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

Mohammed A. Massoud 1 , Serry A. El Bialy 1 , Waleed A. Bayoumi 1 , and Walaa M. El Husseiny 1
  • 1 Faculty of Pharmacy, Department of Pharmaceutical Organic Chemistry, Mansoura University, Mansoura 35516, Egypt
Mohammed A. Massoud, Serry A. El Bialy, Waleed A. Bayoumi and Walaa M. El Husseiny

Abstract

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.

Introduction

Quinoline derivatives are an important structural moiety in a number of chemotherapeutic agents and biologically active natural products. Several derivatives of cinchoninic acid (quinoline-4-carboxylic acid, 1) are important quinoline derivatives, including the abandoned analgesic agent cinchophen (2) [1] and brequinar sodium (3) that has been discovered as an anticancer agent [2] and later found to have immunosuppressive activity [3]. 3-Hydroxy-2-phenylcinchoninic acid (HPC, 4) has been reported to possess antirheumatic effects [4]. Other derivatives have been reported to show antipsychotic [5], antiallergic [6], antiarthritic [7] and anxiolytic activities [8]. In addition, a series of styrylquinoline derivatives that contain a COOH 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)ethenyl]-7-quinolinecarboxylic acid (5) [9] (Figure 1). Furthermore, substituted quinolones/hydroxyquinolines have been investigated for their antioxidant activity. Among important derivatives are 7-chloro-4-hydroxyquinoline (6) and 7-fluoro-4-hydroxyquinoline (7), which have been characterized by their antioxidant effect against free radical initiated peroxidation [10]. Additional synthetic quinolone derivatives with effective antioxidant activity are TA 270 (8) [11] and quinoline-3-carbohydrazides (9) [12] (Figure 1). 2-Substituted benzimidazoles were recently reported to possess antioxidant activity [13]. Based on the previous data and literature review, new starting synthons were designed and synthesized: 3-aryl-2-hydroxyquinoline-4-carboxylic acids (17a,b) and 2-aryl-3-hydroxyquinoline-4-carboxylic acids (12a-d). 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-benzimidazolyl 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 donating and the other is electron withdrawing (-CH3 and -Br respectively) were designed to discover their effect on potentiation of the antioxidant activity. The introduction of the latter group is useful where bromo-substituent as halogen bonding of the type R−X···Y−R′, where the halogen X acts as a Lewis acid and Y can be any electron donor moiety (electrostatic attraction) has been successfully harnessed for lead identification and optimization. In addition, halogenated aromatic systems are considered as common scaffolds in medicinal chemistry [14, 15]. As part of this work, a series of quinoline derivatives were synthesized and evaluated for their antioxidant activity using an improved ABTS decolorization assay [16]. ABTS is 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt.

Figure 1
Figure 1

Biologically important hydroxyquinolines and quinolinecarboxylic acids.

Citation: Heterocyclic Communications 20, 2; 10.1515/hc-2013-0163

Results and discussion

Chemistry

The structural core of quinoline has generally been synthesized by various conventional reactions such as Skraup, Doebner-Von Miller, Friedlander, Pfitzinger, Conrad-Limpach and Combes. These classical syntheses are well known and still used frequently for the preparation of quinoline backbone. However, these methods for quinoline synthesis often do not allow for adequate diversity and substitution on the quinoline ring system. Among the synthetic strategies which could be conceived for the synthesis of quinoline derivatives, the Pfitzinger reaction offers a very convenient synthetic entry to the quinoline-4-carboxylic acid derivatives from isatins and a ketone.

Synthesis of the substituted quinoline-4-carboxylic acid derivatives 12a–d, which are the starting compounds of Scheme 1, was achieved through Pfitzinger reaction by heating isatins 10a,b [17] with compounds 11a,b [18] in an aqueous/alcoholic KOH solution. The conversion of compounds 12a–d into their esters 13a–d was accomplished by using Fischer esterification [19], that is, heating 12a-d in methanol in the presence of sulfuric acid as a catalyst and a dehydrating agent. Benzimidazole derivative 14 was obtained by conventional condensation of 12b with o-phenylenediamine under solvent-free condition. Esterification of 12b with 8-hydroxyquinoline afforded the ester 15. O-Acetylated compounds 16a–d were obtained by heating of the respective substrates 12a–d with a mixture of acetic anhydride and acetic acid (Scheme 1). Synthesis of 2-hydroxyquinoline-4-carboxylic acid derivatives 17a,b was achieved through reaction of isatin derivatives 10a,b and phenyl acetic acid via fusion in presence of sodium acetate as a catalyst (Scheme 2) [20]. The conversion of 17a,b into their methyl esters 18a,b was achieved through esterification following the same procedure already mentioned for the esters 13a–d. Alkylation and aralkylation of compounds 18a,b at the 2-hydroxy group affording 19a,b was achieved through Williamson ether synthesis [21]. In a similar way, alkylation of the 2-hydroxyl group of compounds 17a,b with ethyl bromoacetate in DMF using K2CO3 as a catalyst to afford esters 20a,b [22, 23]. In addition, treatment of the carboxylic acids 17a,b with o-phenylenediamine furnished the respective benzimidazoles 21a,b (Scheme 2). The synthesis of new target 2- or 3-hydroxyquinoline 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-hydroxylated quinolone derivatives have been previously obtained by using several synthetic methods [24–28].

