Novel 6,8-dibromo-4(3H)quinazolinone derivatives of anti-bacterial and anti-fungalactivities

Article abstract of DOI:10.1016/j.ejmech.2010.04.014

Starting from 4-(6,8-dibromo-2-phenyl-4-oxo-(4H)-quinazolin-3-yl)-benzoic acid ethyl ester (II) and its acid hydrazide III,a new series of Schiff bases IV and their cyclized products,thiazolidinones V,oxa-diazole VIII,pyrazoles XeXII,pyrroles XIIIeXV and other related products were synthesized. These compounds were screened for their anti-bacterial activity against Gram-positive bacteria (Staphylococcus aureus,Legionella monocytogenes and Bacillus cereus) and Gram-negative bacteria (Escherichia coli,Pseudomonas aeruginosa and Salmonella typhimurium) and anti-fungal activity (Candida albicans and Aspergillus flavus) using paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of the compounds were also determined by agar streak dilution method. Among the synthesized compounds 2-(4-(2-phenyl-6,8-dibromo-4- oxo-(4H)quinazolin-3-yl)-N-ethylamido benzoic acid hydra-zide VIIa was found to exhibits the most potent in vitro anti-microbial activity with the MICs of 1.56,3.125,1.56,25,25 and 25 mg/ml against E. coli,S. typhimurium,L. monocytogenes,S. aureus,P. aeruginosa,and B. cereus respectively. Compound 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-methyl thioamido benzoic acid hydrazide VIIc was found to exhibit the most potent in vitro anti-fungal activity with MICs 0.78 and 0.097 mg/ml against C. albicans and A. flavus.

Full text of DOI:10.1016/j.ejmech.2010.04.014

European Journal of Medicinal Chemistry 45 (2010) 3311e3319
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Novel 6,8-dibromo-4(3H)quinazolinone derivatives of anti-bacterial and
anti-fungal activities
Mosaad S. Mohamed a, Mohsen M. Kamel b, Emad M.M. Kassem b, Nageh Abotaleb a,
,
Sherein I. Abd El-moez b, Marwa F. Ahmed a
*
a Faculty of Pharmacy, Helwan University, Dokki, Cairo, Egypt
b National Research Centre, Dokki, Cairo 12, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting from 4-(6,8-dibromo-2-phenyl-4-oxo-(4H)-quinazolin-3-yl)-benzoic acid ethyl ester (II) and its
acid hydrazide III, a new series of Schiff bases IV and their cyclized products, thiazolidinones V, oxa-
diazole VIII, pyrazoles XeXII, pyrroles XIIIeXV and other related products were synthesized. These
compounds were screened for their anti-bacterial activity against Gram-positive bacteria (Staphylococcus
aureus, Legionella monocytogenes and Bacillus cereus) and Gram-negative bacteria (Escherichia coli,
Pseudomonas aeruginosa and Salmonella typhimurium) and anti-fungal activity (Candida albicans and
Aspergillus flavus) using paper disc diffusion technique. The minimum inhibitory concentrations (MICs) of
the compounds were also determined by agar streak dilution method. Among the synthesized
compounds 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-ethylamido benzoic acid hydra-
zide VIIa was found to exhibits the most potent in vitro anti-microbial activity with the MICs of 1.56,
Received 25 February 2010
Received in revised form
11 April 2010
Accepted 13 April 2010
Available online 20 April 2010
Keywords:
Ethyl-4-(6,8-dibromo-2-phenyl-4-oxo(4H)-
quinazolin-3-yl)benzoate,benzoic acid
hydrazide
3.125, 1.56, 25, 25 and 25 mg/ml against E. coli, S. typhimurium, L. monocytogenes, S. aureus, P. aeruginosa,
Schiff bases
Thiazolidinones
Mannich beses
Oxadiazole
Pyrazols
and B. cereus respectively. Compound 2-(4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-methyl
thioamido benzoic acid hydrazide VIIc was found to exhibit the most potent in vitro anti-fungal activity
with MICs 0.78 and 0.097
m
g/ml against C. albicans and A. flavus.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Pyrrole
Urea and thiourea derivatives
Anti-bacterial
Anti-fungal
1. Introduction
moieties [10,11], bridged phenyl rings [12,13], heterocyclic rings
[14] and aliphatic systems [15,16]. On the other hand, diverse
chemotherapeutic agents contain pharmacophores like Br, phenolic
OH, and Cl substitutions, are reported to possess anti-microbial
activities [17e19].
Based on these findings, and in continuation of our drug
research program concerning synthesis of new safer and more
biologically active quinazolinones [20e22], it was of interest to
synthesize a new series of 6,8-dibromo-3-substituted phenyl-
quinazoline-4(3H)-one derivatives with the hope to obtain more
active and less toxic anti-microbial agents.
The rapid rise in bacterial resistance to the traditional antibiotics
such as penicillin’s [1] and tetracycline [2] has encouraged
a continuing search for new classes of compounds with novel modes
of anti-bacterial activity. The quinazolinones have emerged as anti-
microbial agents of an immense interest because of their broad
spectrum of in-vitro activity and their in-vivo chemotherapeutic
activity [3,4]. Diverse examples of anti-microbial quinazolinones
such as (structure 1) which exerted anti-bacterial effect against
Staphylococcus aureus in a very low concentration [5], quinazolinone
derivatives(structure 2)[6]and(structure3)[7], showed potentanti-
microbial activities. Also (structure 4) exhibited high in-vivo activity,
low toxicity and good pharmacokinetic profile [8,9].
2. Chemistry
Quinazolin-4(3H)-ones with substitution at position 3, has been
reported to be associated with anti-microbial properties [10e17].
Examples of these substitutions were substituted phenyl ring
Synthesis of the desired compounds was achieved by allowing
6,8-dibromo-2-phenyl-4(H)-3,1-benzoxazin-4-one (I) [23] to
undergo fusion with ethyl-p-aminobenzoate at 140 ꢀC to give the
intermediate ethyl-4-[6,8-dibromo-2-phenyl-4-oxo(4H)quinazo-
lin-3-yl)-benzoate (II), which upon reaction with excess
* Corresponding author. Tel.: þ20 0103875225.
E-mail address: marwafarag80@yahoo.com (M.F. Ahmed).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.04.014

3312
M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
O
Reaction of III with different aromatic aldehydes, namely, benz-
aldehyde, p-anisaldehyde, p-tolualdehyde, p-chlorobenzaldehyde, 3,
4-dichlorobenzaldehyde, 2-hydroxybenzaldehyde, naphthalene-2-
carboxaldehyde and/or furfural in glacial acetic acid, afforded the
corresponding arylmethylidine-hydrazides (Schiff bases) IVaeh,
respectively (Scheme 1).
Compounds IVaeh gave correct values in elemental analyses.
The 1H NMR spectrum of compound IVb showed signal at 3.7 ppm
of methoxy group and at 12.07 ppm (s, 1H, NH, exchangeable with
D2O). 1H NMR spectrum of compound IVc showed signal at 2.5 ppm
of methyl group and at 11.2 ppm (s, 1H, NH, exchangeable with
D2O). Mass spectrum of IVf showed (m/z, R.I.): Mþ 615.97, 617.97,
619.97 (4.1%, 8.3%, 4.4%).
