Journal of Molecular Structure 1181 (2019) 261e269

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Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc

Green synthesis, antioxidant and antibacterial activities of 4-aryl-3,4-

dihydropyrimidinones/thiones derivatives of curcumin. Theoretical
calculations and mechanism study
Nassima Khaldi-Khellafi a, b, Malika Makhloufi-Chebli a, *, Djamila Oukacha-Hikem a,
Souhila Terachet Bouaziz b, Kamilia Ould Lamara a, Taous Idir a,
Amina Benazzouz-Touami a, Françoise Dumas c, **
a
Laboratoire LPCM, D
epartement de Chimie, Facult

e des Sciences, Universit

e Mouloud Mammeri, 15000, TiziOuzou, Algeria
b
Department of Chemistry, Faculty of Sciences, University Mohamed Bouguerra, Boumerdes, Algeria
c
Laboratoire BioCIS, UMR CNRS 8076, Chimie des Substances Naturelles, IPSIT, Universit

e Paris-Sud, CNRS, Universit

e Paris-Saclay, Facult

e de Pharmacie, 5,
rue Jean-Baptiste Cl
ement, 92296 Cha^tenay-Malabry Cedex, France

a r t i c l e i n f o a b s t r a c t

Article history: 3,4-Dihydropyrimidin-2(1H)-one/thione analogs of curcumin were synthesized in good yield by a one-
Received 24 November 2018 pot multi-component cyclocondensation using curcumin, substituted aromatic aldehydes, and urea/
Received in revised form thiourea in less volume of ethanol catalysed by commercial heteropolyacide Keggin type H3PMo12O40 5%
23 December 2018
mol as a recyclable and nontoxic catalyst under conventional heating and microwave irradiation. All the
Accepted 26 December 2018
Available online 29 December 2018
synthesized curcumin derivatives 4aen were screened for antioxidant and antimicrobial activity. Bio-
logical activity data of the synthesized showed that most of the synthesized compounds exhibited
greater antioxidant and antibacterial activity than curcumin. Geometries of synthesized compounds
Keywords:
Nitrogen heterocycles
were optimized by using B3LYP method with 6-31G* basis set. Then, DFT based reactivity descriptors
Curcumin-dihydropyrimidinones/thiones such as HOMO, LUMO, chemical hardness, electronegativity, chemical potential were calculated and
Microwave irradiation discussed.
Antioxidant capacity © 2018 Elsevier B.V. All rights reserved.
Antibacterial activity
Theoretical studies

1. Introduction by blocking intracellular signalling events in mast cells. The anti-

allergy activities of curcumin 1 and curcumin-related compounds
Curcumin 1, which imparts the yellow color to curry, is a natural are in relation to their antioxidant activities. Most of these com-
product of the spice turmeric, Curcuma longa L. (Zingiberaceae). pounds were shown to inhibit histamine release from RBL-2H3
Curcumin 1 exhibits a variety of pharmacologic activities including cells induced by concanavalin A or a calcium ionophore [8].
anti-inflammatory, anticancer, antioxidant, wound-healing and Chemically, curcumin 1 or 1,7-bis(4-hydroxy-3-methoxy phenyl)-
antimicrobial effects [1], antiallergic activity [2,3] and inhibits 1,6-heptadiene-3,5-dione consists of two backbones, each with a
degranulation of the RBL-2H3 tumor mast cell line in culture [4,5]. ketone linked to a central eCH2 group separating the backbones
Also, it prevents biliary disorders, anorexia, coughs, diabetes, he- and a terminal meta-methoxy-para hydroxyl phenyl ring on each
patic disorders, rheumatism, sinusitis, cancer and Alzheimer's side. It has been suggested that the antioxidant activity of the
disease [6,7]. The ethyl acetate extract of Curcuma longa L. and curcumin molecule depends upon the presence of a phenolic group
curcumin were found to decrease histamine release from mast cells [9]. Other studies concluded that the hydrogens of active methy-
lene group are important for antioxidant activity [10], or that the
both active methylene group and phenolic groups are responsible
as well [11].
* Corresponding author. Pyrimidinone derivatives are widely distributed in nature and
** Corresponding author.
exhibit various biological properties, such as antimalarial [12e14],
E-mail addresses: makhloufi[email protected], [email protected]
(M. Makhloufi-Chebli), [email protected] (F. Dumas). antibacterial [15], antifungal [l6], anti-HIV [17], antiviral [18],

https://doi.org/10.1016/j.molstruc.2018.12.104
0022-2860/© 2018 Elsevier B.V. All rights reserved.
262 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269

