Synthesis, characterization and antioxidant studies of quinazolin derivatives

Article abstract of DOI:10.13005/ojc/320166

3-((4-(dimethylamino)benzylidene)amino)-2-methylquinazolin-4(3H)-one (3), 3-((4-hydroxybenzylidene)amino)-2-methylquinazolin-4(3H)-one (4), 2-methyl-3-(pyrrolidin-2-ylideneamino) quinazolin-4(3H)-one (5) and 3,3'-((1,4-phenylenebis(methanylylidene)) bis(a

Full text of DOI:10.13005/ojc/320166

ISSN: 0970-020 X
CODEN: OJCHEG
2016, Vol. 32, No. (1):
Pg. 585-590
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis, Characterization and Antioxidant
Studies of Quinazolin Derivatives
KHALIDA AL-AzAwI
Department of Chemistry, College of Science, University of Technology, Baghdad, Iraq.
*Correspondence author E-mail: khalidachemistry@gmail.com
http://dx.doi.org/10.13005/ojc/320166
(Received: December 19, 2015; Accepted: February 28, 2016)
AbSTRACT
3-((4-(dimethylamino)benzylidene)amino)-2-methylquinazolin-4(3H)-one (3), 3-((4-
hydroxybenzylidene)amino)-2-methylquinazolin-4(3H)-one (4), 2-methyl-3-(pyrrolidin-2-ylideneamino)
quinazolin-4(3H)-one (5) and 3,3'-((1,4-phenylenebis(methanylylidene)) bis(azanylylidene))bis(2-
methylquinazolin-4(3H)-one) (6) derived from 3-amino-2-methylquinazolin-4(3H)-one have been
synthesized and characterized by elemental analysis, FT-IR, NMR techniques and screened to
establish their potential as antioxidants against 1,1-diphenyl-2-picrylhydrazyl (DPPH) and Nitric oxide
(NO) radical scavengers.The results revealed that synthesized compounds (5 and 6) are much higher
than common antioxidants ascorbic acid and they showed excellent scavenging capacity against
DPPH and Nitric oxide (NO). The synthesized compounds (3 and 4) demonstrated encouraging
results comparable with ascorbic acid.
Key words: Antioxidant activity; Avenging activities; 1,1-diphenyl-2-picrylhydrazyl; Nitric oxide.
INTRODUCTION
to the EGFR (epidermal growth factor receptor)3.
Studies of scavengers, antioxidants, enzyme-
inhibitors and anti-bacterials have become enormous
research areas in the field of pharmaceutics and
pharmaceuticalchemistry, withoutwhichdepreciation
of human skin, body, disease, and death rate can’t
be controlled. The discovery of new and useful
drugs for a variety of physiological conditions is the
result of such type of research. The role of reactive
oxygen species (ROS) is of prime consideration in
various diseases because such species oxidize the
human cell or body. The protection from such ROS
Recently there has been an interesting in
the chemistry of quinazoline-4 (3H)-ones because
of their medicinal significance. Many of quinazoline
derivatives show antifungal, antimicrobial,
bronchodilator, antihi-staminic, anti-inflammatory1.
Some sulpha drugs of quinazolin-4-ones showed
exhibited anti-inflammatory and analgesic activities,
angiotensin receptor antagonist, antiherpes,
nantitubercular, anti- insecticidal and cardiovascular
agent2. 4-Aminoquinazolines represent as new
classes of drugs, they were found excellent inhibitor

