Green synthesis, antioxidant and antibacterial activities of 4-aryl-3,4-dihydropyrimidinones/thiones derivatives of curcumin. Theoretical calculations and mechanism study

Article abstract of DOI:10.1016/j.molstruc.2018.12.104

3,4-Dihydropyrimidin-2(1H)-one/thione analogs of curcumin were synthesized in good yield by a one-pot multi-component cyclocondensation using curcumin, substituted aromatic aldehydes, and urea/thiourea in less volume of ethanol catalysed by commercial heteropolyacide Keggin type H₃PMo₁₂O₄₀ 5% mol as a recyclable and nontoxic catalyst under conventional heating and microwave irradiation. All the synthesized curcumin derivatives 4a–n were screened for antioxidant and antimicrobial activity. Biological activity data of the synthesized showed that most of the synthesized compounds exhibited greater antioxidant and antibacterial activity than curcumin. Geometries of synthesized compounds were optimized by using B3LYP method with 6-31G* basis set. Then, DFT based reactivity descriptors such as HOMO, LUMO, chemical hardness, electronegativity, chemical potential were calculated and discussed.

Full text of DOI:10.1016/j.molstruc.2018.12.104

Accepted Manuscript
Green synthesis, antioxidant and antibacterial activities of 4-aryl-3,4-
dihydropyrimidinones/thiones derivatives of curcumin. Theoretical calculations and
mechanism study
Nassima Khaldi-Khellafi, Malika Makhloufi-Chebli, Djamila Oukacha-Hikem, Souhila
Terachet Bouaziz, Kamilia Ould Lamara, Taous Idir, Amina Benazzouz-Touami,
Françoise Dumas
PII:
S0022-2860(18)31537-0
DOI:
https://doi.org/10.1016/j.molstruc.2018.12.104
MOLSTR 26041
Reference:
To appear in: Journal of Molecular Structure
Received Date: 24 November 2018
Revised Date: 23 December 2018
Accepted Date: 26 December 2018
Please cite this article as: N. Khaldi-Khellafi, M. Makhloufi-Chebli, D. Oukacha-Hikem, S.T. Bouaziz,
K.O. Lamara, T. Idir, A. Benazzouz-Touami, Franç. Dumas, Green synthesis, antioxidant and
antibacterial activities of 4-aryl-3,4-dihydropyrimidinones/thiones derivatives of curcumin. Theoretical
calculations and mechanism study, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/
j.molstruc.2018.12.104.
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Graphical Abstract
Green synthesis, Antioxidant and antibacterial
activities of 4-aryl-3,4-dihydropyrimidinones/thiones
derivatives of curcumin. Theoretical calculations and
mechanism study.
Leave this area blank for abstract info.
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 and Françoise Dumas c*
aLaboratoire LPCM, Département de Chimie, Faculté des Sciences, Université 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, Université Paris-Sud, CNRS, Université
Paris-Saclay, Faculté de Pharmacie, 5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France.
R
X
2
CHO
An efficient green synthesis of 3,4-Dihydropyrimidin-2(1H)-
one/thione analogs of curcumin was developed involving a one-
pot multi-component cyclocondensation of curcumin using
substituted aromatic aldehydes and urea/thiourea catalysed by
commercial heteropolyacid Keggin type H3PMo12O40 catalyst
under conventional heating and microwave irradiation. The
derivatives were screened for antioxidant and antimicrobial
activity.
O
H2N
NH2
+
+
H3CO
HO
R
NH
H3PMo12O40 5% mol
3
N
X
Reflux or µW
OCH3
H
O
O
H3CO
HO
HO
4a-n
OH
OCH3
1
.
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.

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Journal of Molecular Structure
journal homepage: www.elsevier.com
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 and Françoise Dumas c*
aLaboratoire LPCM, Département de Chimie, Faculté des Sciences, Université Mouloud Mammeri, 15000, TiziOuzou, Algeria.
bDepartment of Chemistry, Faculty of Sciences, University Mohamed Bouguerra, Boumerdes, Algeria
c Laboratoire BioCIS, UMR CNRS 8076, Chimie des Substances Naturelles, IPSIT, Université Paris-Sud, CNRS, Université Paris-Saclay, Faculté de Pharmacie,
5, rue Jean-Baptiste Clément, 92296 Châtenay-Malabry Cedex, France
.
ARTICLE INFO
ABSTRACT
3,4-Dihydropyrimidin-2(1H)-one/thione analogs of curcumin were synthesized in good yield by
a one-pot multi-component cyclocondensation using curcumin, substituted aromatic aldehydes,
and urea/thiourea in less volume of ethanol catalysed by commercial heteropolyacide Keggin
type H3PMo12O40 5% mol as a recyclable and nontoxic catalyst under conventional heating and
microwave irradiation. All the synthesized curcumin derivatives 4a–n were screened for
antioxidant and antimicrobial activity. Biological activity data of the synthesized showed that
most of the synthesized compounds exhibited greater antioxidant and antibacterial activity than
curcumin. Geometries of synthesized compounds were optimized by using B3LYP method with
6-31G* basis set. Then, DFT based reactivity descriptors such as HOMO, LUMO, chemical
hardness, electronegativity, chemical potential were calculated and discussed.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
