Macro coumarins as novel antioxidants

Article abstract of DOI:10.13005/ojc/340544

The present work pointed at the design and synthesis of novel coumarin compounds as antioxidants. The alteration of 4-hydroxycoumarin by several reaction levels was performed to generate destination compounds. Spectroscopic methods like Infrared Spectra F

Full text of DOI:10.13005/ojc/340544

ISSN: 0970-020 X
CODEN: OJCHEG
2018, Vol. 34, No.(5):
Pg. 2562-2569
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Macro Coumarins as Novel Antioxidants
DUNYA L. AL-DUHAIDAHAwI1*,YASAMEEN K. AL-MAJEDY2,
HIbA H. IbRAHEEM2, AbDUL AMIR H. KADHUM3 and AHMED A. AL-AMIERY2
1Pharmaceutical Chemistry Department, College of Pharmacy, University of Kufa, AL-Najaf 31001, Iraq.
2Branch of Chemistry, Department of Applied Science, University of Technology (UOT), Baghdad 10001, Iraq.
3Department of Chemical and Process Engineering, University Kebangsaan Malaysia (UKM),
Bangi, Selangor 43000, Malaysia.
*Corresponding author E-mail: dunyal.mohammed@uokufa.edu.iq
http://dx.doi.org/10.13005/ojc/340544
(Received: March 29, 2018; Accepted: August 25, 2018)
AbSTRACT
The present work pointed at the design and synthesis of novel coumarin compounds as
antioxidants.The alteration of 4-hydroxycoumarin by several reaction levels was performed to generate
destination compounds. Spectroscopic methods like Infrared Spectra FT-IR, 1H-NMR and 13CNMR,
elemental analysis techniques, melting point, and thin layer chromatography defined the structure of
the prepared compounds.The antioxidant activities of individual compounds were tested against stable
free radical 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH), hydrogen peroxide (H2O2) and FRAP (ferric
reducing antioxidant power) and the results were related to the Gallic acid, ascorbic acid and Trolox as
standards.The effects revealed that most of the syntheses presented greater activity as an antioxidant
than the standards in different concentration range.The distinguished competence inactivating action
was observed for compound 2 (86.3 1%) followed by compounds 3 (85 0.5%) using DPPH method.
The antioxidant mode of action of the prepared compounds was also investigated.
Keywords: Antioxidant, DPPH, FRAP hydroxycoumarin H2O2 in activators, Macromolecules.
INTRODUCTION
have demonstrated much popularity in their used
way back for a long time. This is because these
compounds have shown significant potential in the
production of therapeutic products.They are known
for a variety of uses: physiological, antimicrobial1,2,
antioxidant3,5, anti-inflammatory6,7, anticoagulant
and antitumor8 activities. In recent years, there is
much attention in the search for antioxidants from
natural, industrial sources. As antioxidants inhibit
and scavenge radicals, they play an important role in
protecting humans from infections and degenerative
diseases. As such antioxidants can be defined as
any substrate that significantly delays or prevents
oxidation. According to 9 in comparison with an
Coumarin is a simple molecule that
originates from lactones family. As it possesses a
benzopyrone system, it isolates itself from plants.
Also, it can undergo total synthesis that is conducted
in the laboratory. Furthermore, coumarin can be
synthesized from many established chemical
reactions.Although coumarins can be obtained from
various natural resources, new coumarin derivatives
are continuously being discovered and synthesized
on regular basis.
Coumarinandcoumarin-relatedcompounds
This is an
Open Access article licensed under a Creative Commons Attribution-Non Commercial-Share Alike
4.0 International License (https://creativecommons.org/licenses/by-nc-sa/4.0/), which permits unrestricted
Non Commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