O
N
O
N
H
Cl
Cl
N
N
H
N
O
Cl
Cl
1
N
2
O
CH3
O
N
N
C
H
N
N
F
Br
N
N
N
Cl
Cyclocondensation of the Schiff bases IVaec and IVf with mer-
capto acetic acid in glacial acetic acid [24] afforded the corre-
sponding 4-[6,8-dibromo-2-phenyl-4-oxo(4H)quinazolin-3-yl]-N-
Br
F
(4-oxo-2-substituted
thiazolidin-3-yl)-benzamides
(Vaed),
3
4
respectively (Scheme 2). Assignments of structures (Vaed) are
based on correct elemental analyses. IR spectrum of compounds
(Vaed) assigned for three carbonyl groups (2CO, cyclic amide) and
(CONH). The 1H NMR spectrum of compound Va showed signal at
3.70 ppm of CH2, thiazolidinone ring, 5.90 ppm of CH of thiazoli-
dinone ring, and at 11.2 ppm (s, 1H, NH, exchangeable with D2O).
Compounds (Vb, c) gave correct values in 1H NMR spectra.
The quinazolinyl-thiazolidinones Vaed react with para-
formaldehyde and secondary amines namely, piperidine and/or
diethyl amine to give the corresponding Mannich bases, namely
4-[6,8-dibromo-2-phenyl-4-oxo(4H)-quinazolin-3-yl]-N-[4-oxo-
3-diethylaminomethyl/(or piperidinomethyl)-2-phenyl(and/or
2-hydroxy phenyl)-thiazolidin-3-yl] benzamides (VIaed)
(Scheme 2).
hydrazine hydrate afforded the corresponding 4-(6,8-dibromo-2-
phenyl-4-oxo-(4H)-quinazoline-3-yl)-benzoic acid hydrazide (III)
(Scheme 1).
Assignments of structures II and III are based on correct
elemental analyses. IR spectrum of compound II displayed
absorption bands at 1700,1684 cmꢁ1 for two carbonyl groups. Its 1H
NMR spectrum showed a triplet signal at 1.3 ppm and quartet signal
at 4.18 ppm which supported the presence of ethyl group. IR
spectrum of compound III displayed absorption bands at 3312,
3132 cmꢁ1 for (NH, NH2) groups. The mass spectrum of III showed
(m/z, R.I.): Mþ 512.2, 514.24, 516.2 (49%, 100%, 50%).
O
O
OC2H5
O
Br
Br
N
O
i
ii
N
II
N
Br
Br
Br
I
iii
O
O
NHNH2
O
N
O
N
NHN CHAr
Br
N
N
iv
Br
Br
III
IV a-h
Cl
e =
Cl
a , Ar =
HO
f =
OMe
CH3
b , Ar =
c , Ar =
d , Ar =
g =
h =
Cl
O
Scheme 1. Reagent and conditions: (i) ethyl-p-aminobenzoate; (ii) fusion at 140 ꢀC, sand bath for 1 h; (iii) NH2NH2$H2O in absolute ethanol, reflux, 6 h.; (iv) Ar-CHO in glacial acetic
acid, reflux 5 h.

M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
3313
O
O
Ar
NHN CHAr
i
N N
H
O
N
O
N
S
Br
Br
O
N
N
Br
Br
V a-d
IV a,b,c,f
CH3
a , Ar =
b , Ar =
c , Ar =
d , Ar =
CH3
a , Ar =
b , Ar =
c , Ar =
HO
OMe
ii
HO
f , Ar =
OMe
iii
O
Ar
N
H
N
O
N
N
S
Br
O
R
Br
VI a-d
HO
HO
N
N
R=
R=
c, Ar =
d, Ar =
R=
a , Ar =
N
N
R=
b , Ar =
Scheme 2. Reagent and conditions: (i) thioglycolic acid in glacial acetic acid, reflux, 6 h; (ii) paraformaldehyde; (iii) diethyl amine and/or piperidine in dimethylformamid, refluxed, 6 h.
IR spectrum of compounds (VIaed) assigned for three carbonyl
groups (2CO, cyclic amide) and (CONH). The 1H NMR spectrum of
compound Va showed signal at 1.2 ppm triplet for 2CH3 of diethyl, at
3.8 ppm quartet for 2CH2 of diethyl, at 2.9 ppm eCH2eN, 3.70 ppm of
CH, thiazolidinonering, 5.70 ppm ofCH of thiazolidinone ring), and at
11.3 ppm (s, 1H, NH, exchangeable with D2O). The 1H NMR spectrum
of compound Vc showed signals at 1.47 and 2.6 ppm for piperdine.
Also, condensation of the benzoic acid hydrazide III with phenyl
(or ethyl) isocyanate and/or methyl isothiocyanate in pyridine,
afforded the corresponding phenyl (or ethyl) hydrazine-carbox-
amides VIIaec respectively, (Scheme 3).
Assignments of structures VIIaec are based on correct
elemental analyses. IR spectrum of all compounds revealed the
presence of three NH groups. The 1H NMR spectrum of compound
Va showed signal at 1.1 ppm triplet for CH3 of ethyl, at 3.1 ppm
quartet for CH2 of ethyl, at 5.01, 5.02 and 10.75 ppm (s, 3H, 3NH,
exchangeable with D2O). Compounds (VIIb, c) gave correct values
in 1H NMR spectra. The mass spectrum of VIIb showed (m/z, R.I.):
Mþ 630.9, 630.9, 630.9 (4%, 8.5%, 3.9%).
bands in the NH region. On the other hand IR spectrum of
compound IX revealed the presence of three carbonyl groups 1730,
1710 and 1680 cmꢁ1, 2NH at 3285, 3280 cmꢁ1. The Mass spectra of
compounds VIII, IX are in agreement with their structures.
Further, reaction of III with dikeonic esters or B-diketones, such
as, ethylaceto-acetate, acetylacetone, and/or diethylmalonate,
afforded the corresponding pyrazolyl-carbonyl phenyl quinazoli-
nones XeXII respectively (Schemes 3 and 4).
Assignments of structures XeXII are based on correct elemental
analyses. IR spectrum of compound X revealed the presence of two
carbonyl groups at 1725 and 1680 cmꢁ1 and the absence of any
absorption bands in the NH region. IR spectrum of compound XI
showed the presence of one carbonyl group at 1680 and the
absence of any absorption bands in the NH region. Furthermore IR
spectrum of compound XII revealed the presence of NH group at
3160 cmꢁ1 and three carbonyl groups at 1720, 1715 and 1687 cmꢁ1
.
The 1H NMR spectrum of compound XII showed signal at 3.2 ppm
singlet for CH2, pyrazolone group.
Reaction of the benzoic acid hydrazide III with the cyclic
anhydrides, such as maleic anhydride, succinc anhydride and/or
phthalic anhydride, gave the corresponding pyrrol-2,5-dione, pyr-
rolidin-2,5-dione, and/or 1,3-dioxoisoindoline derivatives XIIIeXV
respectively (Scheme 4).
On the other hand, heating of the acid hydrazide III with acetic
anhydride, gave the corresponding methyl oxadiazole VIII, while its
reaction with acetic anhydride in acetic acid afforded the corre-
sponding acetyl hydrazide IX. (Scheme 3)
Compounds VIIIeIX gave correct values in elemental analyses.
IR spectrum of compound VIII revealed the presence of one
carbonyl group at 1703 cmꢁ1 and the absence of any absorption
Compounds XIIIeXV gave correct values in elemental analyses.