Scheme 1
Scheme 1

Reagents 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.

Citation: Heterocyclic Communications 20, 2; 10.1515/hc-2013-0163

Scheme 2
Scheme 2

Reagents 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.

Citation: Heterocyclic Communications 20, 2; 10.1515/hc-2013-0163

ABTS antioxidant assay

The synthesized compounds were evaluated for their antioxidant activity using an improved ABTS decolorization assay [16]. The assay that uses ABTS, 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt, is a radical cation decolorization test. This spectrophotometric 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 ABTS·+ radical cation, generated by oxidation of ABTS, is quantified spectrophotometrically. The results of the antioxidant screening are shown in Table 1.

Table 1

Results of ABTS antioxidant assay.

Tested compoundSample absorbance (mean)% InhibitionTested compoundSample absorbance (mean)% Inhibition
Control0.5120.0016c0.4737.20±0.29
Ascorbic acid0.05190.04±0.3116d0.4668.97±0.41
12a0.4747.51±0.0217a0.5041.65±0.19
12b0.4914.09±0.0217b0.4904.29±0.24
12c0.4737.60±0.2918a0.4914.19±0.13
12d0.4668.97±0.4018b0.43614.82±0.29
13a0.5120.00±0.0019a0.44612.87±0.39
13b0.39423.02±0.5519b0.45810.63±0.35
13c0.5041.65±0.0819c0.29043.41±0.24
13d0.5041.65±0.1819d0.33534.53±0.47
140.04896.00±0.5220a0.26648.09±0.45
150.4668.97±0.4520b0.11477.65±0.87
16a0.45810.63±0.5721a0.05093.00±0.64
16b0.4737.20±0.1921b0.04994.00±0.55

Data are expressed as mean±SEM, n=3; SEM is standard error of the mean.

Conclusions

The results summarized in Table 1 reveal that 2- or 3-hydroxyquinoline 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 bidentate chelator (-OH at C3 and –NH of benzimidazole) for (Fe2+, Cu2+, Zn2+), thus preventing metal oxidation catalysis, while the high antioxidant activity in 21a,b may be potentiated by benzimidazole ring. However, those 2- or 3-hydroxyquinoline-benzimidazole hybrids may be regarded as lead compounds in combating oxidative stress. Further structural modification at C4 is needed for studying the effect of other functional groups on antioxidant activity.

Experimental

Chemistry

Melting points were recorded using a Fisher-Johns melting point apparatus and were uncorrected. 1H NMR spectra (400 MHz) were 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 technique on silica gel plates 60 F245 E. Merk, and the spots were visualized 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, 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].

Synthesis of 2-aryl-3-hydroxy-6-substituted quinoline-4-carboxylic acids (12a–d)

A mixture of acetoxy ketone 11a,b (5 mmol), 5-substituted isatin 10a,b (5 mmol) and KOH (1.28 g, 23 mmol) in 50% aqueous ethanol (20 mL) was heated under reflux for 24 h. Then, the reaction mixture was diluted with aqueous ethanol (20 mL, 30%) and neutralized with 50% acetic acid. The resultant precipitate was filtered, dried and crystallized from ethanol.

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 exchangeable), 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.

6-Bromo-3-hydroxy-2-(4-methylphenyl)quinoline-4-carboxylic acid (12d)

Yellow crystals; mp 180–182°C; yield 80%; 1H 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 proton 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, 3.91. Found: C, 57.03; H, 3.40; N, 3.92.

General procedure for synthesis of methyl 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. After cooling, the mixture was poured into ice water and the resultant solid was filtered, washed with water, dried and crystallized from ethanol.

Methyl 3-hydroxy-6-methyl-2-phenylquinoline-4-carboxylate (13a)

White crystals; mp 118–120°C; yield 79%; 1H NMR: δ 2.30 (s, 3H, Ar-CH3), 3.40 (s, 3H, COOCH3), 7.10–7.22 (m, 3H, Ar-H), 7.32–7.43 (m, 2H, Ar-H), 7.34 (d, J = 8 Hz, 1H, Quin-7-H), 7.90 (d, J = 8 Hz, 1H, Quin-8-H), 8.00 (s, 1H, Quin-5-H), 11.22 (s, 1H, OH, D2O exchangeable); MS: 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.