anticancer [19] and anti-inflammatory [20,21] activities. Therefore, 2.2. General method for the synthesis of 3,4-dihydropyrimidin-
the corresponding dihydropyrimidinones (DHPMs) exhibited 2(H)-one/thione analogs of curcumin
important therapeutic and pharmacological properties, namely as
the integral backbone of several calcium channel blockers [22], A 50 mL round-bottom flask was charged with equimolar
antihypertensive agents [23] and a1a-antagonists [24]. A broad mixture of curcumin (0.002 mol; 0.736 g) and substituted alde-
range of biological effects including antiviral, antitumor, antibac- hydes (0.002 mol) with urea/thiourea (0.003 mol) dissolved in
terial, and anti-inflammatory activities have been described for ethanol (2 mL) and H3PMo12O40 (5 mol%), and was refluxed for
these compounds [24e26]. Functionalized DHPMs have shown 6e9 h by conventional heating or irradiated under microwaves for
significant antibacterial [27], antiviral [28] and antitumor [29] ac- 150e210 s. The reaction was monitored throughout by TLC plates
tivities. The synthesis of DHPMs has been the focus of great interest (silica gel G) using mobile phase, dichloromethane: methanol (5:1).
for organic and medicinal chemists [24,27]. After completion of reaction, 2/3rd of the solvent was removed, and
The development of dihydropyrimidinones/thiones scaffolds as the reaction mixture was poured into crushed ice. The precipitate
biologically active compounds contributed toward Biginelli cyclo- was filtered, washed with hot water, dried, and purified with
condensation application in drug industry. The biological signifi- diethyl ether. Finally the obtained pure curcumin-3,4-
cance of curcumin 1 and dihydropyrimidinones/thiones inspired us dihydropyrimidin-2(1H)-one/thione derivatives 4a-n were identi-
to synthesize these compounds and evaluate them as antioxidant fied by melting point measurement, UVevisible spectroscopic
and antibacterial agents. Earlier 3,4-dihydropyrimidin-2(H)-one/ methods, FT-IR and elemental analysis. The known compounds
thione analogs of curcumin were reported and synthesized by have been identified by comparison of IR spectral data and Mp with
SnCl2$2H2O [30], chitosamine hydrochloride [31] and H2SO4 [32] as those reported [30e32]. The general pattern of the reaction is
catalysts. depicted in Scheme 1.
In continuation of our interest on the synthesis of heterocycles,
using polyoxometallates as green catalysts [33e36], herein we 2.2.1. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
describe a simple and efficient strategy for the synthesis of a series hydroxy,3-methoxyphenylethylene)-4-phenyl-3,4-
of 4-aryl-5-(4-Hydroxy-3-methoxyphenyl ethylene carbonyl)-6-(4- dihydropyrimidin-2(1H)-one (4a)
hydroxy-3-methoxyphenylethylene)-3,4-dihydropyrimidin-2(1H)- This compound was obtained as dark red powder, mp
ones/thiones 4a-e under mild conditions using curcumin as a key 203e205  C; UV/Vis: labs (DMSO)/nm 272, 365; IR (cm
1): n 3506
synthon. In the present study, commercial heteropolyacide Keggin (OH), 3364 (eNH), 2941 (eCH), 1596 (C]O), 1509 (C]C), 1269
type H3PMo12O40 was used as catalyst to accomplish the synthesis (eCeO); Anal. Calcd. for C29H26N2O6: C, 69.87; H, 5.26; N, 5.62.
by conventional heating and under microwave irradiation, and the Found: C, 69.80; H, 5.30; N, 5.56.
percentage yields of the compounds were compared with the re-
ported ones. Antioxidant and antibacterial studies were also 2.2.2. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
performed. hydroxy,3-methoxyphenylethylene)-4-(4-N,N-dimethylphenyl)-3,4-
dihydropyrimidin-2(1H)-one (4b)
This compound was obtained as dark green crystals, mp
2. Experimental 194e196  C; UV/Vis: labs (DMSO)/nm 270, 347, 426; IR (cm
1): n
3494 (OH), 3405 (eNeH), 2934 (eCH), 1587 (C]O), 1507 (C]C),
2.1. Materials and methods 1261 (eCeO); Anal. Calcd. for C31H31N3O6: C, 68.75; H, 5.77; N, 7.76.
Found: C, 68.81; H, 5.80; N, 7.67.
The chemicals reagents and solvents (Fluka products) used were
of analytical grade and were used without further purification. 2.2.3. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
Melting points were determined on a Stuart scientific SPM3 hydroxy,3-methoxyphenylethylene)-4-(4-chlorophenyl)-3,4-
apparatus fitted with a microscope and are uncorrected. The dihydropyrimidin-2(1H)-one (4c)
infrared spectra were recorded in the region 4000e400 cm
1 on a This compound was obtained as dark red powder, mp
BRUKER TENSOR 27 IR spectrophotometer without KBr. Electronic 198e200  C; UV/Vis: labs (DMSO)/nm 270, 369, 428; IR (cm
1): n
spectra were measured on a JENWAY 6800 ultravioletevisible 3471 (OH), 3368 (eNH), 2940 (eCH), 1583 (C]O), 1507 (C]C), 1265
spectrophotometer; measurements were made from 200 to (eCeO), Anal. Calcd. for C29H25ClN2O6: C, 65.35; H, 4.73; N, 5.26.
800 nm. The elemental microanalysis (C, H, N) was carried out by
the Truspec 630-200-200 Elementary Analysis-Equipment, Service
of Microanalysis, Department of Chemistry-University of Aveiro,
Portugal. The needle voltage was set at 3000 V, with the ion source
at 80  C and desolvation temperature at 150  C. Cone voltage was
35 V. Screening of the compounds for antimicrobial activity was
done at the Pharmaceutics laboratory. The compounds were syn-
thesized using adaptation of previous reports [30,31]. For synthesis
under irradiation, a multimode microwave reactor (a modified
household microwave oven Candy mga20 m) used as a single
magnetron (2450 MHz) with a maximum delivered power of
800 W. It was directly graduated in W (from 100 to 800 W). Ex-
periments were carried out in a Pyrex reactor fitted with a
condenser. During experiments, time, temperature and power were
monitored. Temperature was monitored with the aid of an external
infrared (IR) thermometer (Flashpoint FZ400). The progress of the
reactions was monitored throughout by TLC plates (silica gel G)
using mobile phase, dichloromethane: methanol (5:1), and the Scheme 1. Synthesis of 3,4-dihydropyrimidinones/thiones of curcumin 4a-n under
spots were identified by iodine vapors or UV light. conventional reflux (D) or mW irradiation.
 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269 263