IR spectrum of compounds XIIIeXV revealed the presence of NH
group and four carbonyl groups. The 1H NMR spectrum of

3314
M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
X
O
O
NH
N
H
NHR
O
N
O
N
N
N
Br
Br
N
N
Br
Br
VII a-c
VIII
i
ii
a, x=o R1= - C2H5
b, x
O
=o R1= - C6H5
C, x=s R1= - CH3
NHNH2
O
Br
N
N
Br
III
iii
iv
CH3
O
O
N
N
O
N
H
N
H
O
N
Br
O
Br
N
N
N
Br
Br
IX
X
Scheme 3. Reagent and conditions: (i) iso/isothiocyanate in pyridine reflux, 5 h; (ii) acetic anhydride, reflux, 6 h; (iii) acetic anhydride in acetic acid, refluxed for 6 h; iv) ethylaceto
acetate in ethanol, reflux 5 h.
compound XIII and XIV are in agreement with their structure. The
mass spectrum of XIII showed (m/z, RI): Mþ 591.94, 593.94, 595.94
(10%, 20.3%, 9.9%). Mass spectrum of XV showed (m/z, RI): Mþ
593.95, 595.95, 597.95 (4%, 8.3%, 3.2%)
synthesized compounds were screened for their anti-bacterial
activity against S. aureus, L. monocytogenes, B. cereus, E. coli, P. aer-
uginosa and S. typhimurium and anti-fungal activity against C.
albicans and A. flavus. The minimum inhibitory concentrations
(MIC) of all compounds were also determined. The anti-bacterial
data (Table 1) revealed that all tested compounds of this investi-
gation are moderate to good activity against all the tested patho-
genic bacteria. As compared to the standard drug Ciprofloxacin
3. Biological evaluation
3.1. Materials and methods
with MICs 1.56, 0.39, 1.56, 1.56, 0.78 and 0.39
mg/ml against E. coli, S.
3.1.1. Antimicrobial activity
typhimurium, L. monocytogenes, S. aureus, P. aeruginosa, and B.
cereus respectively, 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quina-
zolin-3-yl)-N-ethylamido benzoic acid hydrazide VIIa showed very
All the synthesized compounds were screened for anti-micro-
bial activities by paper disc diffusion technique. The anti-bacterial
activity of the synthesized compounds was tested against strains
isolated from animal byproducts and were accused of being a direct
cause of food intoxication in human. The strains include three
Gram-positive bacteria (S. aureus, Legionella monocytogenes and
Bacillus cereus) and three Gram-negative bacteria (Escherichia coli,
Pseudomonas aeruginosa and Salmonella typhimurium) using Muller
Hinton agar medium (Oxoid). The anti-fungal activities of the
compounds were tested against two fungi (Candida albicans and
Aspergillus flavus) using Sabouraud dextrose agar medium (Oxoid).
The observed data on the anti-microbial activity of the synthesized
compounds and standard drugs are given in Table 1.
promising activity with MIC 1.56
monocytogenes. Compound II show significant anti-microbial
activity against S. aureus, S. typhimurium with MICs 1.56 g/ml and
3.125 g/ml respevtively. Compound VId show potent anti-micro-
bial activity against S. typhimurium with MIC 0.78 g/ml. Also
compounds VIII, IVe and VIc show potent anti-microbial activity
against B. cereus with MIC 1.56 g/ml.
mg/ml against both E. coli and L.
m
m
m
m
The screening data of anti-fungal activity of these series of
compounds shows wide range of anti-fungal activity. It is of interest
that compound 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazo-
lin-3-yl)-N-methyl thioamido benzoic acid hydrazide VIIc was
found to exhibit the most potent in vitro anti-fungal activity with
4. Results and discussion
MICs of 0.78 and 0.097
is even so much more potent than standard drug Fluconazole with
MICs of 1.56 and 0.78 g/ml against C. albicans and A. flavus.1.56.
Also compounds IVg and XIV showed pronounced anti-fungal
activity against A. flavus with MIC 0.39 g/ml.Compound VIb and
mg/ml against C. albicans and A. flavus. which
In this present work novel series of quinazolin-4(3H)-ones
compounds were synthesized. Synthetic Schemes 1e4 illustrate the
way used for the synthesis of target compounds. All the
m
m

M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
3315
CH3
N
N
O
HN
N
O
N
CH3
Br
O
N
O
Br
N
ii
i
N
Br
O
Br
XI
NHNH2
O
XII
Br
N
N
III
Br
v
iv
iii
O
O
O
O
N N
H
O
O
O
Br
O
N N
H
N
O
O
N N
Br
H
N
Br
O
N
N
O
N
Br
N
Br
Br
XIII
XV
XIV
Scheme 4. Reagent and conditions: (i) acetylacetone in ethanol, reflux 5 h; (ii) diethylmalonate in ethanol, reflux 5 h; (iii) maleic anhydride in ethanol, reflux 7 h; (iv) phthalic
anhydride in ethanol, reflux 7 h; (v) succinic anhydride in ethanol, reflux 7 h.
Vb show potent anti-fungal activity against A. flavus with MIC
1.56 g/ml.
6. Experimental
m
The most potent anti-bacterial activity exhibited by compound
VIIa might be due to the presence of N-ethylamido benzoic acid
hydrazide moiety of the 2-phenyl substituted quinazolin-4(3H)-
one.On the other hand the most potent anti-fungal activity
exhibited by compound VIIc might be due to the presence of N-
methyl thioamido benzoic acid hyrazide moiety of the 2-phenyl
substituted quinazolin-4(3H)-one. It is interesting to note that
a minor alteration in the molecular configuration of investigated
compounds may have a pronounced effect on anti-microbial
screening, e.g. compound VIIc having thioamido benzoic acid
hyrazide moiety have so much more anti-fungal activity than VIIa
and VIIb with ethylamido benzoic acid hydrazide and phenyl-
amido benzoic acid hydrazide moieties respectively. On the other
hand compounds VIIa and VIIb have more anti-bacterial activity
than VIIc.
6.1. Chemistry
All melting points are uncorrected, elemental analyses were
carried out in the micro analytical units of National Research Centre
and Cairo University, Egypt. IR spectra were recorded on FT. IR
spectrophotometer-Nexus 670-Nicolet, USA and Perkin Elmer-9712
spectrophotometer. 1H NMR spectra were determined on a Varian-
Gemmi-300 MHz and Joel-Ex270 MHz NMR spectrometer using
TMS as an internal standard. Mass spectra were recorded on Fin-
negan Mat SSQ 7000 mode EI 70 ev (Thermo Inst. Sys. Inc., USA).
Thin layer chromatography was carried out on silica gel 60 F254
(Merck) thin layer chromatography plates using a chloroform,
petroleum ether, methanol mixture (7:4:1 v/v) as the mobile phase.
6.1.1. 2-Phenyl-6,8-dibromo-(4H)-3,1-benzoxazin-4-one (I)
This compound was prepared according to a reported method
[23]. m.p. 178 ꢀC.
5. Conclusion
We have synthesized novel series of quinazolin-4(3H)-ones
compounds to evaluate them on anti-microbial screen. The anti-
microbial activity of the synthesized compounds may be due the
presence of the versatile pharmacophores and bromine which
might increase the lipophilic character of the molecule, which
facilitate the crossing through the biological membrane of the
micro-organism and thereby inhibit their growth. The data also
revealed that presence of N-methyl thioamido benzoic acid hyra-
zide moiety of the 2-phenyl substituted quinazolin-4(3H)-one
exerted more influence on the anti-fungal profile than ethylamido
benzoic acid hydrazide and phenylamido benzoic acid hydrazide
moieties which might be due to presence of sulphur atom which
has anti-fungal properties [25].
6.1.2. Ethyl 4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)
benzoate (II)
A mixture of the benzoxazine I (3.8 g, 10 mmol) and ethyl-p-
aminobenzoate (1.65 g; 10 mmol) was heated together upon fusion
at 140 ꢀC on sand bath for 1 h. After cooling, the crude mass was
crystallized from ethanol twice to give white crystals of II. M.p.