Nitrogen heterocycles,
Curcumin-dihydropyrimidinones/thiones,
Microwave irradiation,
Antioxidant capacity,
antibacterial activity
2009 Elsevier Ltd. All rights reserved.
theoretical studies
calcium ionophore [8]. Chemically, curcumin 1 or 1,7-bis(4-
hydroxy-3-methoxy phenyl)-1,6-heptadiene-3,5-dione consists
Introduction*
of two backbones, each with a ketone linked to a central –CH2
group separating the backbones and a terminal meta-methoxy-
para hydroxyl phenyl ring on each side. It has been suggested
that the antioxidant activity of the curcumin molecule depends
upon the presence of a phenolic group [9]. Other studies
concluded that the hydrogens of active methylene group are
important for antioxidant activity [10], or that the both active
methylene group and phenolic groups are responsible as well
[11].
Curcumin 1, which imparts the yellow color to curry, is a
natural product of the spice turmeric, Curcuma longa L.
(Zingiberaceae). Curcumin
pharmacologic activities
1
exhibits
a
variety of
including
anti-inflammatory,
anticancer, antioxidant, wound-healing and antimicrobial
effects [1], antiallergic activity [2,3] and inhibits degranulation
of the RBL-2H3 tumor mast cell line in culture [4,5]. Also, it
prevents biliary disorders, anorexia, coughs, diabetes, hepatic
disorders, rheumatism, sinusitis, cancer and Alzheimer’s
disease [6,7]. The ethyl acetate extract of Curcuma longa L.
and curcumin were found to decrease histamine release from
mast cells by blocking intracellular signalling events in mast
cells. The anti-allergy activities of curcumin 1 and curcumin-
related compounds are in relation to their antioxidant activities.
Most of these compounds were shown to inhibit histamine
release from RBL-2H3 cells induced by concanavalin A or a
Pyrimidinone derivatives are widely distributed in nature
and exhibit various biological properties, such as antimalarial
[12-14], antibacterial [15], antifungal [l6], anti-HIV [17],
antiviral [18], anticancer [19] and anti-inflammatory [20,21]
activities. Therefore, the corresponding dihydropyrimidinones
(DHPMs) exhibited important therapeutic and pharmacological
properties, namely as the integral backbone of several calcium
channel blockers [22], antihypertensive agents [23] and α1a-
antagonists [24]. A broad range of biological effects including
antiviral, antitumor, antibacterial, and anti-inflammatory
activities have been described for these compounds [24-26].
Functionalized DHPMs have shown significant antibacterial
———
*Corresponding authors. Tel.: +213- 5 50 51 19 01; e-mail:
makhloufi_malika@yahoo.fr (MM); prhamdi@gmail.comm (MH);
francoise.dumas@u-psud.fr (FD)

ACCEPTED MANUSCRIPT
[27], antiviral [28] and antitumor [29] activities. The synthesis
of DHPMs has been the focus of great interest for organic and
medicinal chemists [24,27].
A 50 ml round-bottom flask was charged with equimolar
mixture of curcumin (0.002 mol; 0.736 g) and substituted
aldehydes (0.002 mol) with urea/thiourea (0.003 mol) dissolved
in ethanol (2 mL) and H3PMo12O40 (5 mol%), and was refluxed
for 6-9 h by conventional heating or irradiated under
microwaves for 150-210 s. The reaction was monitored
throughout by TLC plates (silica gel G) using mobile phase,
dichloromethane: methanol (5:1). After completion of reaction,
2/3rd of the solvent was removed, and the reaction mixture was
poured into crushed ice. The precipitate was filtered, washed
with hot water, dried, and purified with diethyl ether. Finally
the obtained pure curcumin-3,4-dihydropyrimidin-2(1H)-
one/thione derivatives 4a-n were identified by melting point
measurement, UV-visible spectroscopic methods, FT-IR and
elemental analysis. The known compounds have been
identified by comparison of IR spectral data and Mp with those
reported [30-32]. The general pattern of the reaction is depicted
in Scheme 1.
The development of dihydropyrimidinones/thiones
scaffolds as biologically active compounds contributed toward
Biginelli cyclocondensation application in drug industry. The
biological
significance
of
curcumin
1
and
dihydropyrimidinones/thiones inspired us to synthesize these
compounds and evaluate them as antioxidant and antibacterial
agents. Earlier 3,4-dihydropyrimidin-2(H)-one/thione analogs
of curcumin were reported and synthesized by SnCl2.2H2O
[30], chitosamine hydrochloride [31] and H2SO4 [32] as
catalysts.
In continuation of our interest on the synthesis of
heterocycles, using polyoxometallates as green catalysts [33-
36], herein we describe a simple and efficient strategy for the
synthesis of a series of 4-aryl-5-(4-Hydroxy-3-methoxyphenyl
ethylene carbonyl)-6-(4-hydroxy-3-methoxyphenylethylene)-
3,4-dihydropyrimidin-2(1H)-ones/thiones 4a-e under mild
conditions using curcumin as a key synthon. In the present
study, commercial heteropolyacide Keggin type H3PMo12O40
was used as catalyst to accomplish the synthesis by
conventional heating and under microwave irradiation, and the
percentage yields of the compounds were compared with the
reported ones. Antioxidant and antibacterial studies were also
performed.