Found: C, 65.31; H, 4.80; N, 5.30. 2.2.11. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-

hydroxy,3-methoxyphenylethylene)-4-(2-hydroxyphenyl)-3,4-
2.2.4. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4- dihydropyrimidin-2(1H)-thione (4k)
hydroxy,3-methoxyphenylethylene)-4-(2-hydroxyphenyl)-3,4- This compound was obtained as dark green crystals, mp
dihydropyrimidin-2(1H)-one (4d) 260e262  C; UV/Vis: labs (DMSO)/nm 272, 374, 428; IR (cm
1): n
This compound was obtained as brick red crystals, mp 3604 (OH), 3339 (eNH), 2940 (eCH), 1579 (C]O), 1513 (C]C), 1261
149e150  C; UV/Vis: labs (DMSO)/nm 271, 363, 427; IR (cm
1): n (eCeO); Anal. Calcd. for C29H26N2O6S: C, 65.65; H, 4.94; N, 5.28.
3462 (OH), 3359 (eNH), 2961 (eCH), 1587 (C]O), 1507 (C]C), 1261 Found: C, 65.49; H, 4.93; N, 5.26.
(eCeO), Anal. Calcd. for C29H26N2O7: C, 67.70; H, 5.09; N, 5.44.
Found: C, 67.65; H, 5.23; N, 5.36. 2.2.12. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-hydroxyphenyl)-3,4-
2.2.5. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4- dihydropyrimidin-2(1H)-thione (4l)
hydroxy,3-methoxyphenylethylene)-4-(4-hydroxyphenyl)-3,4- This compound was obtained as dark brown powder, mp
dihydropyrimidin-2(1H)-one (4e) 261e262  C; UV/Vis: labs (DMSO)/nm 277, 370; IR (cm
1): n 3506
This compound was obtained as dark green crystals, mp (OH), 3372 (eNH), 1579 (C]O), 1507 (C]C), 1261 (eCeO); Anal.
150e152  C; UV/Vis: labs (DMSO) nm 278, 349, 428; IR (cm
1): n Calcd. for C29H26N2O6S: C, 65.65; H, 4.94; N, 5.28. Found: C, 65.45;
3488 (OH), 3358 (eNeH), 2940 (eCH), 1587 (C]O), 1507 (C]C), H, 4.99; N, 5.42.
1268 (eCeO), Anal. Calcd. for C29H26N2O7: C, 67.70; H, 5.09; N, 5.44.
Found: C, 67.55; H, 5.19; N, 5.50. 2.2.13. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(3,4-dihydroxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4m)
2.2.6. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
This compound was obtained as dark green crystals, mp
hydroxy,3-methoxyphenylethylene)-4-(3,4-dihydroxyphenyl)-3,4-
212e214  C; UV/Vis: labs (DMSO)/nm 269, 379; IR (cm
1): n
dihydropyrimidin-2(1H)-one (4f)
3505(OH), 3332 (eNH), 1573 (C]O), 1513 (C]C), 1268 (eCeO);
This compound was obtained as dark green crystals, mp
Anal. Calcd. for C29H26N2O7S: C, 63.72; H, 4.79; N, 5.13. Found: C,
220e222  C; UV/Vis: labs (DMSO)/nm 270, 363, 429; IR (cm
1): n
63.45; H, 4.93; N, 5.26.
3465(OH), 3358(eNH), 2934(eCH), 1573 (C]O), 1500 (C]C), 1268
(eCeO); Anal. Calcd. for C29H26N2O8: C, 65.65; H, 4.94; N, 5.28.
2.2.14. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
Found: C, 65.70; H, 5.03; N, 5.32.
hydroxy,3-methoxyphenylethylene)-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4n)
2.2.7. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
This compound was obtained as dark green crystals, mp
hydroxy,3-methoxyphenylethylene)-4-(3-nitrophenyl)-3,4-
206e208  C; UV/Vis: labs (DMSO)/nm 272, 373; IR (cm
1): n 3664
dihydropyrimidin-2(1H)-one (4g)
(OH), 3339 (NH), 2974 (eCH), 1573 (C]O), 1507 (C]C),
This compound was obtained as brown crystals, mp 157e159  C;
1255(eCeO); Anal. Calcd. for C29H25N3O7S: C, 62.24; H, 4.50; N,
UV/Vis: labs (DMSO)/nm 272, 368, 436; IR (cm