194 ꢀC, in 75% yield. Analysis for C23H16Br2N2O3, M.wt (528.2)
Calcd.: %C, 52.30; H, 3.05; N, 5.30. Found: % C, 52.50; H, 2.95; N, 5.10,
IR (KBr, cmꢁ1): 3059(CH, aromatic), and 1700, 1684 (2CO). 1H NMR
(DMSO-d6,
d
ppm): 1.3 (t, J ¼ 7.1 Hz, 3H, CH3, ethyl group), 4.18 (q,
J ¼ 7.13 Hz, 2H, CH2, ethyl group), 7.26e7.73 (m, 9H, aromatic-H), 7.8
(s, 1H, H-7, Ar-H), and 8.2 (s, 1H, H-5, Ar-H).MS (m/z, R.I.): Mþ
525.95, 527.95, 529.95 (10.1%, 20.4%, 10.4%) and at m/z 108.2 (100%).

3316
M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
Table 1
Anti-microbial activity of the synthesized compounds.
Tested chemicals
In vitro activity-zone of inhibition in mm (MIC in mg/ml)
Tested strains
E. coli O157 (F)
S. typhimurium (3)
L. monocytogenes (A)
S. aureus
P. aeruginosa (C)
B. cereus (E)
C. albicans
A. flavus
II
III
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
Va
Vb
Vc
Vd
VIa
VIb
VIc
VId
VIIa
VIIb
VIIc
VIII
IX
X
XI
XII
XIII
XIV
11 (50)
10 (>50)
11(45)
8 (>50)
11(40)
16 (3.125)
11(50)
10 (>50)
10 (>50)
15 (5)
10 (>50)
11(50)
13 (30)
12 (50)
16 (5)
16 (4.1)
12 (40)
15 (7)
12 (50)
11(50)
10 (>50)
15 (12.5)
18 (0.78)
16 (3.125)
16 (3.2)
12 (50)
12 (50)
14 (30)
14 (30)
14 (20)
12 (50)
17 (2.9)
11(>50)
18 (1.7)
20 (0.39)
e
14 (25)
11 (50)
13 (35)
12 (50)
13 (30)
14 (30)
13 (25)
11 (50)
16 (3.125)
11 (>50)
13 (32)
11 (>50)
10 (50)
15 (15)
15 (13)
13 (25)
12 (50)
14 (12.5)
16 (1.56)
13 (30)
11(>50)
15(12.5)
14 (35)
16 (6)
17 (1.56)
10 (>50)
12 (25)
11 (50)
12 (25)
12 (25)
14 (25)
15 (12.5)
14 (25)
13 (20)
12 (25)
10 (45)
10 (>50)
11 (45)
12 (30)
12 (25)
12 (50)
12 (25)
11(25)
10 (50)
10 (>50)
15 (12.5)
11 (40)
11 (40)
10 (50)
9 (>50)
9 (>50)
10 (>50)
9(>50)
18 (1.56)
e
12 (50)
13 (25)
12 (50)
11(>50)
15 (2.5)
12 (20)
14 (25)
11(>50)
13 (25)
8 (>50)
12 (35)
11(50)
16 (10.1)
12 (35)
14 (10)
13 (25)
11(25)
12 (50)
12 (25)
12 (50)
14 (25)
12 (50)
13 (25)
12 (50)
12 (30)
11(>50)
11(>50)
11(>50)
11(>50)
19 (0.78)
e
9 (50)
12 (25)
12 (30)
13 (35.5)
11 (35)
16 (5.5)
17 (1.56)
13 (25.5)
12 50)
12 (50)
9 (50)
18 (1.9)
9 (50)
9 (>50)
12 (25)
12 (30)
16 (1.56)
13 (25)
13 (25)
14 (12.5)
9 (>50)
17 (1.56)
9 (>50)
11 (>50)
13 (25)
10 (>50)
9 (50)
ꢁve
10 (25)
15 (18.5)
10 (25)
11 (25)
12 (20)
16 (12.5)
12 (19)
15 (10.5)
26 (0.39)
ꢁve
ꢁve
ꢁve
ꢁve
ꢁve
12 (20)
14 (25)
10 (50)
13 (25)
9 (>50)
10 (>50)
11 (45)
9 (>50)
13 (30)
11 (45)
10 (>50)
12 (35)
10 (50)
18 (1.56)
10 (50)
11 (50)
14 (25)
9 (>50)
8 (>50)
10 (50)
9 (>50)
9 (>50)
11(50)
ꢁve
11(25)
ꢁve
13 (25)
12 (25)
ꢁve
ꢁve
10 (25)
10 (30)
ꢁve
20 (1.56)
16 (12.5)
ꢁve
12 (35)
14 (12.5)
15 (12.5)
12(25)
ꢁve
14 (20)
18 (1.56)
16 (12.5)
14 (18)
16 (12.5)
ꢁve
9 (50)
22 (0.78)
11 (25)
ꢁve
38 (0.097)
18 (9.5)
22 (1.2)
20 (2.5)
ꢁve
9 (50)
9 (50)
ꢁve
15 (12.5)
10 (>50)
11 (>50)
10 (>50)
12 (50)
17 (1.56)
e
18 (1.9)
17 (4.5)
25 (0.39)
17 (3.5)
e
10 (25)
9 (50)
ꢁve
16 (5.5)
9 (>50)
20 (0.39)
e
XV
9 (>50)
18 (1.56)
e
Ciprofloxacin (100
Fluconazole (100
DMSO
m
g/ml)
e
m
g/ml)
18 (1.56)
ꢁve
22 (0.78)
ꢁve
ꢁve
ꢁve
ꢁve
ꢁve
ꢁve
ꢁve
6.1.3. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-
benzoic acid hydrazide(III)
6.1.5. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (phenyl meth(E)ylidene) hydrazide (IVa)
A solution of the ester derivative II (5.28 g; 10 mmol) and
hydrazine hydrate 98% (1.6 g; 50 mmol) in absolute ethanol (20 mL)
was refluxed for 6 h. Upon cooling, the formed precipitate was
filtered off and recrystalized from ethanol to give the hydrazide
derivative III. m.p. 240 ꢀC, in 85% yield. Analysis for C21H14Br2N4O2,
M.wt. (514.17). Calcd.: %C, 49.05; H, 2.74; N,10.90. Found: %C, 49.00;
H, 2.69; N, 10.80. IR (KBr, cmꢁ1): 3312, 3132 (NH, NH2), 3056 (CH,
aromatic), 1712 (CO, quinazoline ring) and 1640 (CO, amide). 1H
Crystallized from ethanol to give white crystals, m.p. 220 ꢀC, in
70% yield. Analysis for C28H18Br2N4O2, M.wt. (602.28). Calcd.: %C,
55.84; H, 3.01; N, 9.30. Found: 55.75; H, 2.98; N, 9.1. IR (KBr, cmꢁ1):
3360 (NH), 1710, 1683 (2CO) and 1594 (C]N). 1H NMR (DMSO-d6,
d
ppm): 7.2e7.74(m, 14H, aromatic-H), 7.8 (s, 1H, H-7, Ar-H), 8.2 (s,
1H, H-5, Ar-H), 8.66(s, 1H, CH]N) and 12.00 (s, 1H, NH,
exchangeable with D2O). MS (m/z, R.I.): Mþ 599.95, 601.95, 603.95
(3.1%, 6.4%, 3.4%) and at m/z 323.4 (100%).
NMR (DMSO-d6,
d ppm): 4.9 (s, 2H, NH2, exchangeable with D2O),
7.40e7.8 (m, 9H, aromatic-H), 7.9 (s, 1H, H-7, Ar-H), 8.2 (s, 1H, H-5,
6.1.6. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (4-methoxy phenyl meth(E)ylidene) hydrazide (IVb)
Crystallized from ethanol to give yellowish white crystals, m.p.
160 ꢀC, in 79% yield. Analysis for C29H20Br2N4O3, M.wt. (632.30).
Calcd.: %C, 55.09; H, 3.19; N, 8.86. Found, %C, 54.97; H, 3.00; N, 8.56.
