1%), 416 (M+, 1%).
Anal. Calcd for C22H14BrN3O (416.27): C, 63.48; H, 3.39; N, 10.09. Found:
C, 63.46; H, 3.38; N, 10.11.
8.44 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.12 (s, 1H, Quin-5-H), COOH proton
seems to be exchanged by the solvent; MS: m/z 432 (M++2, 32%), 430
(M+, 32%). Anal. Calcd for C20H16BrNO5 (430.25): C, 55.83; H, 3.75; N,
3.26. Found: C, 55.85; H, 3.77; N, 3.29.
ABTS antioxidant assay
Synthesis of 4-(1H-benz[d]imidazol-1-yl)-
3-phenyl-6-substituted quinolin-2-ols (21a,b)
A mixture of 17a,b (10 mmol) and o-phenylenediamine (1.08 g, 10
mmol) was thoroughly ground with a pestle in a mortar at room tem-
perature in an open atmosphere until the overall mixture turned into
a melt. The melted mixture was then heated in a sand bath at 140°C
for 1–2 h. The progress of the reaction was monitored by TLC. Afer
completion, the melt was cooled, poured over ice water, filtered,
washed with water, dried and crystallized from water.
The assay was conducted by using a previously published proce-
dure [16] with the following modifications. The major change was
the use of manganese dioxide instead of potassium persulfate. The
ABTS solution was prepared in concentration of 0.1 g/100 mL. The
amount of MnO2 used was 25 mg/mL. All reagents were prepared in
phosphate buffer (pH 7, 0.1 m), ABTS/MnO2 ꢀ= ꢀ 2:3. The mixture was
+
shaken, centrifuged and filtered to give and the green-blue ABTSꢀ× ꢀ
radical solution, the color of which remained stable for more than
1 h. For measurements, the absorbance at 734 nm was adjusted to
approximately 0.2. The control 2% solution of antioxidant ascorbic
acid was used. The concentration of each test sample was 0.01 mg/
mL in methanol/phosphate buffer (1:1). The following function was
used: the percent inhibition of superoxide productionꢀ= ꢀ[(control
absorbance – test absorbance)/control absorbance]ꢀ× ꢀ100.
4-(1H-Benz[d]imidazol-1-yl)-6-methyl-3-phenylquinolin-2-ol
(21a)ꢀWhite crystals; mp ꢀ> ꢀ300°C; yield 83%; 1H NMR: δ 2.33 (s, 3H,
CH3), 7.30–7.38 (3H, m, Ar-H), 7.60 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.15 (d,
J ꢀ= ꢀ 8 Hz, 1H, Quin-8-H), 8.19–8.25 (m, 2H, Ar-H), 8.28–8.35 (m, 4H,
Ar-H), 8.50 (s, 1H, Quin-5-H), 8.98 (s, 1H, OH, D2O exchangeable),
NH proton seems to be exchanged by the solvent; MS: m/z 352 (M++1,
4%), 351 (M+, 5%). Anal. Calcd for C23H17N3O (351.40): C, 78.61; H, 4.88;
N, 11.96. Found: C, 78.63; H, 4.85; N, 11.99.
Acknowledgments: The authors are grateful to Profes-
sor Farid A. Badria, Department of Pharmacognosy, Fac-
ulty of Pharmacy, Mansoura University, for performing
the antioxidant assay and to Professor David W. Boykin,
Department of Chemistry, Georgia State University, for the
permission of performing NMR analysis.
4-(1H-Benz[d]imidazol-1-yl)-6-bromo-3-phenylquinolin-2-ol
(21b)ꢀWhite crystals; mp 209–211°C; yield 79%; 1H NMR: δ 7.30–7.38
(3H, m, Ar-H), 7.60 (d, J ꢀ= ꢀ 8 Hz, 1H, Quin-7-H), 8.15 (d, J ꢀ= ꢀ 8 Hz, 1H,
Quin-8-H), 8.19–8.25 (m, 2H, Ar-H), 8.28–8.35 (m, 4H, Ar-H), 8.50
(s, 1H, Quin-5-H), 8.98 (s, 1H, OH, D2O exchangeable), NH seems to
Received September 22, 2013; accepted December 22, 2013
References
[1] Takayama, K.; Xiong, Y.; Miura, M. Neuronal expression of Fos
protein in the paraventricular nucleus of the hypothalamus after
i.p. injection of ulcergenic cinchophen. Neurosci. Lett. 1994,
172, 55–58.