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Al-AzAwI , Orient. J. Chem., Vol. 32(1), 585-590 (2016)
species to human body is provided by antioxidants4. Carlo Erba instrument.Nuclear magnetic resonance
Radicals have been implicated in the causation of (NMR) spectra were recorded on Bruker specrospin
several oxidative damages diseases such as liver ultra shield magnets 300 MHz instrument using
chirrhosis, atherosclerosis, cancer, diabetes, ageing. tetramethyl silane (TMS) as an internal standared
An antioxidant can be defined as any substance and DMSO-d6 as a solvent.
that when present at low concentrations compared
with those of an oxidizable substrate5 can inhibit the Synthesis of 2-methyl-4H-benzo[d][1,3]oxazin-4-
oxidation of lipids or other molecules by preventing the one (1) and 3-amino-2-methylquinazolin-4(3H)-
initiation or propagation of oxidative chain reactions one (2)
and can thus prevent or repair the damage done to
The starting materials 2-methyl-4H-benzo[d]
the body’s cells by oxygen6.Metal-based antioxidants [1,3]oxazin-4-one and 3-amino-2-methylquinazolin-
have gained attention recently for their capacity to 4(3H)-one (2) were prepared according to a literature
protect organisms and cells from damage induced by method12.
oxidative stress or scavenge free radicals7.It is worth
mentioning that the antioxidant activity depends on Synthesis of the compounds (3-6)
their reactions with free radicals. Iuga et al. studied
A mixture of 3-amino-2-methylquinazolin-
the antioxidant activity of trans-resveratrol toward 4(3H)-one (2) (0.005 mol) in ethanol (50 ml) and
hydroxyl (•OH) and hydroperoxyl (•OOH) radicals in appropriate carbonyl compounds (0.005 mol)
aqueous simulated media, using density functional with a few drops of acetic acid was reûuxed for 8
theory (DFT) and transition state theory (TST) hrs. The mixture allowed to cool and ûltered. The
methods, and they concluded that the reactivity of separated solid was washed with aqueous water
trans-resveratrol with (i) •OH radical (in water at and recrystallized from hot ethanol.
physiological pH) is mainly governed by a sequential Note: Compound (6); was synthesized in the
electron proton transfer (SE-ET) mechanism; and same method with (0.01 mol) of 3-amino-2-
with •OOH, it occurs only by phenolic hydrogen methylquinazolin-4(3H)-one (2).
abstraction8. In another study, leopoldini et al.
found that the addition of OH radical to caffeic acid 3-((4-(dimethylamino)benzylidene)amino)-2-
is slightly favored with respect to the hydrogen atom methylquinazolin-4(3H)-one (3)
transfer, while the single electron transfer is unlikely,
Yield 68%, mp 191-193 oC. FT-IR: 3047.4
since thermodynamically, it is unfavorable9.Mayer et for C-H aromatic, 1699.6 for carbonyl, 1611.3 (C=N).
al. and Oksana et al. reported that the reactivity of 1H-NMR 2.410 (s, 3H, CH3 ), 7.01-7.32 (m, 1H, Ar-H),
phenols toward free radicals, such as CH3 OO• and 8.99 (d, 1H, H-C=N).). Elemental analysis (CHN); C:
PhO, involved a PCET mechanism10,11. In this study, 70.90% (70.57 %) H: 6.03% (5.92%) and N: 18.78
we describe the synthesis of quinozoline derivatives (18.29%).
(Scheme 1) and we describe their characterization
through spectral data (FT-IR, H-NMR) and elemental 3-(4-Hydroxybenzylideneamino)-2-methyl
analysis (CHN) inadition to discuss the in vitro quinazolin-4-(3H)-one
o
antioxidant activities of the compounds (3-6).
MATERIALS AND METHODS
Chemicals
Yield 72%, mp 204-206 C. FT-IR: 3189
br for O-H aromatic, 1704.3 for carbonyl, 1609.0
(C=N). 1H-NMR 2.37 (s, 3H, CH3 ), 6.84-7.01 (m,
1H, Ar-H), 5.32 (s, 1H, OH), 9.33 (d, 1H, H-C=N).
Elemental analysis (CHN); C: 69.11% (68.81 %) H:
All chemical used as supplied and they 4.91% (4.69%) and N: 14.82 (15.05%).
were of reagent grade, supplied by Segma-Aldrige
and Merck . Melting points were determined 2-methyl-3-((2-oxoindolin-3-ylidene)amino)
on SMP40 melting point apparatus and were quinazolin-4(3H)-one (5)
uncorrected.The IR spectra of the compounds were
Yield 65%, mp 118 oC.FT-IR:3396.4 (N-H),
recorded on a shimadzu FT-IR-8300 spectrometer 3088.1 and 3074.0 for C-H aromatic, 1683.1 and
as KBr disks. Elemental micro analysis, was carried 1669.2 for carbonyls, 1620.9 (C=N). 1H-NMR 2.410
out using C.H.N elemental analyzer model 5500- (s, 3H, CH3 ), 7.01-7.32 (m, 1H, Ar-H), 8.91 (s, 1H,