IR (KBr, cmꢁ1): 3350 (NH), 1714, 1683 (2CO) and 1594 (C]N). 1H
Ar-H) and 10.00 (s, 1H, NH, exchangeable with D2O). 13C NMR
(DMSO-d6,
d
ppm): 113.5 (C-5), 122.4 (C-7), 124.1 (C-2\\,6\\), 125.3
(C-3), 127.8 (C-4\\) 128.2 (C-2\and C-6\), 129.3 (C-3\\ andC-5\\), 129.7
(C-1\,3\, 5\),), 131.3 (C-8), 132.9 (C-6\)137.6 (C-1\\), 139 (C-6), 154 (C-
4), 156 (C-1), 160 (C-2), and 167.8 (C]O). MS (m/z, R.I.): Mþ 512.2,
514.24, 516.2 (49%, 100%, 50%).
NMR (DMSO-d6,
d ppm): 3.7(3H, s, OCH3), 7.2e7.6 (m, 13H,
aromatic-H), 7.8 (s, 1H, H-7, Ar-H), 8.2 (s, 1H, H-5, Ar-H), 8.66(s, 1H,
6.1.4. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (1-substituted meth(E)ylidene) hydrazides (IVaeh)
CH]N), and 12.07 (s, 1H, NH, exchangeable with D2O).
General method: A mixture of compound III (5.14 g; 10 mmol) and
the appropriate aldehyde, namely: benzaldehyde, p-anisaldehyde,
p-tolualdehyde, p-chlorobenzaldehyde, 3,4-dichlorobenzaldehde,
2-hydroxybenzaldehyde, naphthalene-2-carboxaldehyde and/or
furan-2-carboxaldehyde (20 mmol) in glacial acetic acid (30 mL),
was refluxed for 5 h. The reaction mixture was cooled and adding ice
water the formed precipitatewas filtered off, washed with waterand
crystallized from the proper solvent to obtain the desired Schiff
bases (IVaeh) respectively.
6.1.7. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (4-methyl phenyl meth(E)ylidene) hydrazide (IVc)
Crystallized from ethanol to give white crystals, m.p. 200 ꢀC, in
80% yield (Analysis for C29H20Br2N4O2, M.wt. (616.30). Calcd.: %C,
56.52; H, 3.27; N, 9.09. Found, %C, 56.49; H, 3.30; N, 8.97. IR (KBr,
cmꢁ1): 3313 (NH), 1715, 1679 (2CO) and 1595 (C]N). 1H NMR
(DMSO-d6, d ppm): 2.5(3H, s, CH3), 7.03e7.75 (m, 13H, aromatic-H),
7.8 (s, 1H, H-7, Ar-H), 8.2 (s, 1H, H-5, Ar-H), 8.8(s, 1H, CH]N), and
11.2 (s, 1H, NH, exchangeable with D2O). 13C NMR (DMSO-d6,

M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
3317
d
ppm): 20.5 (CH3), 113.5 (C-5), 124.2 (C-7), 125.3 (C-2\\,6\\), 126.4
cmꢁ1): 3260 (NH), 3066(CH, aromatic), 2924 (CH-thiazolidinone),
(C-2\\\ and C-6\\\), 127.3 (C-3), 127.9 (C-4\\) 128.2 (C-2\and C-6\),
129.5 (C-3\\ andC-5\\), 129.7(C-1\,3\, 5\),), 130.1 (C-3\\\ and C-5\\\),
130.4 (C-1\\\) 131.3 (C-8), 132.8 (C-6\)137.6 (C-1\\), 139 (C-6), 144.2
(C-4\\\). 147.8 (-N¼CH)., 154 (C-4), 156 (C-1), 160 (C-2), 162.8 (C]O),
MS (m/z, R.I.): Mþ 613.99, 615.99, 617.99 (5.1%,10.3%, 5.4%) and at m/
z 498.7 (100%).
1717, 1685 (2CO, cyclic amide), 1655 (CONH) and 1590 (C]N). 1H
NMR (DMSO-d6, d ppm): 3.70 (s, 2H, CH2, thiazolidinone ring), 5.90
(s, 1H, CH of thiazolidinone ring), 7.5e7.9 (m, 14H, aromatic-H) 8.01
(s, 1H, H-7, Ar-H), 8.3 (s, 1H, H-5, Ar-H) and 11.2 (s, 1H, NH,
exchangeable with D2O).
6.1.15. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(4-methoxy phenyl) thiazolidin-3-yl]-benzamide (Vb)
6.1.8. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (4-chloro phenyl meth(E)ylidene) hydrazide (IVd)
Crystallized from ethanol to give white crystals, m.p. 116 ꢀC, in
75% yield. Analysis for C31H22Br2N4O4S, M.wt. (706.40). Calcd.: %C,
C, 52.71; H, 3.14; N, 7.93. Found, %C, 52.60; H, 3.00; N, 7.89. IR
(KBr, cmꢁ1): 3363 (NH), 3066 (CH, aromatic), 2925 (CH-thiazoli-
dinone), 1712, 1687 (2CO, cyclic amide), 1660 (CONH) and 1600
Crystallized from ethanol to give white crystals, m.p. 180 ꢀC, in
82% yield. Analysis for C28H17Br2ClN4O2, M.wt. (636.72). Calcd.: %C,
52.82; H, 2.69; N, 8.80. Found, %C, 52.79; H, 2.60; N, 8.60. IR (KBr,
cmꢁ1): 3415 (NH), 1710, 1680 (2CO) and 1600 (C]N). 1H NMR
(DMSO-d6,
d
ppm): 7.3e7.76 (m, 13H, aromatic-H), 7.8 (s, 1H, H-7,
(C]N). 1H NMR (DMSO-d6,
d ppm): 3.34 (s, 2H, CH2, thiazolidi-
Ar-H), 8.2 (s, 1H, H-5, Ar-H), 8.8(s, 1H, CH]N), and 11.7 (s, 1H, NH,
exchangeable with D2O).
none ring), 3.6 (s, 3H, OCH3), 5.90 (s, 1H, CH of thiazolidinone
ring),, 7.5e8.0 (m, 13H, aromatic-H) 8.1 (s, 1H, H-7, Ar-H), 8.4 (s,
1H, H-5, Ar-H) and 11.27 (s, 1H, NH, exchangeable with D2O). MS
(m/z, R.I.): Mþ 703.97, 706.97, 709.97 (10.2%, 20.3%, 10.3%) and at
m/z 438.1 (100%).
6.1.9. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)benzoic
acid (3,4-dichloro phenyl meth(E)ylidene) hydrazide (IVe)
Crystallized from ethanol to give white crystals, m.p. 140 ꢀC, in
82% yield. Analysis for C28H16Br2Cl2N4O2, M.wt. (671.17). Calcd.: %C,
52.82; H, 2.69; N, 8.80. Found, %C, 52.79; H, 2.60; N, 8.60. IR (KBr,
cmꢁ1): 3320 (2NH), 1712, 1685 (2CO) and 1605 (C]N).
6.1.16. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(4-methyl phenyl) thiazolidin-3-yl]benzamide (Vc)
Crystallized from ethanol to give white crystals, m.p. 120 ꢀC, in
70% yield. Analysis for C31H22Br2N4O3S, M.wt. (690.40). Calcd.: %C,
C, 53.93; H, 3.21; N, 8.12. Found, %C, 53.88; H, 3.10; N, 8.07. IR (KBr,
cmꢁ1): 3364(NH), 3067(CH, aromatic), 2924 (CH-thiazolidinone),
1698, 1685 (2CO, cyclic amide), 1662 (CONH) and 1600 (C]N). 1H
6.1.10. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)
benzoic acid (2-hydroxy phenyl meth(E)ylidene) hydrazide (IVf)
Crystallized from ethanol to give yellowish white crystals, m.p.
154 ꢀC, in 80% yield. Analysis for C28H18Br2N4O3, M.wt. (618.28).
