Synthesis of quinoline derivatives of tetrahydrocurcumin and zingerone and evaluation of their antioxidant and antibacterial attributes

Article abstract of DOI:10.1016/j.foodchem.2012.08.052

Tetrahydrocurcumin (THC, 1) and zingerone (2) are biologically active molecules originating from the important spices turmeric and ginger, respectively. Novel quinoline derivatives of THC and zingerone have been synthesised by an efficient protocol involving their reaction with substituted 2-aminobenzophenones and 2-aminoacetophenone. Radical-scavenging activities (RSA) of THC, zingerone and their quinoline derivatives were evaluated. The amino-substituted quinoline derivative of THC, 1e, showed antioxidant activity superior to those of 1 and 1a. Derivatives 1b, 1c, 1d and 1f exhibited relatively lower RSA at equimolar concentrations (～50-55 μmol). A similar trend was also seen in zingerone (2) and its derivatives (2a-2e), with 2e displaying the best RSA. Derivatives of THC (1a-1f) showed stronger antimicrobial activity than THC (1) against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Yersinia enterocolitica. Also, derivatives of zingerone (2b-2e) exhibited lower minimum inhibitory concentrations (MIC) values than zingerone (2) and its derivative, 2a for both Gram-positive and Gram-negative bacteria. The molecules may have potential pharmacological applications.

Full text of DOI:10.1016/j.foodchem.2012.08.052

Food Chemistry 136 (2013) 650–658
Contents lists available at SciVerse ScienceDirect
Food Chemistry
journal homepage: www.elsevier.com/locate/foodchem
Synthesis of quinoline derivatives of tetrahydrocurcumin and zingerone
and evaluation of their antioxidant and antibacterial attributes
J.R. Manjunatha a,c, B.K. Bettadaiah a,c, P.S. Negi b,c, P. Srinivas a,c,
⇑
a Department of Plantation Products, Spices and Flavour Technology, Central Food Technological Research Institute, Mysore 570 020, India
b Department of Human Resource Development, Central Food Technological Research Institute, Mysore 570 020, India
c Council of Scientific and Industrial Research, New Delhi, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 June 2012
Received in revised form 14 August 2012
Accepted 19 August 2012
Available online 13 September 2012
Tetrahydrocurcumin (THC, 1) and zingerone (2) are biologically active molecules originating from the
important spices turmeric and ginger, respectively. Novel quinoline derivatives of THC and zingerone
have been synthesised by an efficient protocol involving their reaction with substituted 2-aminobenz-
ophenones and 2-aminoacetophenone. Radical-scavenging activities (RSA) of THC, zingerone and their
quinoline derivatives were evaluated. The amino-substituted quinoline derivative of THC, 1e, showed
antioxidant activity superior to those of 1 and 1a. Derivatives 1b, 1c, 1d and 1f exhibited relatively lower
Keywords:
Quinolines
RSA at equimolar concentrations (ꢀ50–55
lmol). A similar trend was also seen in zingerone (2) and its
derivatives (2a–2e), with 2e displaying the best RSA. Derivatives of THC (1a–1f) showed stronger antimi-
crobial activity than THC (1) against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Yersinia
enterocolitica. Also, derivatives of zingerone (2b–2e) exhibited lower minimum inhibitory concentrations
(MIC) values than zingerone (2) and its derivative, 2a for both Gram-positive and Gram-negative bacteria.
The molecules may have potential pharmacological applications.
Tetrahydrocurcumin
Zingerone
Friedlander reaction
Radical scavenging activity
Antibacterial action
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
bioactive constituent of ginger (Pulbutr, Thunchomnang, Lawa,
Mangkhalathon, & Saenbol, 2011), is structurally similar to THC.
Turmeric (Curcuma longa) and ginger (Zingiber officinale) are
spices that belong to the Zingiberaceae family. Ginger, a common
ingredient for various foods and beverages, is also employed in
medicine for the treatment of various ailments like headaches, nau-
sea, rheumatism and colds. Turmeric is primarily used in Indian cui-
sine for its colouring characteristics. Curcuminoids, viz., curcumin,
demethoxycurcumin and bis-demethoxycurcumin, are the yellow
pigments of turmeric. Curcumin, the major constituent and a nutra-
ceutical used worldwide, exhibits potent anti-inflammatory, anti-
tumour and anti-cancer properties (Aggarwal, Kumar, Aggarwal,
& Shishodia, 2005; Gupta et al., 2011; Joe, Vijaykumar, & Lokesh,
2004; Sharma, Gescher, & Steward, 2005). Biotransformation of cur-
cumin to its reduced forms ꢁ di-, tri-, tetra-, hexa- and octahydro-
curcumins ꢁ has been demonstrated in mice models (Pan, Huang, &
Lin, 1999). Tetrahydrocurcumin (THC, 1), a stable metabolite of cur-
cumin, is indicated to play an important role in the biological effects
of curcumin (Anand et al., 2008). Tetrahydrocurcumin is obtained
by selective reduction of the olefinic bonds in curcumin. Zingerone
[4-(4-hydroxy-3-methoxyphenyl)-2-butanone, 2], an important
Both THC and zingerone contain a 4-hydroxy-3-methoxyphenyl
moiety and a carbonyl group in the side chain. These molecules,
being lipophilic have little solubility in aqueous systems. Our recent
attempts to render curcumin water-soluble by preparing its sugar
and amino acid derivatives led to the preparation of a large number
of curcumin derivatives, which exhibited potent antioxidant,
antimicrobial and antimutagenic properties comparable to, and in
several cases superior than, curcumin (Parvathy, Negi, & Srinivas,
2009, 2010). We also demonstrated that curcumin-b-diglucoside
prevented oligomer formation and inhibited fibril formation of
a-Synuclein, whose aggregation is centrally implicated in Parkin-
son’s disease (PD) (Bharathi, Parvathy, Srinivas, Indi, & Rao, 2012).