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oxidizable substrate (lipid, protein, carbohydrate,
or DNA) only low concentration of antioxidant is
required to delay or prevent numerous diseases
conditions such as swelling, carcinogenesis,
atherogenesis and also in the aging process as well
flavan-3-ols in addition to lignins, tannins and
tocopherols and phenolic acid13. However, the
flavonoids constitute the largest group of phenolic
compounds with a wide range of biochemical and
physiological actions like an antioxidant and free
radical inactivates characteristics14. Furthermore,
the phenolic molecules can serve as antioxidants
by coordinating metal ions, counteracting the
generation of radicals and stimulating the antioxidant
endogenous system forward15. Originally, we
were utilizing 4-hydroxycoumarin as a preliminary
substance and all the integrated coumarins are
manifested in Scheme 1.
as after virulent exposure to xenobiotic10-12
.
Interest in the discovery of new antioxidant
agents has surmounted increased, since the
implication of oxidative damages in many pathology
cases. The other class of compounds that has
caught much attention is polyphenols. This group
of molecules comprises flavonoids Flavonoids
like flavonols, chalcones, flavanones, flavones,
Scheme 1.Transformation series of the prepared compounds Chemicals and Environments: a = Tetrabutylammonium bromide
(TbAb)/reflux; b = diammonium hydrogen phosphate (DAHP)/reflux; c = hydrolysis; d = benzene/ reflux; e = H2SO4 / reflux
ExPERIMENTAL
carbonitrile (1)
General Chemistry
Tetrabutylammonium bromide (TbAb) as catalytic
agent for synthesis of compound (1)
The compounds utilized throughout
synthesis were provided by Sigma-Aldrich (Selangor,
Malaysia). The infrared ranges were achieved on
a Nicolet 6700 FT-IR spectrophotometer (Thermo
Nicolet Corp., Madison, wI, USA), and the data
are displayed in cm−1. NMR bands were verified
manipulating an AVANCE III 600 MHz spectrometer
(Bruker, Billerica, MA, USA), DMSO used as a solvent
and the data are revealed in δ ppm.CHN analysis was
accomplished on an Elemental analyzer Carlo Erba
1108 (Vario El III, SpA, Rodano, Italy).
The reactants, 4-Hydroxy-1-benzopyran-2-
one (0.162 g; 10 mmol) with 4-bromobenzaldehyde
(5 mmol), malononitrile (15 mmol) and Tetra-n-
butyl ammonium bromide (10 mol %) were agitated
under reflux. Then, the combination was chilled to
ambient temperature. The slurry was separated by
filtration and desiccated then recrystallized from
ethanol 16. Then the compound was characterized
by spectroscopic and physical data yields 75%, m.p
(223-225)°C.
Diammonium Hydrogen Phosphate (DAHP) as
catalytic agent for production of compound (1)
In an aqueous ethanol solution (50%
Chemical Synthesis
Synthesis of 2-amino-4- (4-bromophenyl)-
5-oxo-4, 5-dihydropyrano [3, 2-c] chromene-3-