[2] Dexter, D. L.; Hesson, D. P.; Ardecky, R. J.; Gao, G. V.;
Tipett, D. L.; Dusak, B. A.; Paull, K. D.; Plowman, J.;
Delarco, B. M.; Narayanan, V. L.; Forbes, M. Activity of a novel
4-quinolinecarboxylic acid, NSC 368390 [6-fluoro-2-(2-fluoro-
1,1-biphenyl-4-yl)-3-methyl-4-quinolinecarboxylic acid sodium
salt], against experimental tumors. Cancer Res. 1985, 45,
5563–5568.
[3] Batt, D. G.; Copeland, R. A.; Dowling, R. A.; Gardner, T. L.; Jones,
E. A.; Orwat, M. J.; Pinto, D. J.; Pitts, W. J.; Magolda, R. L.; Jaffee,
B. D. Immunosuppressive structure-activity relationships of
brequinar and related cinchoninic acid derivatives. Bioorg. Med.
Chem. Lett. 1995, 5, 1549–1554.
[4] Simon, J.; Bunim, J. The anti-rheumatic effects of 3-hydroxy-
2-phenylcinchoninic acid (Hpc) in gout, rheumatic fever, and
rheumatoid arthritis. J. Am. Med. Sci. 1951, 222, 523–529.
[5] Smith, P. W.; Wyman, P. A.; Lovell, P.; Goodacre, C.;
Serafinowska, H. T.; Vong, A.; Harrington, F.; Flynn, S.; Bradley,
D. M.; Porter, R.; Coggon, S.; Murkitt, G.; Searle, K.; Thomas,
D. R.; Watson, J. M.; Martin, W.; Wu, Z.; Dawson, L. A. New
quinoline NK3 receptor antagonists with CNS activity. Bioorg.
Med. Chem. Lett. 2009, 19, 837–840.
[6] Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst, A.
D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.; Rigolio, R.;
Luttmann, M.; Vecchietti, V.; Hay, D. W. Discovery of a novel
class of selective non-peptide antagonists for the human
neurokinin-3-receptor. 1. Identification of the 4-quinolinecar-
boxamide framework. J. Med. Chem. 1997, 40, 1794–1807.
[7] Kaila, N.; Janz, K.; Huang, A.; Moretto, A.; DeBernardo, S.; Bedard,
P. W.; Tam, S.; Clerin, V.; Keith, J. C., Jr.; Tsao, D. H. H.; Sushkova,
N.; Shaw, G. D.; Camphausen, R. T.; Schaub, R. G.; Wang, Q.
2-(4-Chlorobenzyl)-3-hydroxy-7,8,9,10-tetrahydrobenzo[H]
quinoline-4-carboxylic acid (PSI-697): identification of a clinical
candidate from the quinoline salicylic acid series of P-selectin
antagonists. J. Med. Chem. 2007, 50, 40–64.
[8] Vassout, A.; Veenstra, S.; Hauser, K.; Ofner, S.; Brugger, F.;
Schilling, W.; Gentsch, C. NKP608: a selective NK-1 receptor
antagonist with anxiolytic-like effects in the social interaction
and social exploration test in rats. Regul. Pept. 2000, 96, 7–16.
[9] Mekouar, K.; Mouscadet, J. F.; Desmaele, D.; Subra, F.; Leh, H.;
Savoure, D.; Auclair, C.; d’Angelo, J. Styrylquinoline derivatives:
a new class of potent HIV-1 integrase inhibitors that block HIV-1
replication in CEM cells. J. Med. Chem. 1998, 41, 2846–2857.
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Download Date | 10/1/14 3:21 PM

ꢁꢁꢁꢂ
88ꢀ ꢀM.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants
[10] Liu, Z.-Q.; Han, K.; Lin, Y.-J.; Luo, X.-Y. Antioxidative or
prooxidative effect of 4-hydroxyquinoline derivatives on
free-radical-initiated hemolysis of erythrocytes is due to its
distributive status. Biochim. Biophys. Acta 2002, 1570, 97–103.
[11] Detsi, A.; Bouloumbasi, D.; Prousis, K. C.; Koufaki, M.;
Athanasellis, G.; Melagraki, G.; Afantitis, A.; Igglessi-
Markopoulou, O.; Kontogiorgis, Ch.; Hadjipavlou-Litina, D. J.
Design and synthesis of novel quinolinone-3-aminoamides
and their α-lipoic acid adducts as antioxidant and
anti-inflammatory agents. J. Med. Chem. 2007, 50, 2450–2458.
[12] El Bakkali, M.; Ismaili, L.; Tomassoli, I.; Nicod, L.; Pudlo, M.;
Refouvelet, B. Pharmacophore modelling and synthesis of
quinoline-3-carbohydrazide as antioxidants. Int. J. Med. Chem.
2011, article ID 592879.
[13] Arfa, K.; Shamim, A.; Sarwat, J.; Aneela, K.; Kiran, R.; Sohail, H.
