Synthesis and biological activities of some new 3H-quinazolin-4-one derivatives derived from 3-phenylamino-2-thioxo-3H-quinazolin-4-one

Article abstract of DOI:10.1080/10426500490262559

Reaction of 3-phenylamino-2-thioxo-3H-quinazolin-4-one (1) with methyl iodide, α-chloroethylacetate, and α-bromobenzoylacetophenone in methanol in the presence of KOH with heating resulted in alkylation on the sulfur atom to 2-alkyl thio derivatives 2-4,

Full text of DOI:10.1080/10426500490262559

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESIS AND BIOLOGICAL ACTIVITIES OF SOME NEW
3H-QUINAZOLIN-4-ONE DERIVATIVES DERIVED FROM 3-
PHENYLAMINO- 2-THIOXO-3H-QUINAZOLIN-4-ONE
Mohamed A. Saleh a , Yehia A. Hafez a , Foad E. Abdel-Hay a & Wagdy I. Gad a
a Tanta University , Tanta, Egypt
Published online: 11 Aug 2010.
To cite this article: Mohamed A. Saleh , Yehia A. Hafez , Foad E. Abdel-Hay & Wagdy I. Gad (2004) SYNTHESIS
AND BIOLOGICAL ACTIVITIES OF SOME NEW 3H-QUINAZOLIN-4-ONE DERIVATIVES DERIVED FROM 3-PHENYLAMINO- 2-
THIOXO-3H-QUINAZOLIN-4-ONE, Phosphorus, Sulfur, and Silicon and the Related Elements, 179:2, 411-426, DOI:
10.1080/10426500490262559
To link to this article: http://dx.doi.org/10.1080/10426500490262559
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Phosphorus, Sulfur, and Silicon, 179:411–426, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490262559
SYNTHESIS AND BIOLOGICAL ACTIVITIES OF
SOME NEW 3H-QUINAZOLIN-4-ONE DERIVATIVES
DERIVED FROM 3-PHENYLAMINO-
2-THIOXO-3H-QUINAZOLIN-4-ONE
Mohamed A. Saleh, Yehia A. Hafez, Foad E. Abdel-Hay,
and Wagdy I. Gad
Tanta University, Tanta, Egypt
(Received January 30, 2003; accepted August 27, 2003)
Reaction of 3-phenylamino-2-thioxo-3H-quinazolin-4-one (1) with
methyl iodide, α-chloroethylacetate, and α-bromobenzoylacetophenone
in methanol in the presence of KOH with heating resulted in alkylation
on the sulfur atom to 2-alkyl thio derivatives 2–4, respectively. Treat-
ment of 1 with α-bromo-α-cyanoethylacetate afforded 3-hydroxy-10-
oxo-4-phenyl-4H,10H-1-thia-4,4a,9-triaza-anthrancene-2-carbonitrile
(5). Reaction of the ester 3 with hydrazine hydrate afforded hydrazide
6. The hydrazide 6 on reaction with benzoylacetone, dibenzoylmethane,
and ethyl acetoacetate furnished the corresponding pyrazoles 7 and 8
and pyrazolone 9 respectively. Treatment of 6 with methanolic KOH
and carbon disulphide afforded 1,3,4-oxadiazole-2-thione derivative
10. Compound 1 reacted namely with 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosylbromide, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl
bromide, or with 2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide to yield
S-glycoside derivatives 11–13, respectively. Oxidation of S-glucoside 11
with H2O2 afforded the corresponding sulphone; 2-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-
acetyl-β-D-glucopyranosylsulphonyl)-3-phenlyamino-3H-quinazolin-
4-one (14). The synthesized compounds have been screened for their
antimicrobial activity.
Keywords: 3-Phenylamino-2-thioxo-3H-quinazolin-4-one; alkylation;
antimicrobial activity; hydrazide; pyrazole, pyrazolone and oxadiazole
derivatives; S-glycosides
A variety of substituents have been introduced into many positions of
quinazolinone as means of structural modifications and potentiation
The authors would like to thank Dr. Yehia A. Mahamoud, Assistant Professor of Biolog-
ical Activity, Botany Department, Faculty of Science, Tanta University for antimicorbial
data.
Address correspondence to Mohamed A. Saleh, Tanta University, Chemistry Depart-
ment, Faculty of Science, Tanta, Egypt. E-mail: mahsaleh@hotmail.com
411