Clioquinol (5-chloro-7-iodoquinolin-8-ol), a quinoline compound,
its analogues and their possible beneficial effects via the Zn2+ and
Cu2+ chelating properties on neurodegenerative diseases and can-
cer have been explored in a variety of systems (Wang et al.,
2009). However, this compound has been shown to have SMON
toxicity. Also, the broad range of bio-activities associated with
quinolines has fascinated researchers leading to their chemical -
synthesis and the identification of newer applications. Compounds
with a quinoline ring are known to possess anti-asthmatic, antibac-
terial, anti-inflammatory and anti-hypertension attributes (Chen,
Fang, Sheu, Hsu, & Tzeng, 2001; Maguire, Sheets, Vety, Spada, &
Zilberstein, 1994). Quinolines with various substitutions at 2, 4
⇑
Corresponding author. Address: Department of Plantation Products, Spices and
Flavour Technology, Central Food Technological Research Institute, Cheluvamba
Mansion, Mysore 570 020, India. Tel.: +91 821 2512352; fax: +91 821 2517233.
E-mail address: psrinivas@cftri.res.in (P. Srinivas).
0308-8146/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.foodchem.2012.08.052

J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
651
and 6 positions have important bioactive attributes such as antimi-
crobial and antioxidant activities (Kouznetsov, Mendez, & Gomez,
2005). In the present study, we envisaged the preparation of the
quinoline derivatives of the important bioactive ingredients of cur-
cumin and ginger viz., THC and zingerone, which have the appropri-
ate functional moiety of keto groups with a methylene moiety at
the alpha position for reaction with aromatic amines via a Fried-
lander type reaction.
and acetone in the presence of KOH, at 30 psi hydrogen pressure
in the presence of Pd/BaSO4 in methanol (Kim & Kim, 2004).
2-Aminoacetophenone, 2-aminobenzophenones, BHA and 2,
2-diphenyl-1-picrylhydrazyl (DPPH) were procured from Sigma
Chemical Co. (St. Louis, MO, USA). 1H NMR and 13C spectra for
the compounds were recorded on a 500 MHz NMR spectrometer
(Bruker Avance, Reinstetten, Germany) using CDCl3 solvent.
Chemical shift values and coupling constants are given in d and
Hz, respectively. Mass spectral analyses of compounds were
carried out using MS (Waters Q-Tof Ultima, Manchester, UK) in
the ESI positive mode. Spectrophotometric studies were carried
out on an Ultraviolet–Visible Spectrometer (Cintra-10, GBC,
Australia). Thin-layer chromatographic (TLC) analysis was per-
formed on silica gel 60 F254 (Merck, Germany) coated on alumina
sheet with 3% methanol in chloroform as the developing solvent.
Isolation of the products was carried out by trituration of the crude
product with ethyl acetate and petroleum ether. All the chemicals
and petri-plates used for microbial studies were procured from Hi
Media Ltd., Mumbai, India.
Quinoline derivatives are prepared by various methods like
Skraup, Doebner-Von Miller, Combes and Friedlander (Denmark &
Venkatraman, 2006). Poly-substituted quinolines are synthesised
by the Friedlander method, using various BrØnsted acids such as
sulphamic acid, hydrochloric acid, p-toluenesulphonic acid, per-
chloric acid, phosphoric acid and trifluoroacetic acid (Shaabani,
Soleimani, & Badri, 2007; Wang, Jia, & Dong, 2006). Lewis acids such
as ZnCl2, SnCl2, Bi(OTf)3, AuCl3, CeCl3ꢂ7H2O and ionic liquids have
also been employed in the Friedlander annulations (Bose & Kumar,
2006; De & Gibbs, 2005). These conditions have either the limita-
tions of low yields, severe experimental conditions or prolonged
reaction times. In our efforts to prepare new quinoline derivatives
of biologically important molecules viz., tetrahydrocurcumin
(THC) and zingerone, initially we investigated the reaction of these
substrates with 2-aminobenzophenone and 2-aminoacetophenone
using Y(OTf)3 as catalyst. While the corresponding quinolines were
obtained in good yields, this catalyst failed to achieve the reaction
with mono-chloro, dichloro, nitro and amino substituted 2-amino-
benzophenone substrates. On the other hand, trifluoroacetic acid
(TFA) promoted annulations even with substituted benzophenones.
We report here the synthesis of novel quinoline derivatives of THC
and zingerone with TFA as the catalyst (Fig. 1) and evaluation of
their anti-oxidant and antibacterial activities.