Calcd.: %C, 54.39; H, 2.93; N, 9.06. Found, %C, 54.30; H, 2.70; N, 8.96.
IR (KBr, cmꢁ1): 3310 (NH), 1710, 1680 (2CO) and 1600 (C]N). MS
(m/z, R.I.): Mþ 615.97, 617.97, 619.97 (4.1%, 8.3%, 4.4%) and at m/z
500.3 (100%).
NMR (DMSO-d6,
d ppm): 2.5 (s, 3H, CH3), 3.7 (s, 2H, CH2, thiazoli-
dinone ring), 5.90 (s, 1H, CH of thiazolidinone ring), 7.5e8.1 (m,
13H, aromatic-H) 8.2 (s, 1H, H-7, Ar-H), 8.45 (s, 1H, H-5, Ar-H), and
11.25 (s, 1H, NH, exchangeable with D2O). MS (m/z, R.I.): Mþ 687.98,
689.98, 691.98 (1.3%, 2.8%, 1.3%) and at m/z 438.3 (100%).
6.1.11. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-
benzoic acid (naphthalene-2-yl meth(E)ylidene) hydrazide (IVg)
Crystallized from ethanol to give white crystals, m.p. 145 ꢀC, in
80% yield. Analysis for C32H20Br2N4O2, M.wt. (652.33). Calcd.: %C,
58.92; H, 3.09; N, 8.59. Found, %C, 58.81; H, 3.00; N, 8.50. IR (KBr,
cmꢁ1): 3400 (NH), 1712, 1681 (2CO) and 1595 (C]N). 1H NMR
6.1.17. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(2-hydroxy phenyl) thiazolidin-3-yl]benzamide (Vd)
Crystallized from ethanol to give white crystals, m.p. 250 ꢀC, in
65% yield. Analysis for C30H20Br2N4O4S, M.wt. (692.38). Calcd.: %C,
C, 52.04; H, 2.91; N, 8.09. Found, %C, 51.99; H, 2.80; N, 8.00. IR (KBr,
cmꢁ1): 3360(NH), 3060(CH, aromatic), 2920 (CH, thiazolidinone),
1710, 1683 (2CO, cyclic amide), 1660 (CONH) and 1600 (C]N)
(DMSO-d6,
d ppm): 7.3e7.72 (m, 16H, aromatic-H), 7.8 (s, 1H, H-7,
Ar-H), 8.2 (s, 1H, H-5, Ar-H), 8.7(s, 1H, CH]N), and 11.8 (s, 1H, NH,
exchangeable with D2O).
4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[5-
diethylamino and/or piperidinomethyl)-4-oxo-2-arylthiazolidin-3-
yl]benzamides (VIaed): Mannich bases
6.1.12. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-
benzoic acid (furan-2-yl meth(E)ylidene) hydrazide (IVh)
Crystallized from ethanol to give white crystals, m.p. 160 ꢀC, in
75% yield. Analysis for C26H16Br2N4O3, M.wt. (592.24). Calcd.: %C,
56.52; H, 3.27; N, 9.09. Found, %C, 56.49; H, 3.30; N, 8.97. IR (KBr,
cmꢁ1): 3410 (NH), 1715, 1681 (2CO) and 1605 (C]N).
General method:
A mixture of compounds (Va,d), para-
formaldehyde (0.045 g; 5 mmol) and the appropriate secondary
amine (5 mmol) namely, diethyl amine and/or piperidine in DMF
(20 mL) was refluxed for 6 h. The excess solvent was evaporated
under vacuum and the obtained residue was poured on crushed ice.
The solid product was filtered off and washed with water to obtain
the desired products VIaed respectively.
6.1.13. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(aryl) thiazolidin-3-yl]-benzamides (Vaed)
General method: A mixture of compounds (IVaec,f) (10 mmol)
and thioglycolic acid (0.35 ml; 10 mmol) in glacial acetic acid
(20 mL) was refluxed for 6 h. The excess solvent was evaporated
under reduced pressure and the obtained residue was poured on
crushed ice. The solid product was filtered off and washed with
water to obtain the desired products Vaed respectively.
6.1.19. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-phenyl-5-diethylaminomethyl thiazolidin-3-yl]benzamide
(VIa)
Crystallized from ethanol to give yellow crystals, m.p. 210 ꢀC, in
60% yield. Analysis for C35H31Br2N5O3S, M.wt. (690.40). Calcd.: %C, C,
55.20;H, 4.10N, 9.20. Found, %C, 55.00;H, 4.00;N,9.13.IR(KBr, cmꢁ1):
3363(NH), 3089(CH, aromatic), 1707, 1685 (2CO, cyclic amide), 1662
6.1.14. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-phenyl thiazolidin-3-yl]benzamide (Va)
(CONH) and 1600 (C]N).1H NMR (DMSO-d6,
d
ppm): 1.2 (t, J ¼ 7.3 Hz,
6H, 2CH3 of diethyl), 3.8 (q, J ¼ 7.2 Hz, 4H, 2CH2 of diethyl), 2.9 (s, 2H,
eCH2eN), 3.7 (s, 1H, CH, thiazolidinone ring), 5.70 (s, 1H, CH of thia-
zolidinone ring), 7.5e8.1 (m, 14H, aromatic-H) 8.2 (s, 1H, H-7, Ar-H),
8.48 (s, 1H, H-5, Ar-H) and 11.3 (s, 1H, NH, exchangeable with D2O).
Crystallized from ethanol to give white crystals, m.p. 188 ꢀC, in
70% yield. Analysis for C30H20Br2N4O3S, M.wt. (676.38). Calcd.: %C,
53.27; H, 2.98; N, 8.28. Found, %C, 53.20; H, 2.92; N, 8.22. IR (KBr,

3318
M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
6.1.20. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(2-hydroxyphenyl)-5-diethylaminomethylthiazolidin-3-yl]
benzamide (VIb)
aromatic-H), 7.7 (s, 1H, H-7, Ar-H), 8.5 (s, 1H, H-5, Ar-H), 5.01, 9.02
and 9.2 (s, 3H, 3NH, exchangeable with D2O). MS (m/z, R.I.): Mþ
630.9, 630.9, 630.9 (4%, 8.5%, 3.9%) and at m/z 515.2 (100%).
Crystallized from ethanol to give brown crystals, m.p. 176 ꢀC, in
60% yield. Analysis for C35H31Br2N5O4S, M.wt. (690.40). Calcd.: %C,
C, 54.07; H, 4.02; N, 9.01. Found, %C, 54.00; H, 3.90; N, 8.97. IR (KBr,
cmꢁ1): 3360(NH), 3080(CH, aromatic), 1690, 1683 (2CO, cyclic
amide), 1660 (CONH) and 1601 (C]N). MS (m/z, R.I.): Mþ 775, 577,
579 (2.3%, 4.8%, 2.3%) and at m/z 438.3 (100%).
6.1.26. 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
methyl thioamido benzoic acid hydrazide (VIIc)
Crystallized from ethanol to give white crystals, m.p. 270 ꢀC, in
70% yield. Analysis for C23H17Br2N5O2S, M.wt. (587.29). Calcd.: %C,
C, 47.04; H, 2.92; N,11.92. Found, %C, 46.99; H, 2.90; N,11.90. IR (KBr,
cmꢁ1): 3282, 3263, 3200 (3NH), 3059 (CH-aromatic), 1682, 1660
6.1.21. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-phenyl-5-piperdin-1-ylmethylthiazolidin-3-yl]benzamide
(VIc)
(3CO), 1188 (C]S). 1H NMR (DMSO-d6,
d ppm): 2.5 (3, 3H, CH3),
7.5e8.2 (m, 9H, aromatic-H), 8.4 (s, 1H, H-7, Ar-H), 8.9 (s, 1H, H-5,
Ar-H), 4, 4.04 and 12.3 (s, 3H, 3NH, exchangeable with D2O). MS (m/
z, R.I.): Mþ 584.95, 586.95, 588.95 (5%, 10.5%, 5.4%) and at m/z 435.2
(100%).