2.2.1 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-one (4a): This compound was
obtained as dark red powder, mp 203–205 °C; UV/Vis: λabs
(DMSO)/nm 272, 365; IR (cm-1): ν 3506 (OH), 3364 (-NH),
2941 (-CH), 1596 (C=O), 1509 (C=C), 1269 (-C-O); Anal.
Calcd. for C29H26N2O6: C, 69.87; H, 5.26; N, 5.62. Found: C,
69.80; H, 5.30; N, 5.56.
2.2.2 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-N,N-
Experimental
dimethylphenyl)-3,4-dihydropyrimidin-2(1H)-one (4b): This
compound was obtained as dark green crystals, mp 194–196
°C; UV/Vis: λabs (DMSO)/nm 270, 347, 426; IR (cm-1):
ν 3494 (OH), 3405 (-N-H), 2934 (-CH), 1587 (C=O), 1507
(C=C), 1261 (-C-O); Anal. Calcd. for C31H31N3O6: C, 68.75; H,
5.77; N, 7.76. Found: C, 68.81; H, 5.80; N, 7.67.
2.1. Materials and Methods
The chemicals reagents and solvents (Fluka products) used
were of analytical grade and were used without further
purification. Melting points were determined on a Stuart
scientific SPM3 apparatus fitted with a microscope and are
uncorrected. The infrared spectra were recorded in the region
4000–400 cm−1 on
a
BRUKER TENSOR 27 IR
spectrophotometer without KBr. Electronic spectra were
measured on JENWAY 6800 ultraviolet-visible
2.2.3 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-chlorophenyl)-3,4-
dihydropyrimidin-2(1H)-one (4c): This compound was
obtained as dark red powder, mp 198–200 °C; UV/Vis: λabs
(DMSO)/nm 270, 369, 428; IR (cm-1): ν 3471 (OH), 3368 (-
NH), 2940 (-CH), 1583 (C=O), 1507 (C=C), 1265 (-C-O),
Anal. Calcd. for C29H25ClN2O6: C, 65.35; H, 4.73; N, 5.26.
Found: C, 65.31; H, 4.80; N, 5.30.
a
spectrophotometer; measurements were made from 200 to 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 synthesized 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). Experiments
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 spots were identified by iodine vapors
or UV light.
2.2.4 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(2-hydroxyphenyl)-3,4-
dihydropyrimidin-2(1H)-one (4d): This compound was
obtained as brick red crystals, mp 149–150 °C; UV/Vis: λabs
(DMSO)/nm 271, 363, 427; IR (cm-1): ν 3462 (OH), 3359 (-
NH), 2961 (-CH), 1587 (C=O), 1507 ( C=C), 1261 (-C-O),
Anal. Calcd. for C29H26N2O7: C, 67.70; H, 5.09; N, 5.44.
Found: C, 67.65; H, 5.23; N, 5.36.
2.2.5 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-hydroxyphenyl)-3,4-
dihydropyrimidin-2(1H)-one (4e): This compound was
obtained as dark green crystals, mp 150–152 °C; UV/Vis: λabs
(DMSO) nm 278, 349, 428 ; IR (cm-1): ν 3488 (OH), 3358 (-N-
H), 2940 (-CH), 1587 (C=O), 1507 (C=C), 1268 (-C-O), 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. General method for the synthesis of 3,4-
dihydropyrimidin-2(H)-one/thione analogs of curcumin
2.2.6 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(3,4-dihydroxyphenyl)-

ACCEPTED MANUSCRIPT
3,4-dihydropyrimidin-2(1H)-one (4f): This compound was
1573 (C=O), 1513 (C=C), 1268 (-C-O); Anal. Calcd. for
C29H26N2O7S: C, 63.72; H, 4.79; N, 5.13. Found: C, 63.45; H,
4.93; N, 5.26.
obtained as dark green crystals, mp 220–222 °C; UV/Vis: λabs
(DMSO)/nm 270, 363, 429; IR (cm-1): ν 3465(OH), 3358(-
NH), 2934(-CH), 1573 (C=O), 1500 (C=C), 1268 (-C-O); Anal.
Calcd. for C29H26N2O8: C, 65.65; H, 4.94; N, 5.28. Found: C,
65.70; H, 5.03; N, 5.32.
2.2.14 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4n): This compound was
obtained as dark green crystals, mp 206–208 °C; UV/Vis: λabs
(DMSO)/nm 272, 373; IR (cm-1): ν 3664 (OH), 3339 (NH),
2974 (-CH), 1573 (C=O), 1507 ( C=C), 1255(-C-O); Anal.
Calcd. for C29H25N3O7S: C, 62.24; H, 4.50; N, 7.51. Found: C,
62.19; H, 4.63; N, 7.36.
2.2.7 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(3-nitrophenyl)-3,4-
dihydropyrimidin-2(1H)-one (4g): This compound was
obtained as brown crystals, mp 157–159 °C; UV/Vis: λabs
(DMSO)/nm 272, 368, 436; IR (cm-1): ν 3664 (OH), 3365(-N-
H), 2980 (-CH), 1587(C=O), 1513 (C=C), 1255 (-C-O); Anal.