1): n 3664 (OH),
7.51. Found: C, 62.19; H, 4.63; N, 7.36.
3365(eNeH), 2980 (eCH), 1587(C]O), 1513 (C]C), 1255 (eCeO);
Anal. Calcd. for C29H25N3O8: C, 64.08; H, 4.64; N, 7.73. Found: C,
2.3. Screening for antibacterial activity
64.14; H, 4.70; N, 7.46.
The antimicrobial activities of compounds 4a-n were evaluated
2.2.8. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4- for their antibacterial activities against Escherichia coli (ATCC
hydroxy,3-methoxyphenylethylene)-4-phenyl-3,4- 25922), Pseudomonas aeruginosa (ATCC 27853) and Staphylococcus
dihydropyrimidin-2(1H)-thione (4h) aureus (ATCC 25923) bacterial strains by the agar diffusion method
This compound was obtained as dark brown crystals, mp [37]. A sterile physiological water solution containing a bacterial
214e216  C; UV/Vis: labs (DMSO)/nm 272, 365; IR (cm
1): n 3517 colony was prepared at room temperature, with an optical density
(OH), 3345 (NeH), 2934 (eCH), 1579 (C]O), 1513 (C]C), 1268 of 0.08e0.10 corresponding to a concentration of 106 cells/mL. The
(eCeO); Anal. Calcd. for C29H26N2O5S: C, 67.69; H, 5.09; N, 5.44. bacterial solution was inoculated in the Muller-Hinton agar me-
Found: C, 67.45; H, 4.93; N, 5.26. dium by swabbing using Petri dishes at room temperature. The
tested compounds were dissolved in dimethyl sulfoxide (DMSO)
2.2.9. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4- with a 10
1 M concentration. Twenty-five microliters of tested
hydroxy,3-methoxyphenylethylene)-4-(4-N,N-dimethylphenyl)-3,4- sample were poured onto filter paper disks 6 mm in diameter,
dihydropyrimidin-2(1H)-thione (4i) which were then delicately placed on the surface of the agar plates.
This compound was obtained as dark green crystals, mp These were later maintained at 37  C for 24 h. Activities were
195e197  C; UV/Vis: labs (DMSO)/nm 271, 348, 398; IR (cm
1): n determined by measuring the diameter of the inhibition zone (mm).
3611 (OH), 3345 (eNeH), 2940 (eCeH), 1587 (C]O), 1507 (C]C),
1261 (eCeO); Anal. Calcd. for C31H31N3O5S: C, 66.77; H, 5.60; N, 2.4. Antioxidant activity
7.54. Found: C, 66.45; H, 5.93; N, 5.46.
The antioxidant activity (free radical scavenging activity) of the
2.2.10. 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4- synthesized compounds and curcumin was evaluated by the first
hydroxy,3-methoxyphenylethylene)-4-(4-chlorophenyl)-3,4- time using the 2,2-diphenyl-1-picrylhydrazyl free radical (DPPH.)
dihydropyrimidin-2(1H)-thione (4j) scavenging assay [38,39]. DPPH. solution was prepared by dissolv-
This compound was obtained as dark brown powder, mp ing DPPH. in ethanol to give a concentration of 4 mg/100 mL.
198e200  C; UV/Vis: labs (DMSO)/nm 272, 370; IR (cm
1): n 3504 Compounds 4a-n and curcumin 1 were dissolved in DMSO to
(OH), 3352 (eNeH), 2927 (eCH), 1579 (C]O), 1507 (C]C), 1261 obtain a 10
1 M solution. The solutions of test compounds were
(eCeO); Anal. Calcd. for C29H25ClN2O5S: C, 63.44; H, 4.59; N, 5.10. diluted with DMSO to get final concentrations of 0.05, 0.025 and
Found: C, 64.05; H, 4.83; N, 5.26. 0.0125 mol/L for all the compounds. The standards were further
264 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269