Methyl 3-hydroxy-6-methyl-2-(4-methylphenyl)quinoline-4-carboxylate (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.

Methyl 6-bromo-3-hydroxy-2-phenylquinoline-4-carboxylate (13c)

White crystals; mp 135–136°C; yield 79%; 1H 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.

Methyl 6-bromo-3-hydroxy-2-(4-methylphenyl)quinoline-4-carboxylate (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 exchangeable); 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.

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-phenylenediamine (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 monitored by TLC. After completion, the melt was cooled, poured over ice water, and the solid material was filtered, washed, dried and crystallized 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.

Synthesis of quinolin-8-yl 3-hydroxy- 6-methyl-2-(4-methylphenyl)quinolin- 4-carboxylate (15)

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). The reaction mixture was heated under reflux for 6 h. After cooling, the precipitated solid was filtered, washed with ethanol, dried and crystallized from 95% ethanol: white crystals; mp 285–287°C; yield 71%; 1H 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.

Synthesis of 3-acetoxy-2-aryl-6-substitutedquinoline-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. After cooling, the mixture was poured into ice water and the resultant solid was filtered, washed with water, dried and crystallized from dichloromethane.

3-Acetoxy-6-methyl-2-phenylquinoline-4-carboxylic acid (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 solvent; 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.

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.

3-Acetoxy-6-bromo-2-phenylquinoline-4-carboxylic acid (16c)

White crystals; mp 195–197°C; yield 86%; 1H 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 2-hydroxy-3-phenyl-6-substituted quinoline-4-carboxylic acids (17a,b)

A mixture of 5-methyl or 5-bromoisatin (15 mmol), phenylacetic acid (3.57 g, 26.25 mmol) and sodium acetate (0.3 g) was heated at 200°C for 3 h. After cooling, sodium hydroxide solution (20 mL, 30%) was 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.

2-Hydroxy-6-methyl-3-phenylquinoline-4-carboxylic acid (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.

6-Bromo-2-hydroxy-3-phenylquinoline-4-carboxylic acid (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-hydroxy-3-phenyl-6-substitutedquinoline-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. After cooling, the precipitated solid was filtered, washed with methanol, dried and crystallized from methanol.

Methyl 2-hydroxy-6-methyl-3-phenylquinoline-4-carboxylate (18a)

White crystals; yield 90%; mp 263–265°C; 1H NMR: δ 2.30 (s, 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.

Methyl 6-bromo-2-hydroxy-3-phenylquinoline-4-carboxylate (18b)

White crystals; mp 247–248°C; yield 91%; 1H 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.

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. After cooling, the solid product was filtered, washed with water, dried and crystallized from absolute ethanol.

Methyl 2-methoxy-6-methyl-3-phenylquinoline-4-carboxylate (19a)

Yellow crystals; mp 262–264°C; yield 92%; 1H 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.

Methyl 6-bromo-2-methoxy-3-phenylquinoline-4-carboxylate (19b)

Yellow crystals; mp 250–251°C; yield 90%; 1H 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.

Methyl 2-benzyloxy-6-methyl-3-phenylquinoline-4-carboxylate (19c)

Yellow crystals; mp 270–272°C; yield 89%; 1H 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.

Synthesis of 6-substituted-2-{[(ethoxycarbonyl)methyl]oxy}-3-phenylquinoline-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. After cooling, the mixture was poured on ice water and the resultant solid was filtered, washed with water, dried and crystallized from water.

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.

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), 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.

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 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 reaction was monitored by TLC. After completion, the melt was cooled, poured over ice water, filtered, washed with water, dried and crystallized from water.

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.

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 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.

ABTS antioxidant assay

The assay was conducted by using a previously published procedure [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 ABTS×+ 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 production=[(control absorbance – test absorbance)/control absorbance]×100.

Acknowledgments

The authors are grateful to Professor Farid A. Badria, Department of Pharmacognosy, Faculty 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.

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If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [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.

    • PubMed
  • [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-quinolinecarboxamide 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.

  • [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. Acta2002, 1570, 97–103.

    • PubMed
  • [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.

    • Crossref
  • [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. Acta1919, 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.

  • [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 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. Tetrahedron2002, 58, 9933.

    • Crossref
  • [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. Heterocycles2003, 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.

    • Crossref
  • [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.

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    Biologically important hydroxyquinolines and quinolinecarboxylic acids.

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    Reagents 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.

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    Reagents 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.