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Medicinal Chemistry Research

, Volume 23, Issue 11, pp 4907–4914 | Cite as

Chromenone and quinolinone derivatives as potent antioxidant agents

  • Praveen Vats
  • Vera Hadjimitova
  • Krassimira Yoncheva
  • Abha Kathuria
  • Antara Sharma
  • Karam Chand
  • Arul J. Duraisamy
  • Alpesh K. Sharma
  • Atul K. Sharma
  • Luciano Saso
  • Sunil K. Sharma
Original Research

Abstract

The antioxidant activity (AOA) of three different classes of phenolic compounds viz chromen-2-ones, chromen-4-ones, and quinolin-2-ones was systematically studied using DPPH, ABTS, FRAP, and in vitro lipid peroxidation inhibition assays. The effect of incorporation of hydrophobic group on AOA was also studied. In DPPH, ABTS, and FRAP assays, the highest AOA was registered for the dihydroxy chromenones among all the phenolic derivatives. Presence of alkyl group led to reduction in AOA in the above three assays. However, in lipid peroxidation inhibition assay for selected compounds, incorporation of alkyl group led to enhancement in AOA. The AOA of few compounds was observed to be more than three times higher in comparison to standard “Trolox” in lipid peroxidation inhibitory assay.

Keywords

Antioxidant activity Chromen-2-ones Chromen-4-ones Quinolin-2-ones Lipid peroxidation inhibitory activity 

Introduction

In vivo, lipid oxidation may play a role in coronary heart disease, atherosclerosis, cancer, and the aging process. Lipid oxidation occurs when reactive oxygen species (ROS) reacts with lipids in a series of free radical chain reactions that lead to complex chemical changes. Oxidation of lipids in foods causes quality loss and is thus a major concern for such industry (Devasagayam et al., 2004). Antioxidants, the compounds that can delay or inhibit lipid oxidation, when added to foods can minimize rancidity and retard the formation of toxic oxidation products.

The antioxidant property of a compound is attributed to its ability of (a) oxygen radical scavenging, (b) inhibiting cellular microsomal P-450-linked mixed function oxidation (MFO) reaction, and (c) suppressing the formation of ROS. Thus, antioxidants are considered as remedies to overcome the lethal action of oxygen free radicals (Malhotra et al., 2008). A criterion for a good antioxidant is that the compound should contain a highly labile hydrogen atom forming a radical; the radical formed should be stable and non-reactive so that it does not participate in the reactive species (RS) propagation step. Sterically hindered phenolic compounds satisfy most of the above-mentioned requirements. Thus, the anti-oxidant and radical scavenging effects of polyphenols are highly cited and reviewed (Prochazkova et al., 2011; Bubols et al., 2013). Phenolic compounds are also abundant natural products as they occur often in significant concentrations (0.5–1.5 %). In model systems, many natural products show antioxidant activity (AOA), for instance, tocopherols (Seppanen et al., 2010; Halliwell et al., 2005), flavonoids (Terao, 1999; Cao et al., 1997), coumarins (Kumar et al., 2005; Raj et al., 1998), phenolic acids (Kartika et al., 2007; Yoshida et al., 2010), cinnamates (Garrido et al., 2012), etc. The antioxidant potential of dietary phenolic compound from fruits and vegetables has been well explored, and there is always an ever increasing demand to identify more effective antioxidants that are analogs of naturally occurring phenolic compounds. Herein, we have designed and developed a series of phenolic derivatives of chromen-2-ones, chromen-4-ones, and quinolin-2-ones and evaluated their antioxidant potential using DPPH, ABTS, and FRAP assays. The lipid peroxidation inhibitory activity of few select compounds was also studied.

Chromen-2-one (coumarin or benzopyran-2-one) affects the formation and scavenging of ROS and influence free radical-mediated oxidative damage (Raj et al., 1998; Pedersen et al., 2007). The derivatives viz 4-hydroxychromen-2-one, 7-hydroxychromen-2-one, 7,8-dihydroxychromen-2-one, 4-methylesculetin, and 7-hydroxy-4-methylchromen-2-one were found to possess potent radical scavenging ability (Lin et al., 2008). Although the chromenone core does not ensure the radical scanvenging activity by itself, but the phenolic character/hydroxy substitution on these cores is responsible for the radical scavenging activity through the formation of stable radical due to extended resonance stabilization by pyran ring (Raj et al., 1999) and Wenum et al. (2013).

