Synthesis, characterization and antimicrobial activity of new 2-phenylquinoline-4(3H)-one derivatives

Article abstract of DOI:10.13005/ojc/330344

Quinazolinones is an important chemical synthesis with different physiological significance and pharmacological utility. Reaction of anthranilic acid with benzoyl chloride in pyridine yielded 2-phenyl-4H-benzo[d][1,3]oxazin-4-one, which on condensation reaction with the tryptophan in glacial acetic acid afforded 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanoic acid (2). Treatment of compound (2) with thionyl chloride produced 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanoyl chloride (3).Condensation of compound (3) with hydrazine hydrate gave 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanehydrazide (4). Condensation of compound (4) with ethyl aceto acetate in glacial acetic acid yielded 3-(3-(1H-indol-3-yl)-1-(3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)-1-oxopropan-2-yl)-2-phenylquinazolin-4(3H)-one (5). The reaction of compound (4) with carbon disulfide and sodium hydroxide yielded3-(2-(1H-indol-3-yl)-1-(5-mercapto-1,3,4-oxadiazol-2-yl) ethyl)-2-phenylquinazolin-4(3H)-one (6).Condensation of compound (6) with hydrazine hydrate afforded 2-hydrazinyl-5- (2-(1H-indol-3-yl) ethyl)-2-phenylquinazolin-4(3H)-one(7). Compound (8) 2-(3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl)propanoyl)-2,3-dihydrophthalazine-1,4-dione was synthesized by condensing compound (4) with phthalic anhydride in glacial acetic acid. When compound (4) was reacted with different aromatic aldehydes in abs. ethanol afforded different substituted (9a-d).Moreover, N-(1,5-dioxo-3-substituted-1,5-dihydrobenzo[e][1,3] oxazepin-4(3H)-yl)-3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanamide (10a,b) were prepared from the cyclic condensation of Schiff bases compounds with phthalic anhydride. The structures of newly synthesized compounds were characterized by m.p., TLC, FTIR and ¹H, ¹³C-NMR spectral analysis. The antimicrobial activity of the synthesized phenylquinazoline on two kinds of bacteria namely, staphylococcus aureous and Escherichia coli was investigated.

Full text of DOI:10.13005/ojc/330344

ISSN: 0970-020 X
CODEN: OJCHEG
2017, Vol. 33, No. (3):
Pg. 1422-1432
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Synthesis, Characterization and Antimicrobial Activity of New
2-Phenylquinoline-4(3H)-one Derivatives
ALI HAMMADI SAMIR*
Department of Chemistry, College of Education for Pure Science-Ibn Al-Haitham,
Baghdad University, Baghdad, Iraq.
*Corresponding author E-mail: dr.mohammd08@gmail.com
http://dx.doi.org/10.13005/ojc/330344
(Received: April 21, 2017; Accepted: May 29, 2017)
ABSTRACT
Quinazolinones is an important chemical synthesis with different physiological significance and
pharmacological utility.Reaction of anthranilic acid with benzoyl chloride in pyridine yielded 2-phenyl-
4H-benzo[d][1,3]oxazin-4-one, which on condensation reaction with the tryptophan in glacial acetic
acid afforded 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanoic acid (2).Treatment of
compound (2) with thionyl chloride produced 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl)
propanoyl chloride (3).Condensation of compound (3) with hydrazine hydrate gave 3-(1H-indol-3-yl)-
2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanehydrazide (4).Condensation of compound (4) with ethyl
aceto acetate in glacial acetic acid yielded 3-(3-(1H-indol-3-yl)-1-(3-methyl-5-oxo-4,5-dihydro-1H-
pyrazol-1-yl)-1-oxopropan-2-yl)-2-phenylquinazolin-4(3H)-one (5).The reaction of compound (4) with
carbon disulfide and sodium hydroxide yielded3-(2-(1H-indol-3-yl)-1-(5-mercapto-1,3,4-oxadiazol-2-
yl) ethyl)-2-phenylquinazolin-4(3H)-one (6).Condensation of compound (6) with hydrazine hydrate
afforded 2-hydrazinyl-5- (2-(1H-indol-3-yl) ethyl)-2-phenylquinazolin-4(3H)-one(7). Compound (8)
2-(3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl)propanoyl)-2,3-dihydrophthalazine-1,4-
dione was synthesized by condensing compound (4) with phthalic anhydride in glacial acetic acid.
When compound (4) was reacted with different aromatic aldehydes in abs. ethanol afforded different
substituted (9a-d).Moreover, N-(1,5-dioxo-3-substituted-1,5-dihydrobenzo[e][1,3] oxazepin-4(3H)-
yl)-3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-3(4H)-yl) propanamide (10a,b) were prepared
from the cyclic condensation of Schiff bases compounds with phthalic anhydride. The structures of
1
newly synthesized compounds were characterized by m.p., TLC, FTIR and H, 13C-NMR spectral
analysis. The antimicrobial activity of the synthesized phenylquinazoline on two kinds of bacteria
namely, staphylococcus aureous and Escherichia coli was investigated.
keywords: Phenylquinazoline, oxadiazole, triazole, pyrazole, oxazepin
INTRODUCTION
and its derivatives represent one of the most
active classes of compounds. Medically it
has been exhibited various activites as anti-
bacterial1,2,cytotoxic 3, analgesic , anti-inflammatory4,
Quinazolinone is one of the flourishing
compounds in pharmaceutical fields. Quinazolines