2.2. Synthesis of 1-(2-(4-hydroxy-3-methoxyphenethyl)-4-
methylquinolin-3-yl)-3-(4-hydroxy-3-methoxyphenyl)propan-1-one
(1a, Fig. 1)
2-Aminoacetophenone (0.675 g, 5 mmol) was taken in a round-
bottomed flask along with THC (2.23 g, 6 mmol). To this was added
TFA (2–3 mL) and the mixture stirred at 100 °C for 40 min. The pro-
gress of the reaction was monitored by TLC. Also, the formation of a
solid mass was noticed towards completion of the reaction. It was
then neutralised with saturated NaHCO3 solution (100 mL). The so-
lid that separated was filtered, washed with water and dried. The
resultant crude material was then triturated using ethyl acetate
and petroleum ether. The material at this stage was dried in a des-
iccator over fused CaCl2 for 12 h. Yield: 1.98 g, 84%. Light yellow so-
lid; m. p. 112–115 °C; 1H NMR: d 8.17 (d, J = 8.3 Hz, 1H, H-8), 7.98
(d, J = 8.3 Hz, 1H, H-5), 7.7 (ddd, J1 = 8.6 Hz, J2 = 6.8 Hz, J3 = 1.2 Hz,
1H, H-7), 7.6 (ddd, J1 = 8.3 Hz, J2 = 6.9 Hz, J3 = 1.1 Hz, 1H, H-6),
6.84 (d, J = 8 Hz, 1H, H-26), 6.81 (d, J = 8 Hz, 1H, H-19), 6.75 (d,
J = 1.4 Hz, 1H, H-29), 6.73 (d, J = 1.9 Hz, 1H, H-16), 6.70 (dd,
J1 = 7.9 Hz, J2 = 1.9 Hz, 1H, H-25), 6.63 (dd, J1 = 8 Hz, J2 = 1.8 Hz,
1H, H-20), 5.79 (br, 2H, Hydroxyls at C-27 & C-18), 3.82 (s, 3H, H-
30), 3.78 (s, 3H, H-21), 3.04–3.08 (m, 4H, H-23 & H-14), 3.0–3.04
2. Materials and methods
2.1. Materials and equipment
All the solvents and reagents used for the syntheses were of
analytical grade. THC was prepared in the laboratory by hydroge-
nation of curcumin over Pd/BaSO4 in acetone at 30 psi hydrogen
pressure (Sneharani, Sridevi, Annapurna Singh, Srinivas, & Appu
Rao, 2011). Zingerone was prepared by hydrogenation of dehydro-
zingerone, which was obtained by aldol condensation of vanillin
R
O
OH
N
O
O
O
R1
1
HO
OH
HO
O
R1
O
1a-f
R
O
TFA
OH
0.5-2h
NH 2
R1
R
O
O
O
N
OH
2
HO
2a-e
1a
1b
1c
: R=H, R1=Ph; : R=NO2, R1=Ph;
1d
1e
1f
: R=NH2, R1=Ph; : R= -Cl(Ph), R =Ph
: R=H, R1=CH3;
: R=Cl, R1=Ph;
o
1
2a
2b
: R=H, R1=Ph;
2c
2d
2e
: R=H, R1=CH3;
: R=NO2, R1=Ph;
: R=Cl, R1=Ph; : R=NH2, R1=Ph
Fig. 1. Synthesis of quinoline derivatives.

652
J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
(m, 4H, H-13 & H-22), 2.48 (s, 3H, H-11); 13C NMR: d 207.27(C-12),
155.40 (C-2), 146.29 (C-27), 146.20 (C-18), 146.09 (C-10), 143.92
(C-28), 143.69 (C-17), 139.87 (C-4), 135.05 (C-3), 133.02 (C-24),
131.89 (C-15), 129.89 (C-7), 128.53 (C-8), 126.45 (C-6), 125.82 (C-
9), 123.36 (C-5), 120.68 (C-25), 120.66 (C-20), 114.25 (C-26),
114.04 (C-19), 111.06 (C-16 & C-29), 55.56 (C-30), 55.50 (C-21),
47.16 (C-13), 38.61 (C-14), 35.10 (C-23), 28.69 (C-22), 15.04 (C-
11); mass: calculated 471.2046; found; [M+ + 1] = 472.8925.
131.60, 130.51, 129.87, 129.43, 126.78, 126.04, 125.60, 121.04,
120.81, 114.57, 111.39, 111.20, 55.90, 55.86, 46.67, 37.03, 36.39,
29.06; mass: calculated 567.1813; found [M+ + 1] = 568.6889.
1-(6-Amino-2-(4-hydroxy-3-methoxyphenethyl)-4-phenylquino-
lin-3-yl)-3-(4-hydroxy-3-methoxyphenyl)propan-1-one (1e); light
yellow solid; m. p. 177–179 °C; 1H NMR: d 8.17 (d, J = 9.7 Hz,
1H), 7.95 (dd, J1 = 7.4 Hz, J2 = 2.1 Hz, 1H), 7.94 (s, 1H), 7.48–7.54
(m, 3H), 7.32–7.37 (m, 2H), 6.82 (d, J = 7.9 Hz, 1H), 6.76 (d,
J = 1.6 Hz, 1H), 6.71 (d, J = 8 Hz, 1H), 6.68 (dd, J1 = 8 Hz,
J2 = 1.6 Hz, 1H), 6.37 (d, J = 1.6 Hz, 1H), 6.33 (dd, J1 = 8 Hz,
J2 = 1.6 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 3.04–3.15 (m, 4H), 2.51
(t, J = 7.3 Hz, 2H), 2.35 (t, J = 7.6 Hz, 2H); 13C NMR: d 206.58,
156.62, 146.05, 145.93, 145.37, 143.69, 143.50, 135.05, 134.36,
133.24, 133.09, 131.87, 130.17, 129.79, 128.90, 128.58, 125.03,
123.26, 120.76, 120.42, 115.99, 113.90, 110.98, 110.65, 55.55,
55.47, 46.58, 38.74, 34.91, 28.85; mass: calculated 548.2311; found
[M+ + Na] = 571.7599.
2.3. General synthetic method for quinoline derivatives of
tetrahydrocurcumin (1b-1f) and zingerone (2a–2e)
In a typical reaction, 2-aminoacetophenone, 2-aminobenzophe-
none or a substituted 2-aminobenzophenone (5 mmol) was added
with THC or zingerone (6 mmol) into a round-bottomed flask. To
this mixture, TFA (2–3 mL) was added and stirred at 100 °C for
the period mentioned in Tables 1 and 2. After completion of the
reaction, as indicated by TLC analysis, the reaction mixture was
neutralised with 100 mL of saturated sodium bicarbonate solution.
The solid that separated was filtered and washed with distilled
water and dried. The resultant crude material was further purified
by triturating with ethyl acetate and petroleum ether (60–80 °C). It
was then dried in a desiccator over fused calcium chloride for 12 h.
The physical and spectroscopic data of individual pure compounds
is presented below.