Calcd. for C29H25N3O8: C, 64.08; H, 4.64; N, 7.73. Found: C,
64.14; H, 4.70; N, 7.46.
2.3. Screening for Antibacterial Activity
The antimicrobial activities of compounds 4a-n were
evaluated for their antibacterial activities against Escherichia
coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853)
and Staphylococcus aureus (ATCC 25923) bacterial strains by
the agar diffusion method [37]. A sterile physiological water
solution containing a bacterial colony was prepared at room
temperature, with an optical density of 0.08–0.10
corresponding to a concentration of 106 cells/mL. The bacterial
solution was inoculated in the Muller-Hinton agar medium by
swabbing using Petri dishes at room temperature. The tested
compounds were dissolved in dimethyl sulfoxide (DMSO) with
a 10-1 M concentration. Twenty-five microliters of tested
sample were poured onto filter paper disks 6 mm in diameter,
which were then delicately placed on the surface of the agar
plates. These were later maintained at 37 °C for 24 h. Activities
were determined by measuring the diameter of the inhibition
zone (mm).
2.2.8 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-phenyl-3,4-
dihydropyrimidin-2(1H)-thione (4h): This compound was
obtained as dark brown crystals, mp 214–216 °C; UV/Vis: λabs
(DMSO)/nm 272, 365; IR (cm-1): ν 3517 (OH), 3345 (N-H),
2934 (-CH), 1579 (C=O), 1513 (C=C), 1268 (-C-O); Anal.
Calcd. for C29H26N2O5S: C, 67.69; H, 5.09; N, 5.44. Found: C,
67.45; H, 4.93; N, 5.26.
2.2.9 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-N,N-
dimethylphenyl)-3,4-dihydropyrimidin-2(1H)-thione (4i): This
compound was obtained as dark green crystals, mp 195–197
°C; UV/Vis: λabs (DMSO)/nm 271, 348, 398; IR (cm-1): ν
3611 (OH), 3345 (-N-H), 2940 (-C-H), 1587 (C=O), 1507
(C=C), 1261 (-C-O); Anal. Calcd. for C31H31N3O5S: C, 66.77;
H, 5.60; N, 7.54. Found: C, 66.45; H, 5.93; N, 5.46.
2.4. Antioxidant activity
2.2.10 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-chlorophenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4j): This compound was
obtained as dark brown powder, mp 198-200 °C; UV/Vis: λabs
(DMSO)/nm 272, 370; IR (cm-1): ν 3504 (OH), 3352 (-N-H),
2927 (-CH), 1579 (C=O), 1507 (C=C), 1261 (-C-O); Anal.
Calcd. for C29H25ClN2O5S: C, 63.44; H, 4.59; N, 5.10. Found:
C, 64.05; H, 4.83; N, 5.26.
The antioxidant activity (free radical scavenging activity) of
the synthesized compounds and curcumin was evaluated by the
first time using the 2,2-diphenyl-1-picrylhydrazyl free radical
(DPPH.) scavenging assay [38,39]. DPPH. solution was
prepared by dissolving DPPH. in ethanol to give
a
concentration of 4 mg/100 mL. Compounds 4a-n and curcumin
1 were dissolved in DMSO to obtain a 10-1 M solution. The
solutions of test compounds were diluted with DMSO to get
final concentrations of 0.05, 0.025 and 0.0125mol/L for all the
compounds. The standards were further diluted to give
additional concentration solutions of 0.00625, 0.003125 and
0.0015625 mol/L. Each tested concentration of each compound
(40 µL) was added to each well separately in duplicate and then
DPPH.solution (2 mL) was added. Each negative control wells
were loaded with DMSO (40 µL) and DPPH.solution (2 mL).
After vortexing, the mixtures were incubated at room
temperature for 1 h in darkness at 25 °C, and then the
absorbance of these compounds at different concentrations was
recorded at 517 nm. Ascorbic acid (AA) was used as standard
for the antioxidant activity screening. A blank containing only
ethanol with DMSO was used as the control. Each
measurement was performed in triplicate. The reduction of the
DPPH radical was measured by monitoring continuously the
decrease of absorption at 517 nm. DPPH scavenging effect was
calculated as percentage of DPPH discoloration using equation
(1):
2.2.11 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(2-hydroxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4k): This compound was
obtained as dark green crystals, mp 260–262 °C; UV/Vis: λabs
(DMSO)/nm 272, 374, 428; IR (cm-1): ν 3604 (OH), 3339 (-
NH), 2940 (-CH), 1579 (C=O), 1513 (C=C), 1261 (-C-O);
Anal. Calcd. for C29H26N2O6S: C, 65.65; H, 4.94; N, 5.28.
Found: C, 65.49; H, 4.93; N, 5.26.