Crystallized from ethanol to give white crystals, m.p. 155 ꢀC, in
64% yield. Analysis for C36H31Br2N5O3S, M.wt. (773.54). Calcd.: %C,
C, 55.90; H, 4.04; N, 9.05. Found, %C, 55.80; H, 4.00; N, 8.93. IR (KBr,
cmꢁ1): 3356(NH), 3066(CH, aromatic), 1695, 1682 (2CO, cyclic
6.1.27. 2-Phenyl-6,8-dibromo-3-[4-(5-methyl-1,3,4-oxadiazol-2-yl)
phenyl]-2-phenylquinazolin-4(3H)-one (VIII)
amide), 1660 (CONH) and 1601 (C]N). 1H NMR (DMSO-d6,
d ppm):
1.47 (m, 6H, 3CH2 of piperdine), 2.6 (m, 4H, CH2NCH2 of piperdine),
2.8 (s, 2H, eCH2eN), 3.73 (s, 1H, CH, thiazolidinone ring), 5.70 (s,
1H, CH of thiazolidinone ring), 7.5e8.0 (m, 14H, aromatic-H) 8.2 (s,
1H, H-7, Ar-H), 8.43 (s, 1H, H-5, Ar-H), and 11.3 (s, 1H, NH,
exchangeable with D2O).
A mixture of the hydrazide III (5.14 g; 10 mmol) and acetic
anhydride (20 mL) was refluxed for 6 h. The precipitated solid
formed upon cooling, was filtered and recrystalized from ethanol to
give white crystals of VIII. M.p. 180 ꢀC, in 75% yield. Analysis for
C23H14Br2N4O2, M.wt. (538.19). Calcd.: %C, C, 51.33; H, 2.62; N, 10.41
Found: %C, 51.24; H, 2.53; N, 10.38. IR (KBr, cmꢁ1): 3075 (CH-
6.1.22. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-[4-
oxo-2-(2-hydroxyphenyl)-5-piperdin-1-ylmethylthiazolidin-3-yl]
benzamide (VId)
aromatic), 1703, (CO). 1H NMR (DMSO-d6,
d ppm): 2.7 (s, 3H,
methyl), 7.9e8.2 (m, 9H, aromatic-H). 8.1 (s, 1H, H-7, Ar-H) and 8.6
(s, 1H, H-5, Ar-H), MS (m/z, RI): Mþ 535.95, 537.95, 539.95 (7%,
14.3%, 6.9%) and at m/z 23.01 (100%).
Crystallized from ethanol to give white crystals, m.p. 230 ꢀC, in
65% yield. Analysis for C36H31Br2N5O4S, M.wt. (789.54). Calcd.: %C,
C, 54.76; H, 3.96; N, 8.87. Found, %C, 54.60; H, 3.90; N, 8.80. IR (KBr,
cmꢁ1): 3350(NH), 3062(CH, aromatic), 1693, 1680 (2CO, cyclic
amide), 1660 (CONH) and 1601 (C]N).
6.1.28. N0-Acetyl-4-(2-phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-
3-yl)benzohydrazide (IX)
A mixture of hydrazide III (5.14 g; 10 mmol), and a mixture of
acetic anhydride (10 mL) and acetic acid (10 mL) was refluxed for
6 h. The precipitated solid formed upon cooling, was filtered and
recrystalized from ethanol to give white crystals of IX. M.p. 170 ꢀC,
in 70% yield. Analysis for C23H16Br2N4O3, M.wt. (556.21). Calcd.: %C,
C, 49.67; H, 2.90; N, 10.07 Found: %C, 49.60; H, 2.83; N, 9.88. IR (KBr,
cmꢁ1): 3285, 3280 (2NH), 3061 (CH-aromatic), 1730, 1710 and 1680
6.1.23. 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
substituted amido/(thioamido) benzoic acid hydrazides (VIIaec)
General method: a mixture of compound III (5.14 g; 10 mmol),
the appropriate iso/isothiocyanate, namely: ethyl isocyanate,
phenyl isocyanate and/or methyl isothiocyanate (10 mmol) in
pyridine (20 ml) was refluxed for 5 h. The solvent was poured on
crushed ice containing few drops HCl. The solid product was
filtered off and washed with water to obtain the desired products
Vaec respectively.
(3CO). 1H NMR (DMSO-d6,
d ppm): 2.3 (s, 3H, methyl), 7.5e7.9
(m, 9H, aromatic-H) 8.1 (s, 1H, H-7, Ar-H), 8.5 (s, 1H, H-5, Ar-H), 11,
and 11.1 (s, 2H, 2NH, exchangeable with D2O). MS (m/z, RI): Mþ
553.96, 555.96, 557.96 (10%, 20.3%, 9.9%) and at m/z 506.2 (100%).
6.1.24. 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
ethylamido benzoic acid hydrazide (VIIa)
6.1.29. 2-Phenyl-6,8-dibromo-3-]4-(3-methyl-4,5-dihydro-5-
oxopyrazolin-1-yl)carbonyl]phenyl quinazolin-4(3H)-one (X)
A mixture of the hydrazide III (5.14 g; 10 mmol), and ethylaceto
acetate (1.3 g; 10 mmol) in absolute ethanol (20 mL) was refluxed
for 5 h. The precipitated solid formed upon cooling, was filtered and
recrystalized from ethanol to give white crystals of X. M.p. 290 ꢀC,
in 70% yield. Analysis for C24H16Br2N4O2, M.wt. (552.22). Calcd.: %C,
C, 52.20; H, 2.92; N, 10.15. Found: %C, 52.07; H, 2.80; N, 10.09. IR
(KBr, cmꢁ1): 3062 (CH-aromatic), 1725, 1680 (2CO). MS (m/z, RI):
Crystallized from ethanol to give white crystals, m.p. 120 ꢀC, in
70% yield. Analysis for C24H19Br2N5O3, M.wt. (585.25). Calcd.: %C, C,
49.25; H, 3.27; N, 11.97. Found, %C, 49.20; H, 3.19; N, 11.91. IR (KBr,
cmꢁ1): 3313, 3270, 3200 (3NH), 3064 (CH-aromatic), 1709, 1669,
1659 (3CO). 1H NMR (DMSO-d6,
d
ppm): 1.1 (t, J ¼ 7.2 Hz, 3H, ethyl),
3.1 (q, J ¼ 7.4 Hz, 2H, ethyl), 7.5e8.2 (m, 9H, aromatic-H), 8.4 (s, 1H,
H-7, Ar-H), 8.9 (s, 1H, H-5, Ar-H), 5.01, 5.02 and 10.75 (s, 3H, 3NH,
exchangeable with D2O). 13C NMR (DMSO-d6,
d
ppm): 15.5 (CH3),
M
þ 549.96, 551.96, 553.96 (5%, 10.3%, 4.9%) and at m/z 105.2 (100%).
34.5 (CH2) 113.7 (C-5), 123.9 (C-7), 125.1 (C-2\\,6\\),126.2 (C-3), 127.8
(C-4\\) 128.2 (C-2\and C-6\), 129.3 (C-3\\ andC-5\\),129.7(C-1\,3\,5\),),
131.8 (C-8), 132.9 (C-6\)137.6 (C-1\\), 139 (C-6), 154 (C-4), 156.3 (C-
1), 160 (C-2), 162.8 (NHC ¼ O), 167.8 (C]O).