1-(2-(4-Hydroxy-3-methoxyphenethyl)-4-phenylquinolin-3-yl)-3-
(4-hydroxy-3-methoxyphenyl)propan-1-one (1b); off-white solid; m.
p. 165–166 °C; 1H NMR: d 8.17 (d, J = 8.3 Hz, 1H), 7.76 (ddd,
J1 = 8.4 Hz, J2 = 6.8 Hz, J3 = 1.3 Hz, 1H), 7.67 (dd, J = 8.6 Hz,
J2 = 1.5 Hz, 1H), 7.50–7.54 (m, 3H), 7.49 (ddd, J1 = 8.5 Hz,
J2 = 6.8 Hz, J3 = 1.1 Hz, 1H), 7.35–7.37 (m, 2H), 6.83 (d, J = 8 Hz,
1H), 6.79 (d, J = 1.9 Hz, 1H), 6.72 (d, J = 8 Hz, 1H), 6.70 (d,
J = 1.9 Hz, 1H), 6.38 (d, J = 2 Hz, 1H), 6.34 (dd, J1 = 8 Hz, J2 = 2 Hz,
1H), 3.84 (s, 3H), 3.80 (s, 3H), 3.07–3.16 (m, 4H), 2.51 (t,
J = 7.4 Hz, 2H), 2.36 (t, J = 7.8 Hz, 2H); 13C NMR: d 206.85, 156.32,
147.34, 146.02, 145.91, 144.01, 143.46, 134.97, 134.28, 133.41,
131.99, 129.93, 129.82, 128.69, 128.55, 128.36, 126.36, 125.80,
124.72, 120.78, 120.42, 113.86, 111.02, 110.65, 55.54, 55.46,
46.68, 38.87, 35.11, 28.92; Mass: Calculated 533.2202; Found;
[M+ + Na] = 556.5859.
1-(2-(4-Hydroxy-3-methoxyphenethyl)-6-nitro-4-phenylquinolin-
3-yl)-3-(4-hydroxy-3-methoxyphenyl)propan-1-one (1c); light yel-
low solid; m. p. 172–175 °C; 1H NMR: d 8.61 (d, J = 2.3 Hz, 1H),
8.51 (dd, J1 = 9.2 Hz, J2 = 2.5 Hz, 1H), 8.27 (d, J = 9.1 Hz, 1H), 7.54–
7.61 (m, 3H), 7.36 (d, J = 6.4 Hz, 2H), 6.83 (dd, J1 = 7.9 Hz,
J2 = 0.6 Hz, 1H), 6.77 (d, J = 1.2 Hz, 1H), 6.72 (dd, J1 = 8 Hz,
J2 = 0.6 Hz, 1H), 6.68 (dd, J1 = 7.9 Hz, J2 = 1.2 Hz, 1H), 6.38 (d,
J = 1.4 Hz, 1H), 6.34 (dd, J1 = 8 Hz, J2 = 1.4 Hz, 1H), 5.64 (b, 2H),
3.85 (s, 3H), 3.80 (s, 3H), 3.09–3.19 (m, 4H), 2.54 (t, J = 7.2 Hz,
2H), 2.37 (t, J = 7.4 Hz, 2H); 13C NMR: d 205.79, 160.56, 149.37,
146.16, 146.02, 145.64, 145.45, 143.72, 143.67, 135.74, 133.41,
132.93, 131.68, 130.64, 129.80, 129.45, 128.88, 124.02, 123.24,
122.83, 120.75, 120.43, 114.06, 114.01, 110.94, 110.65, 55.57,
55.48, 46.47, 38.99, 34.51, 28.78; mass: calculated 578.2053;
found; [M+ + 1] = 579.6473.
1-(6-Chloro-2-(4-hydroxy-3-methoxyphenethyl)-4-phenylquino-
lin-3-yl)-3-(4-hydroxy-3-methoxyphenyl)propan-1-one (1d); light
yellow solid; m. p. 125–128 °C; 1H NMR: d 8.44 (d, J = 9 Hz, 1H),
7.89 (dd, J1 = 8.9 Hz, J2 = 1.9 Hz, 1H), 7.73 (d, J = 1.9 Hz, 1H), 7.53–
7.66 (m, 3H), 7.34 (d, J = 6.9 Hz, 2H), 6.81 (d, J = 1.6 Hz, 1H), 6.77
(d, J = 8 Hz, 1H), 6.67 (dd, J1 = 7.8 Hz, J2 = 1.6 Hz,, 1H), 6.59 (dd,
J1 = 8 Hz, J2 = 1.6 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 6.31 (dd, J1 = 8 Hz,
J2 = 1.9 Hz, 1H), 5.01 (b, 2H), 3.86 (s, 3H), 3.77 (s, 3H), 3.14–3.24
(m, 2H), 2.98–3.12 (m, 2H), 2.53 (t, J = 7.1 Hz, 2H), 2.35 (t,
J = 7.1 Hz, 2H); 13C NMR: d 204.03, 156.98, 149.39, 146.93, 146.64,
144.43, 144.16, 140.61, 135.88, 135.36, 134.14, 133.02, 131.86,
1-(6-Chloro-4-(2-chlorophenyl)-2-(4-hydroxy-3-methoxypheneth-
yl) quinolin-3-yl)-3-(4-hydroxy-3-methoxyphenyl)propan-1-one (1f);
light yellow solid; m. p. 70–75 °C; 1H NMR: d 8.12 (d, J = 9 Hz, 1H),
7.68 (dd, J1 = 9 Hz, J2 = 2.3 Hz, 1H), 7.55 (dd, J1 = 8.1 Hz, J2 = 1 Hz,
1H), 7.46 (dt, J1 = 8.1, J2 = 1.7 Hz, 1H), 7.37 (dt, J1 = 7.5 Hz,
J2 = 1.3 Hz, 1H), 7.30 (dd, J1 = 2.3 Hz, J2 = 0.4 Hz, 1H), 7.21 (dd,
J1 = 7.5 Hz, J2 = 1.7 Hz, 1H), 6.82 (d, J = 8 Hz, 1H), 6.74 (d, J = 8 Hz,
1H), 6.71 (d, J = 1.8 Hz, 1H), 6.64 (dd, J1 = 8 Hz, J2 = 1.8 Hz, 1H),
6.48 (d, J = 1.9 Hz, 1H), 6.42 (dd, J1 = 8 Hz, J2 = 1.9 Hz, 1H), 5.89 (b,
2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.12–3.17(m, 2H), 3.06–3.11(m,
2H), 2.62–2.69 (m, 1H), 2.50–2.58 (m, 2H), 2.38–2.46 (m, 1H);
13C NMR:
d 205.68, 156.87, 146.20, 146.09, 145.39, 143.70,
143.67, 140.49, 135.39, 133.05, 132.97, 132.66, 131.99, 131.82,
130.90, 130.57, 130.42, 129.63, 127.06, 125.12, 124.21, 120.76,
120.45, 114.11, 111.02, 110.72, 55.46, 45.79, 38.66, 34.90, 28.49;
mass: calculated 601.1423; found [M+ + 1] = 602.6826.