2.2.12 5-(4-Hydroxy-3-methoxyphenylethylene carbonyl)-6-(4-
hydroxy,3-methoxyphenylethylene)-4-(4-hydroxyphenyl)-3,4-
dihydropyrimidin-2(1H)-thione (4l): This compound was
obtained as dark brown powder, mp 261–262 °C; UV/Vis: λabs
(DMSO)/nm 277, 370; IR (cm-1): ν 3506 (OH), 3372 (-NH),
1579 (C=O), 1507 (C=C), 1261 (-C-O); Anal. Calcd. for
C29H26N2O6S: C, 65.65; H, 4.94; N, 5.28. Found: C, 65.45; H,
4.99; N, 5.42.
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): This compound was
obtained as dark green crystals, mp 212–214 °C; UV/Vis: λabs
(DMSO)/nm 269, 379; IR (cm-1): ν 3505(OH), 3332 (-NH),
RSA (%) = [(Ac - As)/Ac] x 100
Eq (1)

ACCEPTED MANUSCRIPT
where Ac is the absorbance of the control (absorbance of
reaction. It was shown that only 5 mol% of catalyst was
sufficient to promote the reaction. Lower amounts gave a low
yield even after long reaction time, and higher amounts did not
improve the efficiency of this transformation. After
optimization of the reaction conditions, in order to investigate
the scope of this approach, we carried out the three component
cyclocondensation reaction of curcumin 1 and urea/thiourea 2
with a series of aromatic aldehydes 3 under similar conditions.
Color and physical appearance are given in table 1. Analytical
and physicochemical data of synthesized curcumin-DHPMs
using H3PMo12O40 are given in Table 2. The reactions were
completed after 6–9 h by conventional reflux and 2-3 min
under µW irradiation, affording the corresponding curcumin-
DHPMs in good to excellent yields. The structure of these
compounds was confirmed by elemental analysis and by
comparing the melting points and the spectroscopic data of FT-
IR and UV-Visible with those reported in the literature.
DPPH.ethanol solution without sample), and As is the
absorbance of the sample compounds tested after 60 min
incubation.
2.5. DFT analysis
Synthesized compounds were optimized by density
functional theory (DFT) employing Becke’s three-parameter
hybrid model, Lee–Yang–Parr (B3LYP) correlation functional
method with 6-31G* basis set and tight SCF convergence criteria.
Geometries optimization was followed by frequency
calculations at the same level of theory using ORCA v4
software [40]. In order to study the reactivity of studied
compounds, the optimized structures were used to calculate
some DFT-based global reactivity descriptors, such as Highest
Occupied Molecular Orbital (HOMO) and Lowest Unoccupied
Molecular Orbital energy (LUMO). The energy associated with
HOMO and LUMO were used to calculate the chemical
potential (µ) and hardness (η) of system using the equations (2)
and (3) below:
Table 1. 3,4-Dihydropyrimidinones of curcumin 4a-n synthesized
under conventional reflux and µW irradiation using H3PMo12O40.
Entry
Compound
R
X
Color and physical
appearance
Eq (2)
Eq (3)
1
2
4a
4b
4c
4d
4e
4f
H
4-N(CH3)2
4-Cl
O
O
O
O
O
O
O
S
Dark red powder
Dark green crystals
Dark red powder
3
4
2-OH
Brick red crystals
Dark green crystals
Dark green crystals
Brown crystals
3. Results and discussion
3.1. Chemistry
5
4-OH
6
3,4-OH
3-NO2
H
Curcumin 1 was used as the starting material for the
preparation of all compounds described in this paper (Scheme
1). A mixture of curcumin 1, substituted aromatic aldehydes 3
(1eq) and urea/thiourea 2 (1.5eq) in minimum amount of
ethanol (2mL) using commercial heteropolyacid Keggin type
H3PMo12O40 as a recyclable and nontoxic acid catalyst under
conventional reflux and microwave irradiation through an
improved procedure to obtain 3,4-dihydropyrimidin-2(1H)-
one/thione analogs of curcumin 4a-n.
7
4g
4h
4i
8
Dark brown crystals
Dark green crystals
Dark brown powder
Dark green crystals
Dark brown powder
Dark green crystals
Dark green crystals
9
4-N(CH3)2
4-Cl
S
10
11
12
13
14
4j
S
4k
4l
2-OH
S
4-OH
S
O
O
O
X
4m
4n
3,4-OH
3-NO2
S
H3CO
HO
OCH3
OH
H
+
+
H2N NH2
S
R
3
2
1
X = O, S
Excellent yields were obtained with the two heating
methods; they are ranging from 80 to 98%. Earlier three
different catalysts were used to accomplish the synthesis using
conventional method: SnCl2.2H2O; yield 92-97% [30],
microwave assisted synthesis: chitosamine hydrochloride; yield
90-96 % [31] and H2SO4, yield 71-86% [32]. When the same
reaction carried out with conventional method and under
microwave irradiation in the presence of H3PMo12O40, the yield
of the compounds was ranging between 80 and 98%. The use
of H3PMo12O40 as catalyst in these particular reaction was
comparatively more efficient than the use of H2SO4 and by the
two heating modes, while with the use of SnCl2.2H2O catalyst
R
O
H3CO
HO
H3PMo12O40 5 mol%
NH
∆ or µW
N
X
H
HO
OCH3
4a-n
Scheme 1. Synthesis of 3,4-dihydropyrimidinones/thiones of
curcumin 4a-n under conventional reflux (ꢀ) or µW irradiation.
and chitosamine hydrochloride the yields are always high
.