In the present study, efforts have been made to compare the specificities of dihydroxy- and monohydroxychromen-2-ones on AOA, and to delineate a structure activity relationship (SAR) with special reference to the effect of alkyl group at the C-3 position of the chromen-2-one nucleus. Further, the radical scavenging activity was studied for 9-hydroxy pyranochromen-2-ones (911), obtained by the reaction of corresponding 3-alkyl-7,8-dihydroxychromen-2-ones with 2-methyl-but-3-ene-1-ol (Fig. 1).
Fig. 1

Hydroxy derivatives of chromen-2-ones and pyranochromen-2-ones

Chromen-4-ones, also known as chromones, are the important class of naturally occurring compounds containing 1-benzopyran-4-one skeleton and are ubiquitously found in the plant kingdom. Its derivatives are considered as privileged structure in chemotherapeutics as they possess a wide spectrum of biological activities that include anti-proliferative, anti-oxidant, anti-viral, anti-inflammatory, kinase inhibitory, anti-hypertensive, anti-allergic, anti-fungal, anti-cancer, and various others (Singh et al., 2002; Piao et al., 2002; Khan et al., 2009, 2010; Sersen et al., 2008). A few chromone-based antioxidants are reported to downregulate the expression of intercellular cell adhesion molecule-1 (ICAM-1) on endothelial cells (Kumar et al., 2007; Walther et al., 1999). In order to understand the mechanisms underlying the antioxidant activities and establishing structure–activity relationships, herein, efforts have been made to compare the AOA of differently substituted chromen-4-ones (Fig. 2).
Fig. 2

Hydroxychromen-4-ones and its acrylate derivatives

2-Quinolones (1-aza coumarins) account for the extraordinary range of biochemical and pharmacological activities in mammalian and other biological systems and have important effects in plant biochemistry and physiology, acting as antioxidants, enzyme inhibitors, anticancer, antiviral, antibacterial, anti-hypertensive, cardio tonic, diuretic, anti-inflammatory, and bronchodilator agents (Michael, 2008; Abeer and Mohsen, 2012). In this report, we have studied the anti-oxidant activity of few hydroxy derivatives of quinolin-2-ones (Fig. 3) and compared them with their chromen-2-one counterparts.
Fig. 3

Hydroxy derivatives of quinolin-2-ones

Materials and methods

Chemistry

The hydroxy coumarins 18 were synthesized following the procedure reported in the literature (Pechmann and Duisberg, 1883; Kathuria et al., 2009). The pyranocoumarins 911 were synthesized according to the earlier published procedure from our group (Kathuria et al., 2011). The hydroxy chromones 1214 and chromone acrylates 1520 were synthesized following the earlier published method from our group (Chand et al., 2014). Quinolin-2-ones (2224) too were synthesized according to the literature procedure (Priya et al., 2010).

8-Hydroxycoumarin (5)

A mixture of 10 mL hydrobromic acid and acetic acid (7:3) was added to 1 g of 2,3-dimethoxy cinnamic acid. The reaction mixture was refluxed for 12 h and then poured on crushed ice. The resulting precipitate was filtered and washed with water to yield 8-hydroxycoumarin. It was obtained as off white solid in 50 % yield. Mp = 158.9 °C; UV (acetonitrile) λ max: 296 and 326 nm; IR (KBr) ν max: 3,386.1 (OH), 1,706.9 (C=O), 1,576.3 cm−1; 1H NMR (400 MHz, CDCl3): δ 4.67 (1H, brs, OH), 6.39 (1H, d, J = 9.52 Hz, H-3), 6.99–7.02 (1H, m, H-5), 7.14 (2H, m, H-6 and H-7), 7.69 (1H, d, J = 9.52 Hz, H-4); 13C NMR (100.5 MHz, CDCl3): δ 116.31 (C-3), 118.33 (C-7), 118.99 (C-5) 119.14 (C-10), 124.85 (C-6), 141.84 (C-9), 143.57 (C-4), 144.17 (C-8), 160.04 (C-2).; HRMS calcd. for C9H6O3: 162.0317; found: 162.4670.