4-((2,4-Dimethylquinolin-3-yl)methyl)-2-methoxyphenol
(2a);
off-white solid; m. p. 208–210 °C; 1H NMR: d 8.03 (dt J1 = 8.6
J2 = 1.1 Hz, 2H, H-5 & H-8), 7.68 (ddd, J1 = 8.4 Hz, J2 = 6.8 Hz,
J3 = 1.4 Hz, 1H, H-7), 7.54 (ddd, J1 = 8.5 Hz, J2 = 6.7 Hz, J3 = 1.3 Hz,
1H, H-6), 6.80 (d, J = 8.1 Hz, 1H, H-18), 6.58 (d, J = 1.7 Hz, 1H, H-
15), 6.47 (dd, J1 = 8 Hz, J2 = 1.7 Hz, 1H, H-19), 5.74 (br, 1H, Hydroxyl
at C-17), 4.23 (s, 2H, H-13), 3.79 (s, 3H, H-20), 2.68 (s, 3H, H-12),
2.64 (s, 3H, H-11); 13C NMR: d 158.62 (C-2), 146.45 (C-16),
146.02 (C-10), 143.79 (C-17), 141.78 (C-4), 130.31 (C-14), 129.73
(C-3), 128.87 (C-8), 128.15 (C-7), 126.90 (C-9), 125.30 (C-6),
123.44 (C-5), 120.10 (C-19), 114.16 (C-18), 110.11 (C-15), 55.58
(C-20), 34.42 (C-13), 24.07 (C-12), 14.24 (C-11); mass: calculated
293.1416; found [M+ + 2] = 295.5308.
2-Methoxy-4-((2-methyl-4-phenylquinolin-3-yl)methyl)phenol
(2b); light yellow solid; m. p. 186–188 °C; 1H NMR: d 8.19 (d,
J = 8.2 Hz, 1H), 7.69 (ddd, J1 = 8.3 Hz, J2 = 6.8 Hz, J3 = 1.5 Hz, 1H),
7.44–7.48 (m, 3H), 7.35–7.43 (m, 2H), 7.22–7.25 (m, 2H), 6.75 (d,
J = 8.2 Hz, 1H), 6.46 (d, J = 1.5 Hz, 1H), 6.36 (dd, J1 = 8.2 Hz,
J2 = 1.5 Hz, 1H), 6.16 (B, 1H), 3.97 (s, 2H), 3.75 (s, 3H), 2.70 (s,
3H); 13C NMR: d 159.00, 148.17, 146.41, 145.39, 143.75, 136.53,
131.01, 129.52, 128.89, 128.77, 128.11, 127.70, 127.57, 126.68,
126.21, 125.70, 120.18, 114.11, 110.40, 55.537, 35.22, 23.50; mass:
calculated 355.1572; found [M+ + 2] = 357.6760.
2-Methoxy-4-((2-methyl-6-nitro-4-phenylquinolin-3-
yl)methyl)phenol (2c); yellow solid; m. p. 172–175 °C; 1H NMR: d
8.43 (dd, J1 = 9 Hz, J2 = 2.5 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.18 (d,
J = 9.2 Hz, 1H), 7.50–7.53 (m, 3H), 7.23–7.26 (m, 2H), 6.77 (d,
J = 8.1 Hz, 1H), 6.45 (d, J1 = 1.8 Hz, 1H), 6.36 (dd, J1 = 8.1 Hz,
J2 = 1.8 Hz, 1H), 5.58 (b, 1H), 4.00 (s, 2H), 3.77 (s, 3H), 2.71 (s,
2H); 13C NMR: d 163.53, 148.99, 148.35, 146.35, 144.86, 143.83,
135.12, 131.57, 130.44, 130.02, 128.82, 128.53, 128.47, 125.82,
123.16, 121.96, 120.13, 114.12, 110.27, 55.55, 35.33, 24.42; mass:
calculated 400.1423; found [M+ + 1] = 401.4695.

J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
653
Table 1
Quinoline derivatives of THC.
Reactant
Product
1a
Structure
Time (min)
40
Yield (%)a
84
11
O
O
5
8
16
19
14
12
4
15
20
25
17
21
9
O
6
7
3
2
13
18
22
10
NH2
N
OH
1
23
24
29
26
27
30
28
OH
O
1b
1c
1d
1e
1f
30
93
O
O
O
NH2
N
OH
OH
O
120
65
95
70
95
O
O2N
O
O2N
O
NH2
N
OH
OH
O
40
O
Cl
O
Cl
O
NH2
N
OH
OH
O
90
O
H2N
O
H2N
O
OH
NH2
N
OH
O
60
O
Cl
Cl
Cl
O
Cl
O
NH2
N
OH
OH
O

654
J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
Table 2
Quinoline derivatives of zingerone.