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SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
6,7
anticonvusant5,antitubercular
, anticancer8, and (1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-
antioxidant9 , anti-HIV10,antitumour11,and anti- 3(4H)-yl) propanoylchloride3
microbial12.Quinazolinones derivatives were exhibit
A solution of compound 2 (0.01 mol.) and
substantial in treating of leukemia than the common SOCl2(2 ml.) in (20 ml.) benzene(dry) was refluxed
drugs13.Recent studies demonstrated the significant for 4 hr. Crystals of the product were obtained by
effect of quinazolinones derivatives via breast cancer removing the excess of thionyl chloride and benzene
in vitro study14-16
.
under vacuum. yield (75%), m.p. (158-160) C 19
.
Aim of the present study is to synthesis a 3-(1H-indol-3-yl)-2-(4-oxo-2-phenylquinazolin-
new phenyl quinazoline derivatives as antibacterial 3(4H)-yl) propanehydrazide (4)
agents.
0.01 mol.of compound 3was mixed with
80% N2H4.H2O solution (0.5 ml., 5 mmol.) in dry
benzene (10 ml.). After refluxing the mixture for five
hours, the mixture was let to cool down to room
temperature before removing the excess solvent and
MATERIAL AND METHOD
Chemistry
Melting points were determined using hydrazine under reduce pressure. The precipitate
electrothermal melting point apparatus.A SHMADZU- that obtained was washed with ether, and purified
FT-IR-8400 spectrometer was used to record by recrystallized from ethanol. Yield (85%), m.p.
the Infrared spectra atyrhe miss KBr disc. All (178-180) C 19
1H,13C-NMR spectra measurement were made at
.
Al-Albayt University, Jordan and Cairo University, (3-(1H-indol-3-yl)-1-(3-methyl-5-oxo-4,5-
Egypt on a Bruker 300 MHz and Avance III HD dihydro-1H-pyrazol-1-yl)-1-oxopropan-2-yl)-
spectrometers using DMSO-d6 a solvent andTMS as phenylquinazolin-4(3H)-one 5
internal reference.The progress of the reaction was
This compound was synthesized by
monitored by TLC using aluminum silica gel plates. refluxing (0.01 mol.) of compound 4 and ethyl
Grade solvent and reagents were purchased from acetoacetate (0.01 mol.) in 20 ml. glacial acetic acid
commercial suppliers.
for 6 hrs.After then, the mixture was cooled and 25 ml
of icy distilled water was added, the reaction product
(compound 5) was filtered out and dried.Yield (80%),
2-phenyl-4H-benzo[d][1,3] oxazin-4-one 1
0.01 mol. of C7H5OCl was gradually added m.p. (221-223) C 20
to a 30 ml solution of 3.33x10-4 M of anthranilic acid
.
in pyridine with continuous stirring at about 15 Cfor 3-(2-(1H-indol-3-yl)-1-(5-mercapto-1,3,4-
30 min.The formed product was separated while the oxadiazole-2-yl)ethyl)-2- phenylquinazolin-
reaction mixture stirred for 3 hours room temperature. 4(3H)-one 6
Finally, apale-yellow solid was yielded upon the
Twenty milliliters of ethanolic solution of
addition of 15 ml. of 10% NaHCO3 was added to (0.015 mol.) NaOH was mixed with (0.01 mol.) of
the solution. The formed precipitate was filtered off compound 4 with continuous stirring for 15 min.Two
and washed with distilled water, dried and ethanol milliliters of CS2 was then added before heating the
was used for recrystallization. Yield (68%), m.p. mixture under reflux for 8 hrs. After concentrating
(118-120) C17.
the mixture, the reaction product was collected by
acidification with dilute HCl solution. The product
Synthesis of 3-(1H-indol-3-yl)-2-(4-oxo-2- was then washed with water and recrystallized from
phenylquinazolin-3(4H)-yl) propanoicacid 2
ethanol.Yield (76%), m.p. (229-231) C 21
.
(0.001mol.) of 2-phenyl-4H-benzo[d][1,3]
oxazin-4-one was mixed with tryptophan in 15 ml 2-hydrazinyl-5- (2-(1H-indol-3-yl) ethyl)-2-
of glacial acetic acid. The mixture was refluxed for phenylquinazolin-4(3H)-one 7
(3-4) hr., followed by the addition of (25 ml) of Icy
To 20 ml of the ethanolic solution of
distilled water. The product was separated off by compound 6 (0.01 mol), two milliliters of N2H4.H2O
filtration and washed with distilled water, the dried.
Recrystallization of the obtained product was carried
out from ethanol.Yield (70%), m.p. (165-167) C18.
solution were added.After 7 hrs of reflux, the reaction
mixture was left to cool down to room temperature.
The pure yellow crystals of the product were

SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
1424
obtained after removing the solvent under vacuum
and recrystallization from ethanol.Yield (80%), m.p.
2-(3-(1H-indol-3-yl)-2-(4-oxo-2-phenyl quinazolin-
3(4H)-yl) propanoyl)-2,3-dihydrophthalazine-1,4-
dione8
(154-156) C 21
.
This compound was obtained by refluxing
a solution of an equimolar mixture (0.001 mol.) of
compound 4 and phthalic anhydride in glacial acetic
Scheme 1

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SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
acid. After the addition of 20 ml. icy distilled water, to room temperature23. The molecular formulas,
the product was filtered and dried.Yield (80%), m.p. melting points, and the yields of the synthesized
(121-123) C 22
.
compounds are presented in Table (1).
General method for synthesis of Schiff bases General method for synthesis of oxazepines
9a-d compounds 10 a,b
An equimolar mixture (0.01 mol.) of
An equimolar mixture (0.01 mol.) of and
compound 4 with an appropriate aldehydein (25 ml.) compounds 9a,b and phthalic anhydride was
of absolute ethanol was refluxed in water bath for dissolved in (10 ml) of dry benzene and refluxed in a
8 hr after the addition of three drops of anhydrous water bath for 10 hr.The solution was then cooled and
CH3COOH. The formed product was collected by treated with sodium bicarbonate to formed compound
filtration and dried, after cooling the reaction mixture 10a,b.The reaction product i.e.10a,b was separated
Fig. 1:
Table 1: Physical properties for Schiffs bases and 1,3-oxazepine compounds
Comp. No.
Ar
Ar
Molecular formula
M.(c)
Yield
(%)
9a
9b
9c
9d
10a
10b
4-BrC6H4-
4,4-N,N(CH3)2C6H4-
4-ClC6H4-
C32H25N5O2Br
C34H31N6O2
C32H25N5O2Cl
198-200
C40H28N5O5Br
C42H34N6O5
240-242
220-222
217-219
78
211-213
206-208
70
75
80
C6H5-
C32H26N2O2
4-BrC6H4-
4,4-N,N(CH3)2C6H4-
60
70

SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
1426
by filtration, dried and recrystallized from ethanol24.
Table (1) shows the data for compound (10a,b).
acid. Analytical and spectral data were used to
elucidate the structure of compound 2. The FTIR
absorption spectrum of the compound displayed
bands at 1685 cm-1 for carbonyl of acid, 2500-3200
cm-1 due to OH group of acid.
Biological Activity
The antimicrobial activity of the synthesized
phenyl quinazoline on two kinds of bacteria namely,
staphylococcus aureous and Escherichia coli was
investigated. The investigation was carried out
via cup method with nutrient agar as a media for
bacterial growth using 0.1ml of DMF as a solvent
for all samples. The agar was scoop up from the
sterilized cork borer cups and transferred into a
bacterially inoculated petri dish. After then, a 0.1 ml
aliquot of the solution of the investigated compound
was introduced to each dish and the dishes were
incubated for 24 hrs at 37°C.
Compound 3 was obtained upon treatment
of compound2 with thionyl chloride in dry benzene.
The presence of acyl chloride group was confirmed
using its FTIR spectrum which display a strong
absorption band at 1762 cm-1. The reaction of acyl
chloride derivative 3 with hydrazide hydrate in
refluxing ethanol gave the corresponding hydrazide
derivative 4. The compound shows several bands
at 1660 cm-1which belong to carbonyl of amide,
and at 3307, 3215 cm-1 for NH2 group. Moreover, its
The1H-NMR spectrum, fig.(1),shows characteristics
chemical shifts, i.e.singlet signals at 5.67, 10.30, and
12.70 ppm which could be related to the protons of
NH2 group, proton of NH group and the proton of OH
group present in two tautomeric forms.
RESULTS AND DISCUSSION
Chemistry
The starting materials 2-amino-3-(1H-
indol-3-yl) propanoic acid 2, used in this work was
prepared by refluxing of tryptophan with 2-phenyl-
4H-benzo[d][1,3]oxazin-4-one (1) in glacial acetic
The triplet signal of proton for CH group
at 4.30 ppm. Also showed the multiple signal at
Fig. 2:

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SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
6.92-8.68 ppm for aromatic protons of three benzene the presence of CO amide, C=N, NH groups. The
rings. The two peaks at at 164 and 167 in the treatment of compound 4 with CS2 in presence of
13C NMR spectrum of compound 4.fig. (2),indicate NaOH yields compound 6.The appearance of two
the presence of two resonating carbonyl groups of peaks at (1616, 1600) cm-1 in the FTIR spectrum
amide, while peaks at (127.40, 128.90)ppm are due of the formed compound could be attributable to
to carbon of C=N group.
the presence of C=N of cyclic imine. Moreover, the
1H NMR spectrum of compound 6,fig. (3),exhibited
Compound 4 was treated with ethyl aceto two singlets at d 11.69 and 11.71 which are specific
acetate in boiling glacial acetic acid to give compound for NH and SH protons, a triplet signal at d 3.45 for
5. Bands at 1726, 1678 cm-1, 1637 cm-1, and 3309 proton of CH proton, a multiplet at d 7.45-8.69 related
cm-1 in the FTIR spectrum of compound 5 indicate to the aromatic-protons, a singlet at d 8.69 for NH of
Fig. 3:
Table 2:The FTIR absorption bands for Schiffs bases and 1,3-oxazepine
compounds
Comp.
No
N-H
C-H ar. C-H ali.
C=O C=O cyclic C=N
C=C
amide
amide
9a
9b
9c
9d
10a
10b
3192
3186
3227
3221
3223
3180
3053
3062
3057
3062
3050
3047
2988
2970
2960
2983
2966
2970
1649
1676
1680
1660
1656
1664
1623
1635
1604
1649
1600
1589
1591
1600
1604
1600
1693
1691

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1428
Fig. 4:
Fig. 5:

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1429
Fig. 6:
Fig. 7:

SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
1430
Fig. 8:
Fig. 9:

SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
1431
Table 3 : Antibacterial activity of some
synthezised compounds
Compound 4 condensed easily with
different aldehydes in ethanol containing piperidine
at reflux temperature affording the corresponding
Schiffs bases compounds 9a-d.The FTIR spectrum
of compounds 9a-d showed disappearance of amino
group and exhibited peak at region (1604-1649) cm-1
Zone of inhibition
Escherichia coli
(mm)
Staphylococcus
aureus
Comp.
No.
1
belonging to (C=N) group. The H NMR spectrum
5
6
7
8
9
16
25
40
14
12
15
25
28
16
14
of compound 9a,fig.(6),showed singlet signals at
d 10.57, 11.78, 11.95, and 12.13 corresponding to
CH=N, NH of tryptophan, NH and OH protons in two
tautomeric forms respectively. A multiple signals at
d 7.27-8.60 region owing to aromatic protons. The
13CNMRspectrum of compound 9a,fig. (7), (DMSO):
d 123.10-132.58(benzene rings), (127.24,128.89)
ppm due to two carbon of C=N groups. While
(164.49-164.94) ppm due to two carbonyls of amide
groups.
cyclic tryptophan. Singlet signal at d 4.38 for CH of
cyclic tryptophan.
Reaction of compound 6 with hydrazine
hydrate in refluxing ethanol gave the corresponding
compound7 The FTIR spectrum of compound 7
confirmed the presence of intense absorption bands
at 3329, 3105, 1662, and 1620 cm-1 due to amino,
carbonyl amide and imine groups respectively. The
1H NMR spectrum of compound 7, fig.(4), showed
two signals, triplet signal at d 3.44 for CH proton
and doublet signal at d 2.68 for proton of CH2
group. A singlet signal at d 10.45 for proton of NH,
a multiple signal at d 7.18-8.20 region related to
aromatic protons, a signal at d 8.40 for proton of NH
of tryptophan.
Synthesis of compounds 10 a,b was carried
out via condensation of compounds9 a,b with phthalic
anhydride in dry benzene. The purity structural
formula ofcompounds10a,b were confirmed by FTIR
1
and H, 13C NMR spectroscopic techniques. The
FTIR of compounds10a,b showed a peak at (1664-
1691) cm-1 belong to carbonyl of cyclic ester. The
carbonyl absorption band of amide was observed at
(1656-1691) cm-1. The1H-NMR spectrum of
compound 10 b, fig. (8),display two singles at d
11.83 and 12.09 for NH and OH protons in the two
tautomeric forms, singlet at d 8.61 owing to protons
of NH of tryptophan group, a multiple signal at d
(6.75-8.58) region attributed to aromatic protons.
Two signals, triplet signal at 3.32 d for CH proton
and doublet signal at 2.86 d for protons of CH2 group,
singlet signals at 3.84 d for CH of tryptophan.Singlet
signal at 8.58 d for (-CH-O-N) group. The 13C NMR
spectrum of compound 10b,fig.(9), (DMSO):d 28.23
(CH2), 123.01-132.33 (benzene rings), 164.40 (CO
amide), 195.63 (CO of cyclic ester).
Compound 8 was synthesized by the
condensation of compound 4 with phthalic anhydride
in dry benzene. The chemical structure of this
1
compound was determined by FTIR and H NMR
spectroscopic techniques. The recorded infrared
spectrumofthecompounddepictsthedisappearance
of νs and νas of NH2 group at (3317, 3165) cm-1, the
appearance of two bands (1703, 1786) cm-1 for
carbonyl group of cyclic amide, and a band rise at
(1678) cm-1 due to carbonyl of amide. On the other
hand, the proton-NMR spectrum of compound
8, fig. (5), shows many signals, a triplet at d 3.59
and a doublet at d 1.19 for CH and CH2 protons
respectively, a singlet at d 4.39 for the tryptophan
five membered ring CH, two singlets at d 11.76 and
d 12.01 for NH and OH protons in the two tautomeric
forms, a multiple at d 7.26-8.79 for the aromatic
protons, and a singlet at d 9.65 which corresponds
to the tryptophan NH group.
Biological Activity
In this study the antimicrobial activity of
the synthesized phenyl quinazoline on two kinds
of bacteria namely, staphylococcus aureous and
Escherichia coli was investigated. Table (3) shows
the antibacterial activity of some synthesized
compounds and the obtained zones. Results shows
that compound 7 exhibit highly antibacterial activity
against Escherichia coli and Staphylococcus aureus
than other compounds.

SAMIR, Orient. J. Chem., Vol. 33(3), 1422-1432 (2017)
1432
CONCLUSIONS
ACkNOwLEDGEMENTS
A series of newly phenyl quinazoline
compounds were successfully synthesized and
characterized. Some of the newly compounds were
tested for antibacterial activity which compound
7 exhibit highly antibacterial activity against
Escherichia coli and Staphylococcus aureus than
other compounds.
The author would like to thank the University
of Baghdad for supporting this study and provide the
grant for this study.We are also grateful to Dr.Zeinab
M. Al Rubaei for her contributions.
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