diluted to give additional concentration solutions of 0.00625, Table 1

0.003125 and 0.0015625 mol/L. Each tested concentration of each 3,4-Dihydropyrimidinones of curcumin 4a-n synthesized under conventional reflux
and mW irradiation using H3PMo12O40.
compound (40 mL) was added to each well separately in duplicate
and then DPPH.solution (2 mL) was added. Each negative control Entry Compound R X Color and physical appearance
wells were loaded with DMSO (40 mL) and DPPH.solution (2 mL). 1 4a H O Dark red powder
After vortexing, the mixtures were incubated at room temperature 2 4b 4-N(CH3)2 O Dark green crystals
for 1 h in darkness at 25  C, and then the absorbance of these 3 4c 4-Cl O Dark red powder
4 4d 2-OH O Brick red crystals
compounds at different concentrations was recorded at 517 nm.
5 4e 4-OH O Dark green crystals
Ascorbic acid (AA) was used as standard for the antioxidant activity 6 4f 3,4-OH O Dark green crystals
screening. A blank containing only ethanol with DMSO was used as 7 4g 3-NO2 O Brown crystals
the control. Each measurement was performed in triplicate. The 8 4h H S Dark brown crystals
9 4i 4-N(CH3)2 S Dark green crystals
reduction of the DPPH radical was measured by monitoring
10 4j 4-Cl S Dark brown powder
continuously the decrease of absorption at 517 nm. DPPH scav- 11 4k 2-OH S Dark green crystals
enging effect was calculated as percentage of DPPH discoloration 12 4l 4-OH S Dark brown powder
using equation (1): 13 4m 3,4-OH S Dark green crystals
14 4n 3-NO2 S Dark green crystals
RSAð%Þ ¼ ½ðAc
AsÞ=Acx100 Eq (1)

where Ac is the absorbance of the control (absorbance of DPPH.e- order to investigate the scope of this approach, we carried out the
thanol solution without sample), and As is the absorbance of the three component cyclocondensation reaction of curcumin 1 and
sample compounds tested after 60 min incubation. urea/thiourea 2 with a series of aromatic aldehydes 3 under similar
conditions. Color and physical appearance are given in Table 1.
2.5. DFT analysis Analytical and physicochemical data of synthesized curcumin-
DHPMs using H3PMo12O40 are given in Table 2. The reactions
Synthesized compounds were optimized by density functional were completed after 6e9 h by conventional reflux and 2e3 min
theory (DFT) employing Becke's three-parameter hybrid model, under mW irradiation, affording the corresponding curcumin-
LeeeYangeParr (B3LYP) correlation functional method with 6-31G* DHPMs in good to excellent yields. The structure of these com-
basis set and tight SCF convergence criteria. Geometries optimi- pounds was confirmed by elemental analysis and by comparing the
zation was followed by frequency calculations at the same level of melting points and the spectroscopic data of FT-IR and UVeVisible
theory using ORCA v4 software [40]. In order to study the reactivity with those reported in the literature (see Table 3).
of studied compounds, the optimized structures were used to Excellent yields were obtained with the two heating methods;
calculate some DFT-based global reactivity descriptors, such as they are ranging from 80 to 98%. Earlier three different catalysts
Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccu- were used to accomplish the synthesis using conventional method:
pied Molecular Orbital energy (LUMO). The energy associated with SnCl2$2H2O; yield 92e97% [30], microwave assisted synthesis:
HOMO and LUMO were used to calculate the chemical potential (m) chitosamine hydrochloride; yield 90e96% [31] and H2SO4, yield
and hardness (h) of system using the equations (2) and (3) below: 71e86% [32]. When the same reaction carried out with conven-
tional method and under microwave irradiation in the presence of
ELUMO þ EHOMO
m¼ Eq (2) H3PMo12O40, the yield of the compounds was ranging between 80
2 and 98%. The use of H3PMo12O40 as catalyst in these particular re-
action was comparatively more efficient than the use of H2SO4 and
ELUMO
EHOMO
h¼ Eq (3) by the two heating modes, while with the use of SnCl2$2H2O
2 catalyst and chitosamine hydrochloride the yields are always high.
A plausible reaction mechanism is shown in Scheme 2. In order
to explain the formation of the DHPMs/thiones, we have calculated
3. Results and discussion the charges of the electrophilic and nucleophilic sites of the three
reagents via theoretical calculations DFT B3LYP/6-31G* using the
3.1. Chemistry ORCA software method [40] to identify the entities that react first
and deduced the most likely intermediate (Fig. 1 reports the
Curcumin 1 was used as the starting material for the preparation charges of each atom in the molecules that participate in the re-
of all compounds described in this paper (Scheme 1). A mixture of action). Calculations show that the carbonyl carbon atoms of cur-
curcumin 1, substituted aromatic aldehydes 3 (1eq) and urea/ cumin 1 are more positive than the carbon atom of the aldehyde
thiourea 2 (1.5eq) in minimum amount of ethanol (2 mL) using function (see Fig. 1 and the Supplementary material section), sug-
commercial heteropolyacid Keggin type H3PMo12O40 as a recyclable gesting that the reactivity of urea 2 with curcumin 1 is the first step
and nontoxic acid catalyst under conventional reflux and micro- of the reaction, then intermediate 5 reacts with aldehydes 1 to give
wave irradiation through an improved procedure to obtain 3,4- 3,4-dihydropyrimidinones 4aen (Scheme 2).
dihydropyrimidin-2(1H)-one/thione analogs of curcumin 4a-n.
The reaction was monitored throughout by TLC plates (silica gel 3.2. Spectroscopic study, effect of the substituent on the UVevisible
G) using dichloromethane:methanol (5:1) as mobile phase. spectrum
In order to evaluate the catalytic efficiency of H3PMo12O40
catalyst in the three component reaction, the mixture of curcumin The UVevis absorption spectra of compounds 4 and curcumin
1, benzaldehyde and urea was selected as the model reaction. It was 1 at 10
5 M concentration were recorded immediately after prod-
shown that only 5 mol% of catalyst was sufficient to promote the ucts' dissolution in DMSO. The absorption spectrum for compounds
reaction. Lower amounts gave a low yield even after long reaction 4 display a weak band at 270e272 nm attributed to the n-p* tran-
time, and higher amounts did not improve the efficiency of this sition and two other broad bands appearing as shoulders in all cases
transformation. After optimization of the reaction conditions, in at 331e373 nm and 398e429 nm respectively [Fig. 2], attributed to
 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269 265