Reactant
Product
2a
Structure
Time (min)
30
Yield (%)a
90
11
O
5
8
15
18
13
4
14
16
17
O
20
9
6
7
3
2
19
12
10
NH2
O
N
OH
1
2b
2c
2d
2e
30
90
30
60
96
70
86
56
O
NH2
N
OH
O
O2N
O2N
O
NH2
N
OH
O
Cl
Cl
O
NH2
N
OH
O
H2N
H2N
O
NH2
N
OH
a
Isolated yields.
4-((6-Chloro-2-methyl-4-phenylquinolin-3-yl)methyl)-2-
were incubated in the dark at room temperature for 20 min. The
absorbance was then recorded at 517 nm using methanol as a
blank for baseline correction. The % radical-scavenging activity
was calculated using the following formula:
methoxyphenol (2d); light yellow solid; m. p. 168–170 °C; 1H NMR:
d 8.02 (d, J = 8.9 Hz, 1H), 7.59 (dd, J1 = 8.9 Hz, J2 = 2.3 Hz, 1H), 7.45–
7.48 (m, 3H), 7.31 (d, J = 2.3 Hz, 1H), 7.20–7.23 (m, 2H), 6.75 (d,
J = 8.1 Hz, 1H), 6.44 (d, J = 1.7 Hz, 1H), 6.36 (dd, J1 = 8.4 Hz,
J2 = 1.5 Hz, 1H), 5.91 (b, 1H), 3.95 (s, 2H), 3.75 (s, 3H), 2.64 (s,
3H); 13C NMR: d 159.57, 146.58, 146.34, 144.61, 143.71, 136.05,
131.22, 130.93, 130.33, 129.87, 129.25, 128.88, 128.28, 127.89,
127.43, 124.94, 120.18, 114.08, 110.33, 55.52, 35.31, 23.95; mass:
calculated 389.1183; found [M+ + 1] = 390.4632.
Radical-scavenging activityð%Þ ¼ ½ðControl OD—Sample ODÞ=Control ODꢃ
ꢄ100
All the experiments were carried out in triplicate. EC50 values
reported correspond to the concentration of the derivatives where
50% RSA was observed.
4-((6-Amino-2-methyl-4-phenylquinolin-3-yl)methyl)-2-
methoxyphenol (2e): light yellow solid; m.p. 176–178 °C; 1H NMR:
d 9.25 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.94 (dd, J1 = 9 Hz, J2 = 2.1 Hz,
1H), 7.63 (d, J = 2.1 Hz, 1H), 7.33–7.37 (m, 3H), 7.16–7.20 (m, 2H),
6.73 (d, J = 8.1 Hz, 1H), 6.48 (br, 1H), 6.44 (s, 1H), 6.33 (d, J = 8 Hz,
1H), 3.95 (s, 2H), 3.73 (s, 3H), 2.62 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 159.44, 147.33, 146.49, 144.01, 143.77, 136.08, 132.71,
130.87, 130.48, 129.17, 128.73, 128.19, 127.83, 126.94, 122.18,
120.07, 116.72, 114.16, 110.47, 55.47, 35.29, 23.60; mass: calcu-
lated 370.1681; found [M+ ꢁ 1] = 369.6773.
2.5. Antibacterial studies of quinolines
The antibacterial assay of quinolines was tested by the pour
plate method against Bacillus cereus (F 4810, Public Health Labora-
tory, London, UK), Staphylococcus aureus (FRI 722, Public Health
Laboratory, The Netherlands), Escherichia coli (MTCC 108, Microbial
Type Culture Collection, Institute of Microbial Technology, Chandi-
garh, India) and Yersinia enterocolitica (MTCC 851, Microbial Type
Culture Collection, Institute of Microbial Technology, Chandigarh,
India) by the method of Negi, Jayaprakasha, Rao, and Sakariah
(1999). Samples were prepared by dissolving the compounds in
DMSO. To flasks containing 20 mL of melted warm agar, different
concentrations of test material in DMSO were added. An equivalent
2.4. Radical-scavenging activity of quinolines by DPPH method
Radical-scavenging activity of several quinoline derivatives was
analysed by DPPH method (Moon & Terao, 1998). Individual sam-
ples were prepared by dissolving each compound in methanol
(1 mg/ml). The samples were assayed at different concentrations
with suitable dilutions, making them up to 1 mL with 100 mM
Tris–HCl buffer (pH 7.4), followed by addition of 4 mL of 2,2-diphe-
nyl-1-picrylhydrazyl (0.1 mM solution in methanol) and mixing
the contents by vigorous shaking. Controlswere prepared by the
same protocol wherein the compound was not included. The tubes
amount of DMSO was used as controls. One hundred
lL (about
103 cfu/mL) of test bacterium was inoculated into the flasks under
aseptic conditions. The media were then mixed and poured onto
sterilized Petri plates and incubated at 37 °C for 24 h for growth.
The minimum inhibitory concentration (MIC) value, i.e., the lowest
concentration of the compound capable of inhibiting the complete
growth of the bacterium being tested, was determined for each

J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
655
compound by carrying out the experiments in duplicate and was
3. Results and discussion
repeated three times.
3.1. Synthesis of quinoline derivatives of tetrahydrocurcmin and
zingerone
2.6. Statistical analysis
The method is very useful as no solvent is used for the reac-
tion and TFA is easily available and inexpensive. In a typical
experiment, reaction of 2-aminoacetophenone with THC was car-
ried out using TFA at 100 °C. Completion of the reaction was
indicated by solidification of the reaction mass and further
All the experiments were repeated three times and the data
were calculated as mean SD. The data of all the assays were ana-
lysed by one-way ANOVA. The Duncan’s multiple range test
(DMRT) was used to make the comparisons (Gomez & Gomez,
1984).
