DOI 10.1515/hc-2013-0163 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: *Corresponding author: Waleed A. Bayoumi, Faculty of Pharmacy, ester derivatives ( , and ), O-acetyl derivatives Department of Pharmaceutical Organic Chemistry, 13a-d 15 18a,b Mansoura University, Mansoura 35516, Egypt, (16a-d) and O-alkyl/aralkyl derivatives (19a-d and 20a,b). e-mail: [email protected] In addition, a heterocyclic hybrid system, in which 2- or Mohammed A. Massoud, Serry A. El Bialy and Walaa M. El Husseiny: 3-hydroxyquinoline ring is hybridized at C4 with 2-benzimi- Faculty of Pharmacy, Department of Pharmaceutical Organic dazolyl ring (14 and 21a,b) was designed and synthesized. Chemistry, Mansoura University, Mansoura 35516, Egypt The effect of structural modification at C6 of the quinoline with two lipophilic groups one of which is electron donat- 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 group at position 7 and an OH group at position 8 of the Results and discussion 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 82 M.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants O OH O OH O ONa O OH F OH N N N F N 1 2 4 3 OH OH OH HOOC N OH OH Cl N F N OH 5 6 7 OH R O O (CH ) OH O 2 7 R=4-OH H CO N 3 N O N 5-OCH3 H 5-CH OH 3 CH3 N O HO H OCH 3 8 9 Figure 1 Biologically important hydroxyquinolines and quinolinecarboxylic acids. O R1 O O O R1 OH N H 10a,b N R2 13a-d R2 OAc O N NH 11a,b iii OH i, ii 75–79% 80–85% N iv HO O 14 77% R1 OH N v N R2 71% 12a-d O O OH 82–86% Entry 1 2 v R R i a CH3 H N b CH3 CH3 HO O 15 c Br H 1 R OCOCH3 d Br CH3 N 2 16a-d R 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. 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 M.A. Massoud et al.: Hydroxyquinoline-4-carboxylic acid derivatives as antioxidants 83 O HO O O O 1 R 1 i 1 ii R O R N 80–83% 90–91% H N OH N OH Entry R1 R2 10a,b 17a,b 18a,b a CH3 CH3 iii v iv b Br CH3 88–92% 82–87% c CH3 CH2Ph 79–83% d Br CH2Ph HO O N NH O O 1 R 1 R1 R O N O R2 N O N OH O 21a,b 20a,b 19a-d 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. 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 1 Results of ABTS antioxidant assay. Tested Sample % Inhibition Tested Sample % Inhibition compound absorbance compound absorbance (mean) (mean) Control 0.512 0.00 16c 0.473 7.20 ± 0.29 Ascorbic acid 0.051 90.04 ± 0.31 16d 0.466 8.97 ± 0.41 12a 0.474 7.51 ± 0.02 17a 0.504 1.65 ± 0.19 12b 0.491 4.09 ± 0.02 17b 0.490 4.29 ± 0.24 12c 0.473 7.60 ± 0.29 18a 0.491 4.19 ± 0.13 12d 0.466 8.97 ± 0.40 18b 0.436 14.82 ± 0.29 13a 0.512 0.00 ± 0.00 19a 0.446 12.87 ± 0.39 13b 0.394 23.02 ± 0.55 19b 0.458 10.63 ± 0.35 13c 0.504 1.65 ± 0.08 19c 0.290 43.41 ± 0.24 13d 0.504 1.65 ± 0.18 19d 0.335 34.53 ± 0.47 14 0.048 96.00 ± 0.52 20a 0.266 48.09 ± 0.45 15 0.466 8.97 ± 0.45 20b 0.114 77.65 ± 0.87 16a 0.458 10.63 ± 0.57 21a 0.050 93.00 ± 0.64 16b 0.473 7.20 ± 0.19 21b 0.049 94.00 ± 0.55 Data are expressed as mean ± SEM, n = 3; SEM is standard error of the mean.