Table 2
Analytical and physicochemical data of synthesized curcumin-DHPMs/thiones 4a-n using H3PMo12O40 as catalyst.

Compound Time Yield (%) Mp ( C)

This work Reported This work Reported

D(h) mW(s) D mW H2SO4 [32] SnCl2 [30] Chitosamine.HCl [31]

4a 9 150 90 97 79 97 91 203e205 206-207 [31,32]

4b 9 180 80 93 e e e 194e196 e
4c 6 150 79 96 82 94 e 198e200 201-203 [31]
4d 9 150 83 97 e 96 93 149e150 150-152 [32]
4e 9 150 84 96 74 95 92 150e152 151-152 [32]
4f 9 150 81 96 e e e 220e222 e
4g 9 210 88 98 e e e 157e159 e
4h 9 150 85 95 73 95 91 214e216 217-219 [32]
4i 9 150 98 97 e e e 195e197 e
4j 6 150 80 96 76 96 e 198e200 202-204 [31]
4k 9 150 98 94 e e 95 260e262 262-263 [32]
4l 9 150 93 95 71 93 93 261e262 261-263 [32]
4m 9 150 92 98 e e e 212e214 e
4n 9 210 95 97 e e e 206e208 e

D: conventional heating; mW: microwave irradiation.

Table 3
UVeVisible spectroscopic characteristics of compounds 4a-n and curcumin 1 in
DMSO.

Compound l abs (nm) Compound l abs (nm)

Curcumin 1 437 p-p* 4g 272 p -p*
368 p-p*
436 p -p*
4a 272 p -p* 4h 272 p -p*
365 p-p* 365 p-p*
4b 270 p -p* 4i 271 p -p*
347 p-p* 348 p-p*
426 p-p* 398 p-p*
4c 270 p -p* 4j 272 p -p*
369 p-p* 370 p-p*
428 p-p* 4k 272 p -p*
4d 271 p -p* 374 p-p*
363 p-p* 428 p-p*
427 p-p* 4l 277 p -p*
4e 278 p -p* 370 p-p*
349 p-p* 4m 269 p -p*
428 p-p* 379 p-p*
4f 270 p -p* 4n 272 p -p*
363 p-p* 331 p-p*
429 p-p* 373 p-p*