a
100
90
a
a
a
80
70
60
50
40
30
20
10
0
b
b
c
c
d
THC BHA
1a
1b
1c
1d
1e
1f
26.9
55.5
21.2
18.7
17.3 17.6 18.2
18.6
Concentration in
µM
c
b
100
90
80
70
60
50
40
30
20
10
0
100
90
a
a
ab
bc
c
b
b
c
d
d
e
e
80
70
60
50
40
30
20
10
0
f
f
e
f
THC BHA
53.7 111
1a
1b
1c
1d
35.2
1e
1f
THC BHA
40.3
1a
1b
28.1
1c
25.9
1d
26.4
1e
1f
83.2 31.8
27.3 24.9
42.4 37.5 34.6
36.5 33.2
Concentration in µM
Concentration in µM
e
d
100
90
80
70
60
50
40
30
20
10
0
100
90
80
70
60
50
40
30
20
10
0
a
b
b
c
a
ab
b
b
d
e
e
f
c
d
e
f
THC
BHA
1a
1b
46.9
1c
43.2
1d
44.0
1e
45.6
1f
41.5
THC
BHA
1a
1b
1c
1d
52.8
1e
54.7
1f
67.1 138.7 53.0
80.6 166.4 63.6
56.2 51.9
49.8
Concentration in µM
Concentration in µM
Fig. 2. RSA of quinoline derivatives 1a–1f compared with THC and BHA; bar graphs a–e represents concentration 10, 15, 20, 25 and 30 ppm, respectively. Bars followed by
same letter are not significantly (p 6 0.05) different.

656
J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
100
a
90
80
70
a
a
60
50
40
30
20
10
0
b
c
c
d
2
2a
2b
2c
2d
2e
51.5
34.1
28.1
25.0
25.7
27.0
Concentration in µM
c
100
90
80
70
60
50
40
30
20
10
0
b
100
90
80
a
a
b
b
70
60
50
40
30
20
10
0
c
c
c
d
d
d
e
e
2
2a
2b
2c
2d
2e
2
2a
2b
2c
2d
2e
103
68.2
56.3
50.0
51.3
54.0
77.2
51.1
42.2
37.5
38.5
40.5
Concentration in
µM
Concentration in µM
100
e
100
90
80
70
60
50
40
30
20
10
0
d
a
90
80
70
60
50
40
30
20
10
0
a
b
a
c
d
b
c
e
d
f
e
2
2a
2b
2c
2d
2e
2
2a
2b
2c
2d
2e
128.7 85.2
70.3
62.4
64.1 67.5
154.5 102.3 84.4
74.9
77.0
81.0
Concentration in µM
Concentration in µM
Fig. 3. RSA of quinoline derivatives 2a–2e compared with zingerone; bar graphs a–e represent concentrations of 10, 15, 20, 25 and 30 ppm, respectively. Bars followed by
same letter are not significantly (p 6 0.05) different.
confirmed by TLC analyses. Neutralisation with saturated
NaHCO3 resulted in product separation, which was filtered,
washed and dried. Further, trituration of the crude product with
ethyl acetate and petroleum ether afforded the pure compound
(1a, Fig.1). Similarly, substituted quinoline derivatives (1b–1f)
were synthesised from the reaction of various substituted 2-
aminobenzophenones with THC. Further, the scope of the reac-
tion was extended to zingerone, a bio-active ingredient of ginger
containing a methylene group alpha to a carbonyl moiety. The
substituted quinoline derivatives of zingerone (2a–2e) were con-
veniently prepared as above, except in the case of the dichloro
substituted benzophenone. The prolonged heating (>3 h) of the
reaction mixture containing dichloro aminobenzophenone
resulted in its dimerisation.
All the syntheses were carried out on 5 mmol scale of 2-
aminoacetophenone and substituted 2-aminobenzophenones with
1.2 equivalents of THC and zingerone in the presence of 2–3 mL
TFA under solvent free conditions at 100 °C for 0.5–3 h. The
reaction times in the case of the preparation of un-substituted
quinolines (entries 1 & 2, Tables 1 and 2) were usually shorter than
those for reactions with substituted quinolines. The product yield
was good to excellent in all cases (56–96%).

J.R. Manjunatha et al. / Food Chemistry 136 (2013) 650–658
657
To our knowledge, all synthesised compounds (Fig. 1) are new
and are reported here for the first time. They have been character-
ised by 1H NMR, 13C-NMR spectral data and HRMS. The 1H NMR of
1a–1f and 2a–2e for the proton at the 8th position was observed
down field (8.0–8.7 ppm) compared to the same in the reactant
which usually manifests at 6.5–7 ppm. This is the common feature
observed in quinoline derivatives. The signals at 153–163 ppm in
13C-NMR are assigned to a quaternary carbon at the second posi-
tion of compounds 1a–1f and 2a–2e which is typical of quinoline
compounds. Further, from 2D-NMR spectral analyses, the nature
and correlation of protons and carbons were confirmed. In the
HMBC spectra of compounds 1a–1f, the correlation of methylene
protons with the quaternary carbon of the quinoline nucleus indi-
cated the attachment of THC with quinoline (Fig. 1). In the case of
compounds 2a–2e, the HMBC correlations of the benzylic proton of
zingerone with four quaternary and two carbons in the aromatic
nucleus, ascertain connectivity between two moieties involved in
the annulations.
THC and zingerone with aminobenzophenone having the electron
withdrawing groups, NO2 (1c and 2c) and Cl (2c and 2d) had the
lowest antioxidant activity. This Structure–Activity Relationship
(SAR) exhibited by the RSA of these derivatives underscores the
influence of the nature of the substituents on the antioxidant ac-
tion of the compounds.
3.3. Antibacterial activities of quinoline derivatives of
tetrahydrocurcumin and zingerone
Compounds 1a–1f and 2a–2e were tested for their antibacterial
potential against two Gram-positive (B. cereus and S. aureus) and
two Gram-negative bacteria (E. coli and Y. enterocolitica). The MIC
values of these compounds are presented in Table 3. Among all
the compounds tested, 2d was the most effective against Gram-po-
sitive and 1c was the most effective against Gram- negative bacte-
ria as the MIC values were lowest for these compounds against
tested bacteria. In general, 2d, 1c and 1b were found to be very
effective against all the bacteria tested in the present study. Com-
pounds 1e, 2c and 2e showed moderate activity, but 1, 2 and 2a
were less effective against the tested bacteria. The antibacterial
activity of 2b was very high against B. cereus, but it was ineffective
against S. aureus, Y. enterocolitica and E. coli. Similarly 1e and 1f
showed better activity against B. cereus than against the other
bacteria.