The reaction was monitored throughout by TLC plates (silica
gel G) using dichloromethane:methanol (5:1) as mobile phase.
In order to evaluate the catalytic efficiency of H3PMo12O40
catalyst in the three component reaction, the mixture of
curcumin 1, benzaldehyde and urea was selected as the model

ACCEPTED MANUSCRIPT
Table 2 Analytical and physicochemical data of synthesized curcumin-DHPMs/thiones 4a-n using H3PMo12O40 as catalyst.
Yield (%)
Reported
Mp (°C)
Reported
Compound
Time
This work
This work
ꢀ
(h)
µW
(s)
ꢀ
µW H2SO SnCl2
Chitosamine.HCl
[31]
4 [32]
[30]
9
9
6
9
9
9
9
9
9
6
9
9
9
9
150
180
150
150
150
150
210
150
150
150
150
150
150
210
90
80
79
83
84
81
88
85
98
80
98
93
92
95
97
93
96
97
96
96
98
95
97
96
94
95
98
97
79
-
82
-
74
-
-
73
-
76
-
71
-
-
97
-
94
96
95
-
-
95
-
96
-
93
-
91
-
-
93
92
-
-
91
-
203-205
194-196
198-200
149-150
150-152
220-222
157-159
214-216
195-197
198-200
260-262
261-262
212-214
206-208
206-207 [31,32]
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
-
201-203 [31]
150-152 [32]
151-152 [32]
-
-
217-219 [32]
-
-
202-204 [31]
262-263 [32]
261-263 [32]
95
93
-
-
-
-
-
ꢀ: conventional heating; µW: microwave irradiation.
HPA
A plausible reaction mechanism is shown in Scheme
2. In order to explain the formation of the DHPMs/thiones, we
have calculated the charges of the electrophilic and
nucleophilic sites of the three reagents via theoretical
calculations DFT B3LYP/6-31G* using the ORCA software
method [40] to identify the entities that react first and deduced
the most likely intermediate (Figure 1 reports the charges of
each atom in the molecules that participate in the reaction).
Calculations show that the carbonyl carbon atoms of curcumin
1 are more positive than the carbon atom of the aldehyde
function (see Fig.1 and the Supplementary material section),
suggesting that the reactivity of urea 2 with curcumin 1 is the
first step of the reaction, then intermediate 5 reacts with
aldehydes 1 to give 3,4-dihydropyrimidinones 4a–n (Scheme
2).
O
O
X
H3CO
OCH3
OH
H2N
NH2
+
HO
2
1
X
HPA
O
H
N
O
NH2
H
R
3
OCH3
OH
HO
-H2O
-H2O
OCH3
5
R
HPA
-0.442
O
H
0.382
-0.527
O
X
O
-0.614
-0.475
0.173
O
N
NH
H
H3CO
HO
-0.633
O
NH
O
R
H
0.165
H
N
X
0.378
O
O
H
H3CO
-0.431
OH
OCH3
1
HO
HO
OCH3
4a-n
-0.488
O
-0.377
O
0.169
6
0.679
H
-0.766
0.348
H
H
N
H
N
0.099
Scheme
2 Proposed mechanism for the synthesis of 3,4-
dihydropyrimidin-2(H)-one/thione analogs of curcumin 1 catalysed
H
0.323
by H3PMo12O40 (HPA).
2
3
for compounds 4 display a weak band at 270-272 nm attributed
to the n-π* transition and two other broad bands appearing as
shoulders in all cases at 331-373 nm and 398-429 nm
respectively [Figure 2], attributed to the π–π* 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 withdrawing pole
constituted by the carbonyl groups that reinforce the electron
attracting strength on this side of the molecules [Figure 3]. In
Figure 1. Selected partial charges of curcumin 1, urea 2 and
benzaldehyde 3 in ethanol using the ORCA software method.
3.2. Spectroscopic study, Effect of the substituent on the
UV-visible spectrum
The UV-vis absorption spectra of compounds 4 and
curcumin 1 at 10-5 M concentration were recorded immediately
after products’ dissolution in DMSO. The absorption spectrum

ACCEPTED MANUSCRIPT
compounds 4a-n is greater than the one of curcumin 1
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 isomerism of the hydroxy group of compounds
4d, 4e, 4f (dihydropyrimidinones) and 4k (dihydropyrimidin-
thione). The nature and position of the substituent affect the
absorbance much more than the absorption wavelength.
Compounds with hydroxyl substituent show the highest
intensity (4d, 4e and 4k) and -OH in position 2 of the aryl ring
(4d and 4k) presents highest wavelength due to an extended
electron cloud. Compound 4f with 2 hydroxy substituants
substituents shows the lowest intensity.
(standard), compounds 4f and 4m showing even greater
antioxidant activity than ascorbic acid. The results of the
antioxidant activity data are in accordance with theoretical
expectations, because the number and position of the hydroxyl
groups as well as the degree of conjugation of the whole
molecule are important. The antioxidant potency of flavonoids
of similar conjugation level is roughly proportional to the total
number of -OH 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 antioxidant activity, and this was reflected in a lower half
minimum inhibitory concentrations (IC50) value. Figure 5
shows the values of IC50 of the tested compounds, being the
most significant those of 4f and 4m as the best antioxidant
agents.