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Al-AzAwI , Orient. J. Chem., Vol. 32(1), 585-590 (2016)
N
CH3
O
O
(1)
N
CH3
NH2
N
O
(2)
a
b
c
d
N
N
N
N
N
N
CH3
CH3
CH3
O
N
N
CH3
O
O
O
N
N
O
N
N
HC
HC
HN
N
OH
CH3
N
N
H3C
H3C
O
N
(3)
(4)
(5)
(6)
a= N,N-dimethyl-4-aminobenzaldehyde
b= p-hydroxybenzaldehyde
c=indoline-2,3-dione
d=terephthalaldehyde
Scheme 1: Syntheses of quinazoline derivatives (1-6)

Al-AzAwI , Orient. J. Chem., Vol. 32(1), 585-590 (2016)
588
NH). Elemental analysis (CHN); C: 67.92% (67.10
%) H: 4.20% (3.97%) and H: 18.90 (18.41%).
scavenging activity of compounds (3-6). Sodium
nitroprusside (1 ml of 10 mM) prepared in
phosphate buffer saline (pH 7.4) was mixed with 1
ml of compounds (3-6) at various concentrations
ranging from 0.2, 0.3, 0.4 and 0.5 mg/ml. The
mixture was incubated at 25 °C for 150 min. To 1
ml of the incubated solution, 1 ml of Griess’[1.0
ml sulfanilic acid reagent (0.33% prepared in 20%
glacial acetic acid at room temperature for 5 min with
1 ml of naphthylethylene diamine dihydrochloride
(0.1% w/v)] reagent was added. Ascorbic acid
was used as a reference material The mixture was
incubated at room temperature for 30 min, followed
by the measurement of absorbance at 517 nm15.
The inhibition efficiency of nitric oxide radical by
the synthesized compounds (3-6) was calculated
using the equation 2. All tests were performed in
triplicate.
3,3'-((1,4-phenylenebis (methanylylidene))
bis(azanylylidene))bis(2-methylquinazolin-4(3H)-
one) (6)
Yield 59%), mp 177-181 oC. FT-IR: 3084.1
for C-H aromatic, 1679.0 for carbonyl, 1622.5 (C=N).
1H-NMR 2.62 (s, 3H, CH3 ), 6.77-7.06 (m, 1H, Ar-H),
7.9 (dd, 1H, Ar-H). Elemental analysis (CHN); C:
70.21% (69.63 %) H: 4.83% (4.49%) and N: 19.11
(18.74%).
Antioxidant Activities
DPPH free radical scavenging assay
The free radical scavenging activity of the
synthesized compounds (3-6) was measured using
DPPH by the method of Blios (1958)13. A 0.1 mM
solution of DPPH in methanol was prepared and
1 ml of this solution was added to 3 ml of various
concentrations 0.2, 0.3, 0.4 and 0.5 mg/ml. of
sample dissolved in methanol to be tested. After
30 min, absorbance was measured at 517 nm.
Ascorbic acid was used as a reference material. All
measurements were done in triplicates and mean
values were calculated.The scavenging activity was
calculated as follows
\
Statistical Analysis
Data were calculated as means standard
errors of mean. The significance of the relationship
between the concentration and percentage inhibition
were performed with one-way analysis of variance
(ANOVA). Statistical significance was set at
p<0.05.
RESULTS AND DISCUSSION
...(1)
The basic nucleus 2-methyl-4H-benzo[d]
[1,3]oxazin-4-one and 3-amino-2-methylquinazolin-
4(3H)-one were successfully synthesized and
characterized by FT-IR, NMR and CHN techniques.
Nitric oxide radical scavenging assay
The method described by Garrat (1964)14
was adopted to determine the nitric oxide radical
Fig. 1: Effect of compound 3-6 toward DPPH