Benzimidazole derivatives: active class of antioxidants. Int. J.
Sci. Eng. Res. 2013, 4, 1674–1685.
[14] Dumas, J. M.; Peurichard, H.; Gomel, M. CX4·base interactions
as models of weak charge-transfer interactions: comparison
with strong charge-transfer and hydrogen-bond interactions.
J. Chem. Res. 1978, 2, 54–55.
[15] Rainer, W.; Markus, O. Z.; Andreas, L.; Andreas, C. J.;
Frank, M. B. Principles and applications of halogen bonding in
medicinal chemistry and chemical biology. J. Med. Chem. 2013,
56, 1363–1388.
[16] Miller, N. J.; Rice-Evans, C. Factors influencing the antioxidant
activity determined by the ABTS+ radical cation assay. Free
Radical Res. 1997, 26, 195–199.
[17] Sandmeyer, T. Isonitrosoacetanilides and their condensation
to form isatin derivatives. Helv. Chim. Acta 1919, 2, 234–242.
[18] Cragoe, E. J.; Robb, C. M.; Bealor, M. D. The synthesis of
3-hydroxycinchoninic acid and certain of its derivatives.
J. Org. Chem. 1953, 18, 552–560.
indeno[1,2-c]quinoline derivatives. Bioorg. Med. Chem. 2008,
16, 3153–3162.
[21] Kumar, B. V. S.; Vaidya, S. D.; Kumar, R. V.; Bhirud, S. B.;
Mane, R. B. Synthesis and anti-bacterial activity
of some novel 2-(6-fluorochroman-2-yl)-1-alkyl/acyl/aroyl-
1H-benzimidazoles. Eur. J. Med. Chem. 2006, 41,
599–604.
[22] Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu, K. R.
Regioselective aluminium chloride induced heteroarylation
of pyrrolo[1,2-b]pyridazines: its scope and application.
Tetrahedron 2002, 58, 9933.
[23] Chiellini, G.; Nguyen, N.-H.; Apriletti, J. W.; Baxter, J. D.;
Scanlan, T. S. Synthesis and biological activity of novel thyroid
hormone analogues: 5′-aryl substituted GC-1 derivatives.
J. Biomed. Chem. 2002, 10, 333–346.
[24] Garudachari, B.; Satyanarayana, M. N.; Thippeswamy, B.;
Shivakumar, C. K.; Shivananda, K. N.; Hegde, G.; Isloor, A. M.
Synthesis, characterization and antimicrobial studies of some
new quinoline incorporated benzimidazole derivatives. Eur. J.
Med. Chem. 2012, 54, 900–906.
[25] Yu, H.; Kawanishi, H.; Koshima, H. Microwave-assisted
synthesis of aryl and heteroaryl derivatives of benzimidazole.
Heterocycles 2003, 60, 1457–1460.
[26] Romanenko, I. V.; Sheinkman, A. K.; Baranov, S. N.; Poltavets,
V. N.; Klyuev, N. A. Quaternary salts of quinolybenzimidazoles.
Chem. Heterocycl. Comp. 1980, 16, 1261–1267.
[27] Von der Saal, W.; Hoelck, J. P.; Kampe, W.; Mertens, A.; Mueller-
Beckmann, B. Nonsteroidal cardiotonics. 2. The inotropic
activity of linear, tricyclic 5-6-5 fused heterocycles. J. Med.
Chem. 1989, 32, 1481–1491.
[28] Saudi, M. N. S.; Rostom, S. A. F.; Fahmy, H. T. Y.; El Ashmawy,
I. M. Synthesis of 2-(4-biphenylyl)quinoline-4-carboxylate
and carboxamide analogs. New human neurokinin-3 (hNK-3)
receptor antagonists. Arch. Pharm. Pharm. Med. Chem. 2003,
336, 165–174.
[29] Alam, M.; Younas, M.; Zafar, M. A.; Naeem, P. 7313u: an
improved synthesis of isatin. J. Sci. Ind. Res. 1989, 32, 246.
[30] Ursula, M.; France, B.; Manfred, S. 3-Fluoro-2-quinolones from
anilines. Tetrahedron 1996, 52, 3223–3228.
[19] Küçükgüzel, G.; Kocatepe, A.; De Clercq, E.; Şahin, F.; Güllüce,
M. Synthesis and biological activity of 4-thiazolidinones,
thiosemicarbazides derived from diflunisal hydrazide.
Eur. J. Med. Chem. 2006, 41, 353–359.
[20] Tseng, Ch.-H.; Chen, Y.-L.; Lu, P.-J.; Yang, Ch.-N.; Tzeng, Ch.-C.
Synthesis and antiproliferative evaluation of certain
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