the pep* transition related with the carbonyl groups. These bands
completely differ from the one of curcumin absorption spectrum
which appears at 437 nm. These bands can be attributed to the
charge transfer between the aromatic rings and the electron with-
drawing pole constituted by the carbonyl groups that reinforce the
Scheme 2. Proposed mechanism for the synthesis of 3,4-dihydropyrimidin-2(H)-one/
electron attracting strength on this side of the molecules [Fig. 3]. In thione analogs of curcumin 1 catalysed by H3PMo12O40 (HPA).
addition, the wavelength and the intensity of the absorption spectra
were affected when changing the aryl substituent either donor or
acceptor in positions 2, 3 and 4 of the aryl ring as well as positional curcumin-DHPMs derivatives 4a-n was measured in terms of their
isomerism of the hydroxy group of compounds 4d, 4e, 4f (dihy- hydrogen donating or radical scavenging ability by UVeVisible
dropyrimidinones) and 4k (dihydropyrimidin-thione). The nature spectrophotometry using the stable 2,2-diphenyl-1-picrylhydrazyl
and position of the substituent affect the absorbance much more radical (DPPH). DPPH radical is a stable free radical and its radical
than the absorption wavelength. Compounds with hydroxyl sub- character is neutralized in the presence of molecules capable of
stituent show the highest intensity (4d, 4e and 4k) and eOH in donating H atoms. This is visually noticeable as the color changes
position 2 of the aryl ring (4d and 4k) presents highest wavelength from purple to yellow. When a compound is antioxidant, it donates
due to an extended electron cloud. Compound 4f with 2 hydroxy proton to this radical and consequently the initial absorbance of
substituants substituents shows the lowest intensity. DPPH solution decreases. Fig. 4 shows the variation of absorbance
versus concentration of the different compounds 4a-n and curcu-
min 1 (Fig. 4a) and of the standard ascorbic acid (Fig. 4b). The lower
3.3. Antioxidant activity the absorbance of the reaction mixture indicates the higher free
radical scavenging activity (RSA). The capability to scavenge the
The antioxidant activity of curcumin 1 and its synthesized DPPH (as % of inhibition) was calculated using equation (1).
266 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269

Fig. 1. Selected partial charges of curcumin 1, urea 2 and benzaldehyde 3 in ethanol

using the ORCA software method.

Fig. 4. Absorbance at 517 nm vs concentration of 4a-n and curcumin 1 (a) and of the
standard ascorbic acid (b).
Fig. 2. Absorption spectra of compounds 4 and curcumin 1 in DMSO.

molecule are important. The antioxidant potency of flavonoids of

similar conjugation level is roughly proportional to the total
number of eOH groups and is positively affected by the presence of
o-dihydroxy moiety in the benzene ring [41].
The DPPH assay measures the ability of the sample to donate
hydrogen to the DPPH radical, resulting in bleaching of the DPPH
solution. The greater the bleaching action, the higher the antioxi-
dant activity, and this was reflected in a lower half minimum
inhibitory concentrations (IC50) value. Fig. 5 shows the values of
IC50 of the tested compounds, being the most significant those of 4f
and 4m as the best antioxidant agents.

3.4. Antibacterial activity

The newly synthesized curcumin derivatives 4aen were evalu-

ated for their in vitro antibacterial activity against three bacteria
specially causing secondary infections in human being viz. Staph-
ylococcus aureus, Escherichia coli, and Pseudomonas aeuriginosa.
Fig. 3. Possible resonance structures of compounds 4a-n.
Zone of inhibition in mm was measured using disk diffusion
method (Table 4).
All the compounds exhibited high scavenging activity. It is very The test samples were dissolved in DMSO at a concentration of
interesting to note that RSA of all the synthesized compounds 4a-n 10
1 M and the antibacterial activity of curcumin-
is greater than the one of curcumin 1 (standard), compounds 4f and dihydropyrimidinone/thione analogs were compared with the
4m showing even greater antioxidant activity than ascorbic acid. positive control (as standard antibiotic reference drug) chosen ac-
The results of the antioxidant activity data are in accordance with cording to the nature of the bacterial strain (Table 4). In case of
theoretical expectations, because the number and position of the Staphylococcus aureus and Escherichia coli strains, compounds 4a-n
hydroxyl groups as well as the degree of conjugation of the whole did not show any zone of inhibition and were completely inactive.
 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269 267

Fig. 5. IC50 (mg/mL) values of the antioxidant compounds tested.

Fig. 6. Antibacterial activity of compounds 4a-n and the reference antibiotic (ATB)
colistine.