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H2O: 50% EtOH) totally 50 ml starting compounds
comprising 4-hydroxycoumarin (0.162 g; 10 mmol),
4-bromobenzaldehyde (10 mmol), malononitrile
(12mmol)andammoniummonohydrogenphosphate
(26.4 mg, 10 mol %), were agitated for 4 h, at ambient
condition.when the reaction complete, the slurry was
separated by filtration and rinsed with ethanol17.Then
the compound was characterized by spectroscopic
and physical data., yields 70%., m.p ( 225-227°C);
1H-NMR: δ 4.28 (s, 1H, CH), δ 7.11 and δ 7.83 (dd,
2H), δ 7.42-7.83 (m, 1H, C-H aromatic ring), δ8.49 (s,
NH2); 13CNMR (DMSO):40, 58.3, 108, 116.0, 125.1,
128.1, 152.1, 160.5, 161.1 and 165.5; FT-IR:3385.8
cm−1 (NH2), 3189.0 cm−1 (C-H aromatic), 1709.2 cm−1
(C=O, lactone), 2213 cm−1 (C≡N), 1638.0 cm−1 (C=C
aromatic); CHN analysis: Calcd. for C19H11BrN2O3:
C 57.74% H 2.81% N 7.09%, Found: C 57.54% H
2.1% and N 6.91%.
The crude result was filtrated, rinsed with ice-cold
water and evaporated.The result was recrystallized
from ethanol, yields 45%, m.p (244-246°C);
1H-NMR: δ 2.1 (s, 1H, NH), δ 3.91 (s, 1H, CH), δ
7.2 and δ 7.82 (dd, 2H), δ 7.4-7.79 (m, 4H, C-H
aromatic ring), δ8.4 (s, NH2);FT-IR:3433- 3328 cm−1
(NH2), 3055.1 cm−1 (C-H aromatic), 1652 cm−1 (C=O)
1602.9 cm−1 (C=O, lactone); CHN analysis: Calcd.
for C20H14BrClN2O4: C 52.03 % H 3.06 % N 6.07 %,
Found: C 51.5% H 2.88% and N 5.81%.
Synthesisof7-(4-bromophenyl)-10-(chloromethyl)
-6H-chromeno [3', 4’: 5,6] pyrano [2,3-d][1,3]
oxazine-6,8(7H)-dione (4)
To a solution of 2 mmol, 0.941 g of compound
(3) in 50 ml of dry methanol was added concentrated
sulphuric acid (80 mmol). The combination was
refluxed for (3-4) h, Following cooling; the reaction
substance was transferred into an ice-water mixture.
The solid particles were collected by percolation,
rinsed with water and recrystallized from methanol
to obtain compound (4) 19, yields 35%, m.p (
217-219°C); 1H-NMR: δ 3.9 (s,2H,CH2Cl), δ 4.4 (s,
1H, CH), δ 7.1 and δ 7.8 (dd, 2H), δ 7.4-7.79 (m,
1H??, C-H aromatic ring) ; FT-IR: 3181.6 cm−1 (C-H
aromatic), 1670.6, 1612.1 cm−1 (C=O, lactone),
1570.4 cm−1 (C=C aromatic); CHN analysis: Calcd.
for C21H11BrClNO5: C 53.36% H 2.35% N 2.96%,
Found: C 52.64% H 2.1% and N 1.91%.
Synthesis of 2-amino-4- (4-bromophenyl)-5-
oxo-4, 5-dihydropyrano [3,2-c] chromene-3-
carboxylic acid (2)
Aqueous sodium hydroxide solution (1 M,
0.3 ml) was supplemented to compound (1) and
the combination was warmed for 5 min. at 140OC.
hydrochloric acid (1 M, 0.3 ml) was then added to
make solution neutral under these conditions we
got compound (2) at 19–20 minutes After finishing
the reaction, the slurry was separated by filtration
and rinsed with ethanol, 18, yields: 50%, m.p (230-
233°C); 1H-NMR: δ 3.93 (s, 1H, CH), δ 7.10 and δ
7.81 (dd, 2H), δ 7.32-7.82 (m, 4H, C-H aromatic),
δ 8.5 (s, NH2) , δ 11.0 (s, OH); FT-IR: 3221(NH2),
3307 cm−1 (OH); 3090.1 cm−1 (C-H aromatic), 1652
cm−1 (C=O, lactone), 1710 cm−1 (C=O, carboxylic),
1625.3 cm−1 (C=C aromatic); CHN analysis: Calcd.
for C19H12BrNO5: C 55.09% H 2.92% N 3.38%,
Found :C 54.54% H 2.5% and N 3. 1%.
Antioxidant activity
(2,2-Diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl)
(DPPH) free radical scavenging activity
Antioxidantpropertiesofsynthesizedcoumarin
compounds (1-4) were tested spectrophotometrically
utilizing 2,2-diphenyl-1-picrylhydrazyl radical,20,21
.
At first, 0.1 mL of different strengths of prepared
compounds 0.25, 0.5, 0.75 and 1 mg/ml and standard
ascorbic acid were combined 1 ml of 0.2 mM DPPH
solubilized in CH3OH. The reaction admixture was
kept in the darkness for 30 min at 28oC.The control
experiment was carried out as above without
test samples. The DPPH antioxidant activity was
ascertained by determining the absorbance, at
517 nm operating the UV-VIS spectrophotometer.
The reduction of DPPH radical in activator was
computed relative to the measured absorbance of
the control applying the subsequent equation (1):
Synthesis of 2-amino-4- (4-bromophenyl)-5-
oxo-4, 5-dihydropyrano [3,2-c] chromene-3-
carboxylic 2-chloroacetic anhydride (3)
In 100 ml RBF, (0.02 mol, 9.81 g) of
compound (2) in 4 ml ethanol was mixed in magnetic
agitator for 10 minutes. Chlor-acetyl chloride (0. 02
mole, 4 equivalent) was supplemented gradually
for 1 h, Reaction combination was maintained on
stirring for 24-writhe reaction mixture was chilled,
transferred into an ice water (50 ml) including a
drop of pyridine and agitated till the oil solidifies.
(1)