Table 3 UV-Visible spectroscopic characteristics of compounds
4a-n and curcumin 1 in DMSO
Compound
Compound
4g
λ abs (nm)
437 π-π*
λ abs (nm)
Curcumin 1
272 π -π*
368 π-π*
436 π -π*
272 π -π*
365 π-π*
271 π -π*
348 π-π*
398 π-π*
272 π -π*
370 π-π*
272 π -π*
374 π-π*
428 π-π*
277 π -π*
370 π-π*
269 π -π*
379 π-π*
272 π -π*
331 π-π*
373 π-π*
1,5
(curcumin)
(4k)
(4b)
(4c)
(4d)
(4e)
(4g)
(4f)
4a
4b
272 π -π*
365 π-π*
270 π -π*
347 π-π*
426 π-π*
270 π -π*
369 π-π*
428 π-π*
271 π -π*
363 π-π*
427 π-π*
278 π -π*
349 π-π*
428 π-π*
270 π -π*
363 π-π*
429 π-π*
4h
4i
1,0
0,5
0,0
4c
4d
4e
4f
4j
4k
-0,5
300
350
400
450
500
550
600
650
λ
(nm)
4l
4m
4n
Fig. 2. Absorption spectra of compounds 4 and curcumin 1 in
DMSO
3.2. Antioxidant activity
The antioxidant activity of curcumin 1 and its synthesized
curcumin-DHPMs derivatives 4a-n was measured in terms of
their hydrogen donating or radical scavenging ability by UV–
Visible spectrophotometry using the stable 2,2-diphenyl-1-
picrylhydrazyl radical (DPPH). DPPH radical is a stable free
radical and its radical character is neutralized in the presence of
molecules capable of donating H atoms. This is visually
noticeable as the colour changes from purple to yellow. When a
compound is antioxidant, it donates proton to this radical and
consequently the initial absorbance of DPPH solution
decreases. Figure 4 shows the variation of absorbance versus
concentration of the different compounds 4a-n and curcumin 1
(Fig.4a) and of the standard ascorbic acid (Fig.4b). The lower
the absorbance of the reaction mixture indicates the higher free
radical scavenging activity (RSA). The capability to scavenge
the DPPH (as % of inhibition) was calculated using equation
(1).
Fig. 3. Possible resonance structures of compounds 4a-n
3.3. Antibacterial activity
The newly synthesized curcumin derivatives 4a–n were
evaluated for their in vitro antibacterial activity against three
bacteria specially causing secondary infections in human being
viz. Staphylococcus aureus, Escherichia coli, and
Pseudomonas aeuriginosa. Zone of inhibition in mm was
measured using disk diffusion method (Table 4).
All the compounds exhibited high scavenging activity. It is
very interesting to note that RSA of all the synthesized

ACCEPTED MANUSCRIPT
The sensitivity to the different products is classified
CURCUM
4a
4b
4c
4d
4h
4i
4j
4k
4l
according to the diameter of the zones of inhibition as follows:
Not sensitive (-) for diameter less than 8 mm, Sensitive (+) for
a diameter between 9 and 14 mm, highly sensitive (+ +) for a
diameter between 15 and 19 mm and extremely sensitive (+ +
+) for a diameter greater than 20 mm [42]. The results obtained
are given in Table 4 and illustrated in Figure 6.
1,0
0,8
0,6
0,4
0,2
0,0
4e
4f
4m
4g
4n
0,00
0,02
0,04
0,06
0,08
0,10
C mol/L
(a)
Fig. 5. IC50 (mg/mL) values of the antioxidant compounds tested
3.4. DFT analysisaz
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 of imaginary frequency indicated that the
structures were in stationary point. In addition, frontier
molecular orbitals HOMO and LUMO play an important role to
illustrate the chemical reactivity. The HOMO is considered as
electron donor, because it is the outer orbital containing
electrons whereas the LUMO can accept electrons [43]. Hence,
the LUMO energy is directly related to electron affinity (A = -
ELUMO) and ionization potential (I = - EHOMO) is directly related
to the energy of the HOMO [44].
(b)
Fig. 4. Absorbance at 517 nm vs concentration of 4a-n and
curcumin 1 (a) and of the standard ascorbic acid (b).
The test samples were dissolved in DMSO at
a
concentration of 10-1 M and the antibacterial activity of
curcumin-dihydropyrimidinone/thione analogs were compared
with the positive control (as standard antibiotic reference drug)
chosen according to the nature of the bacterial strain (Table 4).
In case of Staphylococcus aureus and Escherichia coli strains,
compounds 4a-n did not show any zone of inhibition and were
completely inactive. In case of Pseudomonas aeuriginosa;
compounds 4g and 4n (bearing electron-withdrawing group on
the benzo ring) were totally inactive whereas compounds 4a-f
and 4h-m, showed much antibacterial activity with better zone
of inhibition as comparison to remaining compounds, but were
less active than the standards.