(E)-Ethyl 3-(7,8-dihydroxy-4-oxo-4H-chromen-3-yl)acrylate (21)

It was synthesized starting from corresponding hydroxyacetophenone by following the method reported earlier from our group (Chand et al., 2014). Mp = 232–234 °C; UV (MeOH) λ max: 270 and 290 nm; IR (KBr) ν max: 3,568.6 (OH), 1,672.0 (OCO), 1,638.0 (C=O), 1,611.2 (C=C) cm−1; 1H NMR (400 MHz, CDCl3): 1.25 (t, 3H, J = 6.6 Hz, H-2”), 4.16 (q, 2H, J = 6.5 Hz, H-1″), 6.97 (d, 1H, J = 8.8 Hz, H-5), 7.18 (d, 1H, J = 16.1 Hz, H-3′), 7.42–7.46 (m, 2H, H-2′ and H-6), 8.70 (s, 1H, H-2); 13C NMR (100.5 MHz, DMSO-d 6 ): 14.24 (C-2″), 59.98 (C-1″), 114.64 (C-6), 115.75 (C-2′), 117.08 (C-5), 117.05 (C-10) 119.69 (C-3), 133.15 (C-8), 136.87 (C-3′), 146.02 (C-9), 150.65 (C-2), 159.41 (C-7), 166.61 (C-1′), 175.06 (C-4).

Biology

Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), TPTZ (2,4,6,-tripyridyl-s-triazine), and ABTS (2,2′-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) were obtained from Sigma-Aldrich Co., USA. DPPH was obtained from Fluka (Buchs, Switzerland). Trolox was used as the reference antioxidant compound in all of the assays.

DPPH radical scavenging assay

The AOA was assessed by modifying the method of Blois (1958) using the DPPH assay. A solution of DPPH in ethanol (2 mL) was added to the solution of substance in ethanol (1 mL) or 1 mL ethanol for the blank. The final radical concentration was 0.09 mmol/L. The absorbance was read at 517 nm after 30 min of incubation. All the analyses were done in three replicates. Percentage inhibition of DPPH activity caused by 1 µM test compound or Trolox was calculated by the formula: % Inhibition = [(Blank OD − sample OD)/Blank OD] × 100. Trolox equivalent antioxidant capacity was calculated by the formula: TEAC = % Inhibition by sample/% Inhibition by Trolox.

ABTS radical scavenging assay

ABTS assay was done following the method of Re et al. (1999) with little modification. The ABTS radical cation was pregenerated by mixing 7 mM ABTS stock solution with 2.45 mM potassium persulfate (1:1) and incubating for 12–16 h in the dark at room temperature until the reaction gets complete and the absorbance becomes stable. Absorbance of ABTS was equilibrated to 1.5 (±0.02) by diluting with water at room temperature, then 1 mL of this solution was mixed with 1 mL of the test sample, and the absorbance was measured at 734 nm after 6 min. Percentage inhibition of ABTS activity caused by 1 µM test compound or Trolox was calculated by the same formula used for DPPH assay. TEAC too was calculated as per DPPH assay.

FRAP assay

The ferric reducing antioxidant power (FRAP) assay was done by the method of Benzie and Strain (1996). The FRAP reagent was freshly prepared by mixing TPTZ (2.5 mL, 10 mM in 40 mM HCl), 25 mL of 300 mM acetate buffer (pH 3.6), and 2.5 mL of FeCl3·H2O (20 mM) and warmed to 37 °C prior use. 150 µL of series of Trolox concentrations (0, 1, 2, 5, 10, 20, 50, 75, and 100 µM) or 10 µM test sample was mixed with 2,850 µL of working FRAP reagent, respectively, and incubated for 30 min in dark. The change in color intensity was read at 593 nm using a spectrophotometer. A plot of Trolox concentration versus absorbance (OD) was used to develop the slope equation. Using this equation, FRAP/10 µM test sample was calculated. TEAC of test compounds was calculated by the formula TEAC = FRAP of sample/FRAP of Trolox.