In case of Pseudomonas aeuriginosa; compounds 4g and 4n (bearing

electron-withdrawing group on the benzo ring) were totally inac- Table 5
tive whereas compounds 4a-f and 4h-m, showed much antibac- Calculated DFT descriptors in (eV) for the synthesized compounds.
terial activity with better zone of inhibition as comparison to
Compound HOMO (eV) LUMO (eV) m h
remaining compounds, but were less active than the standards.
The sensitivity to the different products is classified according to 4a
5.41
2.16
3.79 1.62
4b
4.99
2.05
3.52 1.47
the diameter of the zones of inhibition as follows: Not sensitive (
) 4c
5.50
2.25
3.88 1.62
for diameter less than 8 mm, Sensitive (þ) for a diameter between 9 4d
5.37
2.03
3.70 1.67
and 14 mm, highly sensitive (þþ) for a diameter between 15 and 4e
5.35
2.15
3.75 1.60
19 mm and extremely sensitive (þþ þ) for a diameter greater than 4f
5.02
2.19
3.61 1.42
4g
5.57
2.33
3.95 1.62
20 mm [42]. The results obtained are given in Table 4 and illustrated
4h
5.46
2.32
3.89 1.57
in Fig. 6. 4i
5.09
2.20
3.65 1.44
4j
5.55
2.41
3.98 1.57
4k
5.33
2.19
3.76 1.57
3.5. DFT analysisaz 4l
5.39
2.30
3.84 1.55
4m
5.19
2.34
3.76 1.42
4n
5.64
2.48
4.06 1.58
The DFT analysis was performed to gain a more insight into the
electronic properties of synthesized compounds. According to the
frequency calculations results of the optimized geometries, absence
to the calculated chemical hardness (h) of synthesized compounds
of imaginary frequency indicated that the structures were in sta-
(equation (3)), h (4m) ¼ h (4f) < h (4h) which indicate that 4f and
tionary point. In addition, frontier molecular orbitals HOMO and
4m are more reactive than 4h. Table 5: Calculated DFT descriptors
LUMO play an important role to illustrate the chemical reactivity.
(eV) for the synthesized compounds.
The HOMO is considered as electron donor, because it is the outer
On the other hand, the average values of the HOMO and LUMO
orbital containing electrons whereas the LUMO can accept elec-
energies have been defined as chemical potential (m), equation (2).
trons [43]. Hence, the LUMO energy is directly related to electron
The negative of the chemical potential was known as the electro-
affinity (A ¼ - ELUMO) and ionization potential (I ¼ - EHOMO) is
negativity (c ¼ - m). The electronegativity represents the power of
directly related to the energy of the HOMO [44].
molecules to attract electrons. According to values reported in
The value of HOMO, LUMO, chemical potential (m) and chemical
Table 5, the electronegativity value of 4h is higher than those of 4f
hardness (h) for various compounds are given in Table 5. It is worth
and 4m.
noting that, large HOMO - LUMO gap or when hardness increases
The visualization of HOMO and LUMO of the most potent
the reactivity should decrease and small HOMO - LUMO gap or
compounds (4f and 4m) and the least active compound (4h) are
when hardness decreases the reactivity should increases. According

Table 4
Diameters of inhibition zones (mm) for compounds 4a-n and the references antibiotics at 10
1 M.

Bacterial strain Diameter of inhibition zones (mm)

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n ATBa

S. aureus 6 6 6 6 6 6 6 6 6 6 6 6 6 6 20
e e e e e e e e e e e e e e þþþ
E. coli 6 6 6 6 6 6 6 6 6 6 6 6 6 6 25
e e e e e e e e e e e e e e þþþ
P. aeruginosa 12 12 12 13 10 11 6 11 11 14 13 11 13 6 30
þ þ þ þ þ þ e þ þ þ þ þ þ e þþþ
a
: ATB ¼ Rifampicine (10
1 M?) for S. aureus; Cotrimoxazole (10
1 M?) for E. coli; Colistine (10
1 M?) for P. aeruginosa.
268 N. Khaldi-Khellafi et al. / Journal of Molecular Structure 1181 (2019) 261e269

antioxidant activity but moderate antibacterial activity.

Curcumin-3,4-dihydropyrimidinones/thiones derived from 2-
hydroxybenzaldehyde, 4-hydroxy-benzaldehyde and 3,4-
dihydroxybenzaldehyde showed a high intensity in UVevisible
absorption spectrophotometry but the wavelengths are less
affected by the nature of substituents of the benzaldehyde. The
compound derived from 3,4-dihydroxybenzaldehyde and urea
showed maximum antioxidant activity, while antioxidant activity
decreases in compounds derived from 2-hydroxybenzaldehyde and
others.

Acknowledgments

The authors are indebted to the head of the service of the

microbiology laboratory of the CHU Nedir Mohamed of Tizi Ouzou
in Algeria, to perform the antibacterial analysis of the synthesized
compounds. CNRS (France), MENRT (France) and LabEx LERMIT
(ANR-10-LABX-33) are acknowledged for their financial support.

Appendix A. Supplementary data

Supplementary data to this article can be found online at

https://doi.org/10.1016/j.molstruc.2018.12.104.

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