Table 4. Diameters of inhibition zones (mm) for compounds 4a-n and the references antibiotics at 10-1
M
Diameter of inhibition zones (mm)
Bacterial strain
4a
6
4b
6
4c
6
4d
6
4e
6
4f 4g 4h 4i
4j
6
4k 4l
4m
6
-
4n
6
-
ATBa
20
S. aureus
6
-
6
-
6
-
6
-
6
-
6
-
-
-
-
-
-
-
+++
E. coli
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
6
-
25
+++
P. aeruginosa
12
+
12
+
12
+
13
+
10
+
11
+
6
-
11 11 14 13 11
13
+
6
-
30
+++
+
+
+
+
+
a: ATB = Rifampicine (10-1 M?) for S. aureus; Cotrimoxazole (10-1 M?) for E. coli; Colistine (10-1 M?) for P. aeruginosa

ACCEPTED MANUSCRIPT
The visualization of HOMO and LUMO of the most potent
compounds (4f and 4m) and the least active compound (4h) are
displayed in Figure 7. The positive and negative phases of
molecular orbitals are represented in red and green color,
respectively. The HOMO of compound 4f is localized on the
substituted phenyl
ring
at position
4
of the
dihydropyrimidinone ring whereas the LUMO is mainly
focused on styryl and acryloyl groups.
A
B
Fig. 6. Antibacterial activity of compounds 4a-n and the
reference antibiotic (ATB) colistine.
The value of HOMO, LUMO, chemical potential (µ ) and
chemical hardness (η) for various compounds are given in
Table 5. It is worth noting that, large HOMO - LUMO gap or
when hardness increases the reactivity should decrease and
small HOMO - LUMO gap or when hardness decreases the
reactivity should increases. According to the calculated
chemical hardness (η) of synthesized compounds (equation 3),
η (4m) = η (4f) < η (4h) which indicate that 4f and 4m are
more reactive than 4h. Table 5: Calculated DFT descriptors (eV)
for the synthesized compounds
C
D
Table 5: Calculated DFT descriptors in (eV) for the synthesized
compounds
E
F
HOMO
(eV)
LUMO
(eV)
Compound
µ
η
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
-5.41
-4.99
-5.50
-5.37
-5.35
-5.02
-5.57
-5.46
-5.09
-5.55
-5.33
-5.39
-5.19
-5.64
-2.16
-2.05
-2.25
-2.03
-2.15
-2.19
-2.33
-2.32
-2.20
-2.41
-2.19
-2.30
-2.34
-2.48
-3.79
-3.52
-3.88
-3.70
-3.75
-3.61
-3.95
-3.89
-3.65
-3.98
-3.76
-3.84
-3.76
-4.06
1.62
1.47
1.62
1.67
1.60
1.42
1.62
1.57
1.44
1.57
1.57
1.55
1.42
1.58
Fig. 7: Plots of frontier molecular orbitals surfaces calculated for
the studied compound 4f (A,B), 4m (C,D) and 4h (E,F).
HOMO and LUMO of compound 4m are localized in the same
sites as in compound 4f. In the case of the least active
compound 4h, the HOMO is mainly localized on sulfur atom
and double bond of dihydropyrimidinone ring and along the 4-
hydroxystyryl group, whereas LUMO is displayed on the styryl
and acryloyl groups. It was interesting to observe that LUMO
was never located on the phenyl at position 4 of the
dihydropyrimidinone ring which means that this group has a
less likely chance to attract electrons.
On the other hand, the average values of the HOMO and
LUMO energies have been defined as chemical potential (µ ),
equation 2. The negative of the chemical potential was known
as the electronegativity (χ = - µ ). The electronegativity
represents the power of molecules to attract electrons.
According to values reported in table 5, the electronegativity
value of 4h is higher than those of 4f and 4m.
4. Conclusion
A series of 3,4-dihydropyrimidin-2(1H)-one/thione analogs
of curcumin were synthesized in good yield using simple,
efficient, and improved Biginelli reaction by a one-pot
multicomponent cyclocondensation using curcumin, substituted

ACCEPTED MANUSCRIPT
aromatic aldehydes, and urea/thiourea in ethanol and
cell-mediated allergy model. Malaysian J. Pharm. Sci., 7
H3PMo12O40 Keggin type heteropolyacid as catalyst. These
compounds were evaluated for their antioxidant and
antibacterial activity and showed excellent antioxidant activity
but moderate antibacterial activity.
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2-hydroxybenzaldehyde, 4-hydroxy-benzaldehyde and 3,4-
dihydroxybenzaldehyde showed a high intensity in UV-visible
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-
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The authors are indebted to the head of the service of the
microbiology laboratory of the CHU Nedir Mohamed of Tizi
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synthesized compounds. CNRS (France), MENRT (France)
and LabEx LERMIT (ANR-10-LABX-33) are acknowledged
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Highlights
•
H3PMo12O40
as
green
catalyst
in
the
synthesis
of
4-aryl-3,4-
dihydropyrimidinones/thiones of curcumin
•
•
•
Conventional heating and microwave irradiation
Theoretical calculations and mechanism studies
Antioxidant and antibacterial activity are greater than curcumin
• Geometries of synthesized compounds were optimized by using B3LYP method with
6-31G* basis set.