Lipid peroxidation inhibitory activity assay

In vitro lipid peroxidation inhibition was assayed by the method of Bishayee and Balasubramaniyam (1971). 100 μL of rat liver homogenate (25 %, w/v in 20 mM Tris–HCl buffer, pH 7.0) was incubated with Mohr’s salt (0.16 mM), ascorbic acid (0.06 mM), and different concentrations (0, 1, 2, 5, 10, 20, 50, 75, and 100 µM) of Trolox or test compounds in a final volume of 500 μL for 1 h at 37 °C. After incubation, 400 μL of initial reaction mixture was mixed with 200 μL sodium dodecyl sulfate (SDS) (8.1 %), 1.5 mL thiobarbituric acid (0.8 %), 1.5 mL acetic acid (20 %, pH 3.5), and 400 μL distilled water and kept in boiling water bath for 1 h. The reaction mixture was allowed to cool and then added 1 mL distilled water and 4 mL n-butanol:pyridine (15:1) mixture. The contents were shaken vigorously and centrifuged at 4,000 rpm for 10 min. The n-butanol–pyridine layer was removed, and UV absorption was recorded at 532 nm. Percentage inhibition of lipid peroxidation caused by different concentrations of Trolox and test samples was calculated by the same formula used for DPPH assay. The concentration of Trolox or test compound that caused 50 % inhibition was termed as IC50. TEAC was calculated by the formula TEAC = IC50 of Trolox/IC50 of sample.

Results and discussion

Chemistry

The AOA of three different classes of phenolic compounds viz chromen-2-ones (111), chromen-4-ones (1221), and quinolin-2-ones (2224) was systematically studied.

Synthesis of chromen-2-ones

7-Hydroxy-4-methylchromen-2-one (1) and 7,8-dihydroxy-4-methyl chromen-2-one (6) were synthesised in quantitative yields by Pechmann condensation of resorcinol and pyrogallol, respectively, with ethyl acetoacetate in the presence of sulfuric acid (Pechmann and Duisberg, 1883). The chromen-2-ones 24 and 78 were synthesized following the procedure reported by Kathuria et al. (2009). Synthesis of pyranochromen-2-ones (911) in turn was carried out according to the earlier published procedure from our group (Kathuria et al., 2011). 8-Hydroxychromen-2-one (5) was prepared starting from 2,3-dimethoxy cinnamic acid using a mixture of HBr/acetic acid that facilitates cyclization and deprotection of the methoxy group (Scheme 1).
Scheme 1

Synthesis of 8-hydroxychromen-2-one. i HBr, acetic acid (7:3), reflux, 12 h

Synthesis of chromen-4-ones

The hydroxychromen-4-ones 1214 and chromen-4-one acrylates 1521 were synthesized by following the method of Kumar et al. (2007). Synthesis of (E)-ethyl 3-(7,8-dihydroxy-4-oxo-4H-chromen-3-yl)acrylate (21) was carried out starting from the corresponding trihydroxyacetophenone by following the method reported earlier from our group (Scheme 2) (Chand et al., 2014).
Scheme 2

Synthesis of (E)-ethyl 3-(7,8-dihydroxy-4-oxo-4H-chromen-3-yl)acrylate. i Ac2O, pyridine, 6 h; ii POCl3, DMF, 50 °C, 13 h; iii CH2(COOH)2, pyridine, 1.5 h; iv ethanol, H2SO4 (1–2 drops) 12 h

Synthesis of quinolin-2-ones

Quinolin-2-ones 2224 were synthesized according to the literature procedure (Priya et al., 2010).

Antioxidant activity

Numerous studies on the AOA of chromen-2-ones and its derivatives have been carried out; however, the effect on AOA by incorporating hydrophobic alkyl group on chromenone/quinolinone skeleton has not been investigated earlier. In this report, we have meticulously compared the antioxidant efficacy of hydroxy derivatives of 3-alkyl-4-methylchromen-2-ones and pyranochromen-2-ones using DPPH, ABTS, and FRAP assays. Also, AOA of chromen-4-ones and quinolin-2-ones was studied. Few select compounds were assayed for their in vitro lipid peroxidation inhibition.