A comparable trend has been observed for various natural and
synthetic compounds displaying variable activity depending on
compound and bacterium (Negi, Jayaprakasha, & Jena, 2010;
Parvathy et al., 2009). While comparing the activity of individual
compounds against bacteria, it was observed that almost all the
compounds showed higher MIC values against Gram-negative
bacteria than against Gram-positive ones. A similar trend of higher
resistance to Gram-negative bacteria than Gram-positive bacteria
is reported in the literature and this effect has been attributed to
their differences in cell structure (Negi, Jayaprakasha, & Jena,
2008; Nostro, Germano, D’Angelo, Marino, & Cannatelli, 2000).
The Gram-positive bacteria contain an outer peptidoglycan layer,
which is an ineffective permeability barrier (Scherrer & Gerhardt,
1971). In the case of Gram-negative bacteria, the outer phospholi-
pidic membrane is impermeable to lipophilic solutes. In addition,
porins present in the cell membrane act as a selective barrier to
the hydrophilic solutes, thus making the cells resistant to antibac-
terial compounds (Nikaido & Vaara, 1985).
3.2. Radical-scavenging activities of quinoline derivatives of
tetrahydrocurcumin and zingerone
Radical-scavenging assays were carried out for THC and zinger-
one, using standard BHA as reference. Compounds were dissolved
in methanol at 10–30 ppm concentrations, which corresponded
to different micro molar concentrations as indicated in Figs. 2
and 3. Similarly, quinoline derivatives of THC (1a–1f) and zinger-
one (2a–2e) were dissolved in methanol at 10–30 ppm concentra-
tions and the radical-scavenging activity (RSA) for all the
compounds was determined by the DPPHꢅ method. In all cases,
the RSA was proportional to the concentration. The EC50 values
determined for THC, zingerone and BHA were 16.8, 41.6 and
41.5 lmol, respectively. Radical-scavenging activities of THC, zing-
erone and BHA were 79.8%, 61.8% and 66.8% at 10 ppm, respec-
tively, and at 15 ppm the values were 86%, 81% and 80%,
respectively, showing THC to be a more powerful antioxidant at
lower concentrations (10–15 ppm). At higher concentrations (20
to 30 ppm), THC and BHA showed comparable antioxidant activity,
but was superior to zingerone. The RSA of 90% was achieved with
1e at a much lower concentration (ꢀ55
which showed a similar effect only at a higher concentration
(ꢀ80 mol). However, derivatives 1a, 1b, 1c and 1f exhibited lower
activities compared to those of 1e. This is also reflected by the EC50
value of 1e (11.5 mol) compared to those of 1a, 1b, 1c and 1f
(14.1–14.5 mol). The THC quinoline derivative 1d displayed the
lowest RSA at all concentrations and also had the EC50 value of
17.8 mol. Earlier workers have suggested that THC exhibits the
lmol) compared with 1,
l
l
In conclusion, a facile and efficient synthetic protocol has been
delineated for the synthesis of several novel quinoline derivatives
of THC and zingerone. The results of their in vitro biological assays
demonstrated that certain quinoline derivatives of THC and
l
l
same physiological and pharmacological properties as the active
form of curcumin in vivo by means of its b-diketone moiety as well
as the phenolic hydroxy groups (Sugiyama, Kawakishi, & Osawa,
1996). In the quinoline derivatives of THC one of the keto groups
is involved in the quinolone ring formation, but the phenolic
groups are intact. This explains the marginal reduction in the rad-
ical scavenging activity of the compounds 1b-1d and 1f. In the case
of zingerone derivatives, the amino-substituted quinoline 2e had
Table 3
MIC of quinoline derivatives of THC and zingerone against gram-positive and gram-
negative bacteria.
Entry
Compound
MIC (lM)
B. cereus
S. aureus
Y. enterocolitica
E. coli
1
2
3
4
5
6
7
8
1
1049
724
503
1311
983
914
674
946
800
973
>2000
>2000
1098
792
2098
931
686
506
860
711
811
>2000
>2000
1030
853
1704
1242
823
843
817
978
933
>2000
>2000
1236
975
the lowest EC50 value of 22.7
for 2b, 2c, 2d and 2f were 38.3, 39.5, 36.3 and 73.3
tively. The derivative 2e showed better RSA (78%) compared to
zingerone (2) and its derivatives (2a-2d) at ꢀ50–55 mol concen-
lmol. The corresponding EC50 values
1a
1b
1c
1d
1e
1f
2
2a
2b
2c
2d
2e
l
mol, respec-
422
774
534
649
1256
>2000
412
609
l
trations. Here again, the carbonyl group in zingerone is involved in
the quinoline ring formation, but the phenolic group is unaffected
which could explain the slight reduction in their radical scavenging
activity. The quinoline derivatives of both THC and zingerone (1e
and 2e) with aminobenzophenone substitution exhibited the most
potent radical scavenging activity due to the presence of an elec-
tron donating amino (–NH2) group. In contrast, derivatives of
9
10
11
12
13
219
593
501
790
752
856
877
1054

658
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Acknowledgments
J.R.M. thanks the Indian Council of Medical Research, New Delhi,
India for the scholarship. The authors are grateful to Dr. G.
Venkateswara Rao, Director, CFTRI and Dr. M.C. Varadaraj, Head,
Human Resources Development, CFTRI for their support and
constant encouragement for the work. The help of Mr. Padmere
Mukund Lakshman in the MS studies of the compounds is grate-
fully acknowledged.
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