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Fig. 2: Effect of compound 3-6 toward Nitric oxide radical
Compound (2) used to synthesis of compounds 3-6, shown in Figure (1).The scavenging effect increased
which were confirmed by the absence of NH2 peak with the increasing concentrations of test compounds
in IR spectrum and the presence of CH=N peaks (1-4). From the results of DPPH, It showed that all
at 1611.3, 1609.0, 1620.9 and 1622.5 respectively. compounds are equally effective as antioxidant
NMR spectra confirm the formation of compounds compared to ascorbic acid. DPPH radicals react
3-6. The structures of the Quinazolin Derivatives with suitable reducing agents as a result of which
(1-6) are shown in Scheme 1. The synthesized the electrons become paired off forming the
compounds (1-6) are coloured powders, stable in corresponding hydrazine. The solution therefore
air, non-hygroscopic in nature and insoluble in water, loses color stoicho-metrically depending on the
but easily soluble in ethanol, acetone, DMF and number of electrons taken up. Substances capable
DMSO.
of donating electrons/hydrogen atoms are able to
convert DPPH (Purple) into their non- radical form
DPPH is relatively stable nitrogen 1, 1-diphenyl-2- picrylhydrazine (Yellow), a reaction
centered free radical that easily accepts an which can be followed spectrophotometrically.
electron or hydrogen radical to become a stable
diamagnetic molecule. It is well documented that
All the synthesized compounds (3-6)
reactive oxygen species (ROS) are involved in the were evaluated for antioxidant activity using nitric
etiopathogenesis of numerous chronic diseases oxide method. The nitric oxide assay has been
such as atherosclerosis, hypertension and coronary widely used to evaluate the free radical scavenging
heart disease16. These free radicals are produced effectiveness of various antioxidant substances.
under certain environmental conditions and during Nitric oxide generated as a result of decomposition
normal cellular functions in the body. Antioxidants of sodium nitroprusside in aq.medium, interacts with
thus play an important role to protect the human oxygen at physiological pH to produce nitrite ions,
body against damage by reactive oxygen species. which are measured by using Griess’ reagent. The
The ability of Schiff bases to scavenge free radicals scavenging ability of the synthesized compounds
is an important property17. In this study, we present (3-6) was compared with ascorbic acid as a standard.
the DPPH and Nitric oxide radical scavenging ability Compounds 5 and 6 produced better scavenging
of the synthesized Quinazolin Derivatives (1-6).The ability as shown in Figure 2. This may be due to the
antioxidant assay was carried out using different presence of resonance effect and the hetro atoms.
concentrations of the test samples, while ascorbic
acid (vitamin C) was used as standard. In the DPPH
Free radical scavenging activity, compounds (3-6)
were evaluated for their free radical scavenging
CONCLUSIONS
The synthesized title compounds 1-6, are
activity with ascorbic acid as standard compound and characterized by spectral data and evaluate for

Al-AzAwI , Orient. J. Chem., Vol. 32(1), 585-590 (2016)
590
their antioxidant activity. Among the synthesized
compounds5and6,whicharehavingresonanceeffect
and also have hetro atoms exhibiting good activity
with maximum scavenging free radical. Therefore,
the series has opened new doors for possible
modifications of the pharmacophoric replacements
of antioxidant and future exploitation.
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