The AOA of compounds was compared with “Trolox” taken as standard and expressed as TEAC. In the present study, three types of chromen-2-one derivatives were screened for AOA, i.e., monohydroxychromen-2-ones (15), dihydroxychromen-2-ones (68), and pyranochromen-2-ones (911) having varied alkyl substituents (ethyl/hexyl/decyl) at C-3 position of coumarin skeleton.

In DPPH assay (Fig. 4), dihydroxy chromen-2-ones (68) were found to possess AOA comparable or even higher than the standard “Trolox”, whereas the AOA of monohydroxychromen-2-ones (15) is almost insignificant (for numerical values see supplementary information). In order to evaluate the significance of hydroxyl groups, the AOA of 7-hydroxy-4-methylchromen-2-ones (1) and 8-hydroxychromen-2-ones (5) was compared and both were found to exhibit weak AOA as compared to the dihydroxy analog 6. Although the pyranochromen-2-ones 911 are also monohydroxy chromenones, but these exhibit higher AOA than monohydroxychromen-2-ones, but lower than that of dihydroxychromen-2-ones. This suggest that ortho-dioxygenation at C-7 and C-8 is a primary requirement for AOA of chromen-2-ones. The reason for this strong AOA of ortho dihydroxy systems can be explained by taking into account the stability of the transient seminquinone radical formed after the H-atom transfer to a free radical as shown in Fig. 5 (Foti et al., 2005). Furthermore, among the dihydroxychromen-2-ones (68), the presence of an alkyl group at C-3 position reduces the AOA as compared to parent coumarin 6 that lacks such substituent (Fig. 4). The AOA of dihydroxycoumarin 6 was found to be more than twice (TEAC: 2.26) as compared to that of “Trolox”. Pyranochromen-2-ones (911) exhibit weaker AOA than 6 as well as “Trolox”. Among the hydroxychromen-4-one derivatives, an AOA pattern similar to chromen-2-ones was observed, i.e., dihydroxychromen-4-ones 14 and 21 exhibit high AOA (TEAC > 1) as compared to the monohydroxychromen-4-ones 12, 13, and 1520 in DPPH assay (Fig. 4). Quinolin-2-ones (2224) were observed to possess very low antioxidant potential in comparison to chromen-2-ones and chromen-4-ones (Fig. 4). Since in the literature, the AOA of compounds in different assays has been reported; it was decided to study the AOA of few select compounds in few other assay systems. Considering the preliminary investigation results in DPPH system, the compounds having TEAC of approximately 0.2 and higher were chosen for AOA screening in three systems, i.e., ABTS, FRAP, and lipid peroxidation inhibitory assays. Since compounds 15, 9, 12, 13, and 1520 showed very weak AOA in DPPH assay, these compounds were not studied further in other assays. In ABTS and FRAP assays, the compound 6 exhibits maximum AOA among chromen-2-ones (Figs. 6, 7). The AOA profile for remaining chromen-2-ones (7, 8, 10, and 11) for ABTS and FRAP assays was almost similar as observed in DPPH system (for numerical values see supplementary information). Chromen-4-ones 14 and 21 and quinolin-2-ones 2224, on the other hand, exhibit enhanced TEAC for both ABTS and FRAP assays in comparison to DPPH assay.
Fig. 4

TEAC of chromen-2-ones, chromen-4-ones, and quinolin-2-ones in DPPH assay

Fig. 5

Suggested mechanism of lipid superoxide-mediated radical formation from ortho-dihydroxycoumarin