6.1.30. 2-Phenyl-6,8-dibromo-3-]4-(3,5-dimethyl pyrazol-1-yl)
carbonyl] phenylquinazolin-4(3H)-one (XI)
A mixture of the hydrazide III (5.14 g; 10 mmol) and acetyla-
cetone (1.04 g; 10 mmol) in absolute ethanol (20 mL) was
refluxed for 5 h. The precipitated solid formed upon cooling, was
filtered and recrystalized from ethanol to give white crystals of
XI. M.p. 140 ꢀC, in 70% yield. Analysis for C25H18Br2N4O, M.wt.
(550.24). Calcd.: %C, C, 54.57; H, 3.30; N, 10.18. Found: %C, 54.43;
H, 3.20; N, 10.03. IR (KBr, cmꢁ1): 3075 (CH-aromatic), 1680 (CO).
MS (m/z, RI): Mþ 547.98, 549.98, 551.98 (8%, 17.1%, 8.3%) and at m/
z 323.2 (100%).
6.1.25. 2-(4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
phenylamido benzoic acid hydrazide (VIIb)
Crystallized from ethanol to give yellowish white crystals, m.p.
230 ꢀC, yield (72%). Analysis for C28H19Br2N5O3, M.wt. (633.29).
Calcd.: %C, C, 53.10; H, 3.02; N, 11.06 Found, %C, 52.97; H, 2.96; N,
10.95. IR (KBr, cmꢁ1): 3282, 3275, 3200 (3NH), 3059 (CH-aromatic),
1710,1662,1660 (3CO). 1H NMR (DMSO-d6,
d ppm): 6.9e7.5 (m,14H,

M.S. Mohamed et al. / European Journal of Medicinal Chemistry 45 (2010) 3311e3319
3319
6.1.31. 2-Phenyl-6,8-dibromo-3-]4-(3,5-dioxopyrazol-(1H)-2-yl)
carbonyl]phenyl quinazolin-4(3H)-one (XII)
6.2.1. Paper disc diffusion technique
The sterilized medium [26] (autoclaved at 120 ꢀC for 30 min)
(40e50 ꢀC) was inoculated (1 ml/100 ml of medium) with the
suspension (105 cfu/ml) of the micro-organism (matched to 0.9
McFarland barium sulphate standard) and poured into a Petri dish
to give a depth of 3e4 mm. The paper impregnated with the test
A mixture of hydrazide III (5.14 g; 10 mmol) and dieth-
ylmalonate (1.6 g; 10 mmol) in absolute ethanol (20 mL) was
refluxed for 5 h. The precipitated solid formed upon cooling, was
filtered and recrystalized from ethanol to give white crystals of XII.
M.p. 210 ꢀC, in 70% yield. Analysis for C23H14Br2N4O3, M.wt.
(554.19). Calcd.: %C, C, 49.85; H, 2.55; N, 10.11. Found: %C, 49.76; H,
2.42; N, 10.07. IR (KBr, cmꢁ1): 3160 (NH), 3073 (CH-aromatic), 1720,
chemicals (29 compounds) each dissolved in conc. (100 mg/ml in
DMSO) was placed on the solidified medium. The plates were pre-
incubated for 1 h at room temperature and incubated at 37e28 ꢀC
for 24e48 h for anti-bacterial and anti-fungal activities, respec-
1715, 1687 (3CO). 1H NMR (DMSO-d6,
d ppm): 3.2 (s, 2H, CH2, pyr-
azolone), 7.5e8.0 (m, 9H, aromatic-H), 8.1 (s, 1H, H-7, Ar-H) and 8.2
(s, 1H, H-5, Ar-H), MS (m/z, RI): Mþ 551.94, 553.94, 555.94 (9.2%,
18.3%, 10%) and at m/z 396.2 (100%).
tively. Ciprofloxacin (10 mg/disc) and Fluconazole (10 mg/disc) were
used as standard for anti-bacterial and anti-fungal activity,
respectively. The observed inhibition zone is presented in Table 1.
6.1.32. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzamide (XIII)
6.2.2. Minimum inhibitory concentration (MIC)
MIC [27] of the compound was determined byagar streak dilution
A mixture of the hydrazide III (5.14 g; 10 mmol) and maleic
anhydride (0.72 g; 10 mmol) in absolute ethanol (20 mL) was
refluxed for 7 h. The precipitated solid formed upon cooling, was
filtered and recrystalized from ethanol to give white crystals of XIII.
M.p. 212 ꢀC, in 70% yield. Analysis for C25H14Br2N4O4, M.wt.
(594.21). Calcd.: %C, C, 50.53; H, 2.37; N, 9.43. Found: %C, 50.40; H,
2.29; N, 9.37. IR (KBr, cmꢁ1): 3430 (NH), 3070 (CH-aromatic), 1780,
method. A stock solution of the synthesized compound (100 mg/ml)
in DMSO was prepared and graded quantities of the test compounds
were incorporated in specified quantity of molten sterile agar
(Muller Hinton agar for anti-bacterial activity and Sabouraud
dextrose agar medium for anti-fungal activity). A specified quantity
of the medium (40e50 ꢀC) containing the compound was poured
into a Petri dish to give a depth of 3e4 mm and allowed to solidify.
Suspension of the micro-organism was prepared to contain
approximately 105 cfu/ml and applied to plates with serially
diluted compounds in DMSO to be tested and incubated at 37 ꢀC for
24 and 48 h for bacteria and fungi, respectively. The MIC was
considered to be the lowest concentration of the test substance
exhibiting no visible growth of bacteria or fungi on the plate. The
observed MIC is presented in Table 1.
1770,1710,1680 (4CO). 1H NMR (DMSO-d6,
d ppm): 6.9e7.8 (m, 11H,
aromatic-H) 7.9 (s, 1H, H-7, Ar-H), 8.1 (s, 1H, H-5, Ar-H), and 11.1 (s,
1H, NH, exchangeable with D2O). MS (m/z, RI): Mþ 591.94, 593.94,
595.94 (10%, 20.3%, 9.9%) and at m/z 420.2 (100%).
6.1.33. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
(1,3-dioxoisoindolin-2-yl)benzamide (XIV)
A mixture of the hydrazide III (5.14 g; 10 mmol), and phthalic
anhydride (1.28 g; 10 mmol) in absolute ethanol (20 mL) was
refluxed for 7 h. The formed precipitate upon cooling was filtered
and recrystalized from ethanol to give white crystals of XVI. M.p.
294 ꢀC in 72% yield. Analysis for C29H16Br2N4O4, M.wt. (644.27).
Calcd.: %C, C, 54.06; H, 2.50; N, 8.70. Found: %C, 53.92; H, 2.39; N,
8.57. IR (KBr, cmꢁ1): 3437 (NH), 3074 (CH-aromatic), 1775, 1770,
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6.1.34. 4-(2-Phenyl-6,8-dibromo-4-oxo-(4H)quinazolin-3-yl)-N-
(2,5-dioxopyrrolidin-1-yl)benzamide (XV)
A mixture of the hydrazide III (5.14 g; 10 mmol), and succinic
anhydride (0.71 g, 10 mmol) in absolute ethanol (20 mL) was
refluxed for 7 h. The precipitated solid formed upon cooling, was
filtered and recrystalized from ethanol to give white crystals of XI.
M.p. 280 ꢀC, in 60% yield. Analysis for C25H16Br2N4O4, M.wt.
(596.23). Calcd.: %C, C, 50.36; H, 2.70; N, 9.40. Found: %C, 50.20; H,
2.59; N, 9.37. IR (KBr, cmꢁ1): 3311 (NH), 3070 (CH-aromatic), 1773,
1760, 1710, 1680 (4CO). MS (m/z, RI): Mþ 593.95, 595.95, 597.95 (4%,
8.3%, 3.2%) and at m/z 113.2 (100%).
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