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where Ao is the absorbance of the controller
reaction, and A1 is the absorbance in the existence
of the tests or standards.
Arithmetical analysis
Data obtained were presented as mean
SD and the arithmetical significance of variances
was established using one-way assay of variance
(ANOVA) by the SPSS 17.0 arithmetical software
package. Variances were reflected significant at
P<0.05.The significances are represented as mean
SD (n=3).
H2O2 Scavenging Activity
H2O2 solution (40 mM) was made in buffer
phosphate (pH 7.4). Various dilutions (250, 500,
750 and 1000 g ml–1) of the prepared compounds
(or ascorbic acid) were supplemented to the H2O2
liquid (0.6 ml, 40 mM). The absorbance of H2O2 at
230 nm was revealed after 10 min. in contradiction
of a blank solution having phosphate buffer lacking
H2O222.The H2O2 proportion inactivating activity was
estimated applying equation (1).
RESULTS AND DISCUSSION
Antioxidant assay
Antioxidant activity of prepared compounds
was achieved manipulating different in vitro tests
against 2,2-Diphenyl-1-picrylhydrazyl (DPPH)
radical, hydrogen peroxide) inactivating and (FRAP)
ferric-reducing antioxidant strength test.
(FRAP) Ferric Reducing Antioxidant Power Assay
The method suggested by Muss23 was
applied to establish the antioxidant action through
FRAP with certain minor adjustments. The FRAP
component was made fresh, as in the use of 300
mM acetate buffer, pH 3.6 (3.1 g C2H3NaO2. 3H2O,
with 16 ml glacial acetic acid is adjusted up to
1:1 with Dw; 10 mM of TPTZ, in 40 mM HCl; and
20 mM FeCl3•6H2O are mixed in a ratio of
10:1:1 followed by incubation at 37°C for 10
min. prior to the analysis to allow the reagent
working time. About 1 ml of FRAP substance was
supplemented to 10 μl of each compound after the
additionoftheFRAPreagent,theplateswerepreservedfor
30 min. at ambient condition and the absorbance of the
blue complex (ferrous tripyridyltriazine) was formed from
thereaction.Allthedataweretakenintriplicates.TheTrolox
standard calibration curve was established by plotting the
curvesofvariousconcentrationsinmethanol(0.00625–0.2
mg/ml) against absorbance (at 595 nm using UV-Vis
spectrophotometer see Fig.3.26).Thecalibrationequation
found for Trolox was y=ax+b (r2 = 0.999), where y is
theopticaldensityat593nmandxistheconcentration(mg/
ml) a, b is the constant, r2 is the confidence of coefficient.
The findings were reported in mg Trolox equivalents/g
of synthesis compound. The ferric reducing antioxidant
power was estimated applying the subsequent method:
FRAP= (C x V)/M where FRAP = the ferric reducing
antioxidant power, mg/g compound, in TE; C = the
concentrationofTroloxascertainedfromthestandardization
curve, mg/mL;V= the volume of compound solution,
0.1 mL; M = the weight of synthesis compound,
0.0001 gram.
DPPH Antioxidant Activity of Compounds (1-4)
The function of an antioxidant is to
eliminate free radicals. One significant assumption
of such elimination is by providing hydrogen to FR
(free radicals) in its conversion to inactive type 20.
The hydrogen addition would eliminate the single
electron aspect, which is liable for radical reactivity.
Free radicals have been a topic of considerable
concern between specialists in the preceding
decade. The antioxidant actions of compounds
(1-4) were evaluated in vitro utilizing DPPH (1,1-
Diphenyl-2-picrylhydrazyl radical radical inactivating
methods. Gallic acid was applied as the standard.
Donating hydrogen activity, as estimated using
DPPH radicals as a hydrogen acceptor, revealed
that considerable correlation might be observed
linking the concentration of the recently synthesized
compound and the inhibition rate. DPPH molecules
(1-4) have been proved to diminish the established
radical. As indicated by Fig. (1) the prepared
compounds 1, 2, 3, and 4 possess 61 0.6%,
86.3 1%, 85 0.5%, and 71.2 0.8% DPPH radical-
inactivating action. The compounds (1, 2, and 3)
contain the N-H group, which enables hydrogen atom
transfer (HAT) to the DPPH free radical to provide
a resonance-stabilized radical. The scavenging
influence enhanced with rising concentrations
of samples. In the DPPH technique, the highest
antioxidant effect was 90 1% at a strength 1000