Fig. 6

TEAC of chromen-2-ones, chromen-4-ones, and quinolin-2-ones in ABTS assay

Fig. 7

TEAC of chromen-2-ones, chromen-4-ones, and quinolin-2-ones in FRAP assay

The lipid peroxidation inhibitory activity of select compounds (68, 10, 11, 14 and 2124) was also studied. Quite interestingly in this assay, particularly, the C-3 alkyl dihyroxychromen-2-ones 7 and 8 exhibit a significant enhancement of the AOA. The AOA is 2–3-fold higher with respect to compound 6 and more than threefold as compared to “Trolox” (Fig. 8). A similar trend was observed for 3-alkyl pyranochromen-2-ones 10 and 11. Thus, C-3 alkyl substituted chromen-2-ones are weaker antioxidants than compound 6 as well as “Trolox” in DPPH, ABTS, and FRAP assays, but their lipid peroxidation inhibitory activity significantly exceeds the two compounds. Alkyl substituted chromen-4-one 21 showed either comparable (in DPPH assay) or lower (in ABTS and FRAP assays) AOA when compared with unsubstituted analog 14 (for numerical values see supplementary information). However, the compound 21 showed enhanced AOA in lipid peroxidation inhibition assay. Furthermore, quinolin-4-ones 23 and 24 C-3 alkyl substituent too showed improved lipid peroxidation inhibitory activity in comparison to the unsubstituted analog 22 as well as Trolox (Fig. 8).
Fig. 8

TEAC of select chromen-2-ones, chromen-4-ones, and quinolin-2-ones in in vitro lipid peroxidation inhibitory assay

Since the in vitro lipid peroxidation inhibition more closely resembles with the true biological systems, the observance of significant enhancement of AOA of C-3 alkyl substituted chromen-2-ones, pyranochromen-2-ones, chromen-4-ones, and quinolin-2-ones holds promise in the application of these compounds as efficient antioxidants. These results suggest that the incorporation of lipophilic group on a chromenone and quinolinone moiety enhances the interaction of the resulting compound with the lipids which are hydrophobic in nature, and thus an enhancement in AOA was observed. While in DPPH, ABTS, and FRAP assays, simply the radical scavenging effect or ferric reducing activity is studied, and thus hydrophobic alkyl substituents which reduce the aqueous dispersibility also decrease the AOA.

Conclusion

A total of 24 derivatives of chromen-2-ones, chromen-4-ones, and quinolin-2-ones were screened for AOA. It was observed that nature and position of the substituent have a great influence on their AOA. Among the eleven chromen-2-one derivatives and ten chromen-4-one derivatives screened, the dihydroxychromens showed the highest AOA. Pyranochromen-2-ones, on the other hand, exhibited moderate AOA but higher than the monohydroxy counterparts. The presence of an alkyl substituent at C-3 position of chromenone and quinolin-2-one reduces the AOA in DPPH, ABTS, and FRAP assays as compared to corresponding unsubstituted analogs. However, in lipid peroxidation inhibition assay, it was observed that the AOA of chromen-2-ones and quinolin-2-ones having C-3 alkyl substituent is significantly higher in comparison to the corresponding unsubstituted compounds.

Notes

Acknowledgments

We thank University of Delhi, Defence Research Development Organization (DRDO, India), Indo-German Science and Technology Center (IGSTC), and Council of Scientific and Industrial Research (CSIR) for financial support. The award of Junior/Senior Research Fellowships (JRF/SRF) by CSIR (to KC), University Grants Commission (to AKS at Delhi University) and by DRDO (to DAJ) is gratefully acknowledged.

Supplementary material

44_2014_1054_MOESM1_ESM.doc (109 kb)
Supplementary material 1 (DOC 109 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Praveen Vats
    • 1
  • Vera Hadjimitova
    • 2
  • Krassimira Yoncheva
    • 3
  • Abha Kathuria
    • 4
  • Antara Sharma
    • 5
  • Karam Chand
    • 4
  • Arul J. Duraisamy
    • 1
  • Alpesh K. Sharma
    • 1
  • Atul K. Sharma
    • 4
  • Luciano Saso
    • 6
  • Sunil K. Sharma
    • 4
  1. 1.Defence Institute of Physiology & Allied SciencesDelhiIndia
  2. 2.Department of Medical Physics and Biophysics, Medical FacultyMedical University of SofiaSofiaBulgaria
  3. 3.Department of Pharmaceutical Technology, Faculty of PharmacyMedical University of SofiaSofiaBulgaria
  4. 4.Department of ChemistryUniversity of DelhiDelhiIndia
  5. 5.Kirori Mal CollegeUniversity of DelhiDelhiIndia
  6. 6.Department of Physiology and Pharmacology “Vittorio Erspamer”Sapienza University of RomeRomeItaly

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