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Table 1: DPPH antioxidants activity of comp (1-4)
AL-DUHAIDAHAwI et al., Orient. J. Chem., Vol. 34(5), 2562-2569 (2018)
μg/mL for compound (2), and the least inactivating
power was 26.1 0.5% at 250 μg/mL concentration
for compound (1). Fig. (2) shows the proposed
mechanism for compounds, specifically, 2-amino-
4-(4-bromophenyl)-5-oxo-4, 5-dihydro pyrano (3,
2-c) chromene-3-carboxylic acid (2), and 3-amino-
2-((4-bromophenyl)(2-oxo-2H-chromen-3-yl) methyl)
acrylic 2-chloro acetic anhydride (3).
Comp NO H2O2 inhibition %SD
100μg/ml
IC50 SEM
1
2
3
4
61 0.6%
86.3 1.0%
85 0.5%
31 0.2%
41.3 1%
41 0.8%
26.4 0.5%
71.2 0.8%
Fig. 1. Evaluation of antioxidant properties by DPPH assay for compounds (1-4)
Fig. 2.The schematic mechanism between DPPH FR (free radicals) and compounds 2 and 3
H2O2 Scavenging Capacity
Hydrogen peroxide intact isn’t extremely
of the standard, and the values are 80 1.0%, and
81.5 1.5%, respectively. Compounds 1 and 4show
scavenging activity on hydrogen peroxide with lower
value compared with ascorbic acid.
reactive, but the compound can occasionally be
noxious to the cell due to the subsequent hydroxyl
radical in cells24.Thus, the elimination of H2O2 is very
significant for antioxidant protection in the cell. The
inactivating ability of prepared compounds on H2O2
equaled with ascorbic acid as a reference compound
is shown in Fig.3 the coumarin compounds were able
of inactivating H2O2 in a concentration-dependent
fashion. Results display that H2O2 scavenging
actions of compounds 2 and 3 are higher than that
Table 2: H2O2 scavenging activity of comp (1-4)
Comp NO
H2O2 inhibition %SD
100 μg/ml
IC50 SEM
1
2
3
4
60 0.5%
80 1.0%
81.5 1.5%
54.2 1.1%
29 0.5%
39.4 0.3%
40 0.6%
26.4 0.8%

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Fig. 3. Influence of compound 1-4 on hydrogen peroxide
Ferric Reducing Ability Power (FRAP)
in a redox-associated colorimetric effect28 following
the equation:
The antioxidant potential of all compounds
was ascertained by a FRAP test. The FRAP
assessment was revealed as an equivalent
of compounds (mg/g of standard antioxidant
Trolox). The FRAP test estimated the potency of a
compound to reduce the ferric 2,4,6-Tri(2-pyridyl)-
s-triazine complex to the stained ferrous complexes
compound.FRAP results are acquired by relating the
absorbance alteration at 593 nm in assay reaction
admixtures with those having ferrous ions in identified
concentrations. In general, the reducing properties
of these sets of compounds largely rely on the sum
and position of hydrogen-donor hydroxyl clusters
on the aromatic group of phenolic compounds; in
addition, the properties are influenced by other
aspects, such as H-donor groups (-NH, -SH)25, which
apply their effect by destroying the free radical series
via providing a hydrogen atom26,27. The FRAP test
considers the antioxidants specimen as a reluctant
FRAP: Fe (TPTZ)23++ ArOH → Fe (TPTZ)22++ ArO. + H+
FRAP: [Fe (TPTZ)2]2+ (Ferrous tripyridyl triazine cation)
Several synthetic and naturally existing
coumarins display possible antioxidant activity.
Therefore, the antioxidant influence of coumarin
derivatives 1-4 was assessed utilizing FRAP
test in contrast to Trolox. The linearity of FRAP
(dose–response curve) for conventional solutions
is presented in Fig. (4). The values of the FRAP
test are stated in Table (1), and ferric reducing
ability was represented as the concentrations of
antioxidant as FRAP value (mg/g). Depending on
results, compounds 2 and 3 revealed considerable
antioxidant activity compared with Trolox owing to
the existence of the NH2 group, which donates a
hydrogen atom, in the structure of these compounds.
However, the remaining compounds show poor
antioxidant power.
Fig. 4. Linearity of FRAP for stock solutions (Trolox)

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Table 1: FRAP antioxidant
activities of prepared compounds
analysis (CHN) and spectroscopic methods
(IR and 1H and 13C NMR).The scavenging activities
of prepared coumarins compounds were verified
by utilizing hydrogen peroxide test (H2O2), DPPH
antioxidant examines, and FRAP assess. Results
indicate that DPPH give the best antioxidant activity
observed for compound 2 (86.3 1%) followed by
compounds 3 (85 0.5%). The new coumarins hold
greater scavenging activity compared with vitamin
C, gallic acid, and Trolox as standards.
Compound
FRAP value (mg/ g)
1
2
3
4
10.4
41.6
60.2
9.1
CONCLUSION
The preparation and characterization of
coumarin derivatives are of considerable interest
owing to their potential for various applications based
on their biological activity. A series of 4-hydroxy
coumarin compounds were successfully synthesized
by conventional methods. The recently prepared
molecules were described by using elemental
ACKNOwLEDGMENT
we are grateful to the staff membered
at pharmaceutical chemistry department at Kufa
University for kind help & support.
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