412
M. A. Saleh et al.
of biological activities. 3H-Quinazolin-4-ones are considered to be
very interesting heterocyclic ring systems because of their thera-
peutic importance. For example, derivatives of 3H-quinazolin-4-one
have been found to exhibit interesting biological activities.1 These
include antimicorbial,2,3 antimalarial,4 anticonvulsive,5 antifungal,6,7
and antiviral8 activities. Additionally, several of S-substituted thio-
heterocyclices also exhibit various biological activities.9−11 Thioamide
group is an interesting for heterocyclic chemists because it can used
as a useful synthetic building block and its regioselectivity toward dif-
ferent electrophiles has great importance. Data in the literature show
that in most cases of nucleophilic substitution of an alkyl halide on a
thioamide system the sulfur atom attack is favored.12−16 In this article
we report a study on the regioselectivity of the reaction of several of
electrophilic reagents (alkyl and per-O-acetylglycopyranosyl bromides)
with thioamide moiety of model compound 3-phenylamino-2-thioxo-3H-
quinazolin-4-one (1).
RESULTS AND DISCUSSION
Reaction of 1 with methyl iodide, α-chloroethylacetate and α-
bromobenzoylacetophenone in methanol in the presence of KOH
with heating resulted in alkylation on the sulfur atom to af-
ford 2-methylthio-3-phenylamino-3H-quinazolin-4-one (2), (4-oxo-3-
phenylamino-3,4-dihydroquinazolin-2-ylthio) acetic acid ethyl ester
(3), and 2-(4-oxo-3-phenylamino-3,4-dihydroquinazolin-2-ylthio)-1,3-
diphenyl propane-1,3 dione (4) (Scheme 1). The structure of the S-
substituted derivatives 2–4 was confirmed by analytical data, IR,
1H NMR, and 13C NMR. The IR spectra of 2–4 revealed the absence of
the absorption band at 1220 cm−1 (C S) stretching vibration observed
in 1, thus conforming the S-alkylation. The IR spectrum of 3 showed
absorption bands at 3427 (NH), 1735 (C O of carboxylic ester), 1694
(C O quinazolinone), and 1605 (C N) cm−1. The 1H NMR spectrum of
3 showed signals at 9.48 (s 1H, NH), 8.07 (d), 7.86 (t), 7.57 (d), 7.27 (t)
(4H, quinazolinone moiety), 6.66–7.20 (m, 4H, Ph), 4.00 (s, 2H, SCH2),
3.67 (q, 2H OCH2), 2.51 (t, 3H, CH3). The mass spectrum of 3 showed
molecular ion M+ at m/z 355 and further peaks at 310 and 236 due to
sequential expulsion of fragments OC2H5 and, S CH2CO, respec-
tively (see Experimental for details). The 13C NMR spectrum of 2 was
characterized by the presence of a signal at δ 13.9 corresponding to the
S CH3 and the absence of signal at δ 176.2 due to (C S) band observed
in compound 1. The phenyl and quinazolinone signals appeared at the
expected field17 (see Experimental).

New Quinazolin Derivatives
413
SCHEME 1
On the other hand treatment of 1 with α-bromo- α-cyano ethylacetate
afforded the unexpected new heterocyclic 3-hydroxy-10-oxo-4-phenyl-
4H,10H-1-thia-4,4a,9-triaza-anthracene-2-carbonitrile (5). Formation
of compound 5 may be explained by the formation of S-alkyl derivative
in the first and then internal nucleophilic attack by the NH group on
the C O takes place with loss of C2H5OH molecule to give the cyclized
compound 5 (Scheme 2).
SCHEME 2
The structure of 5 was confirmed on the basis of elemental analy-
sis and spectral data. Its mass was compatible with molecular formula
C17H10N4O2S (M+: 334). The IR spectrum of 5 had no C S band but
displayed bands at 3425 (OH), 2225 (CN), 1687 (C O quinazolinone),
1
1563 (C N) cm−1. The H NMR spectrum of 5 showed a signal band

414
M. A. Saleh et al.
at δ 9.75 ppm, assigned to the OH proton. Ester and NH protons were
missing as well as (see Experimental). Structure 5 was indicated by the
13C NMR spectra, which gave conclusive evidence for thiadiazine struc-
ture. The spectrum reveals low-field signals at 157.3 (thiadiazine C-2),
157.2 (thiadiazine C-3) and 145.5 ppm (thiadiazine C-9a) in addition
to a signal at 114.9 for cyano group (see Experimental). The 13C NMR
of 5 showed the absence of ester and thione signals provided strong
evidence that cyclization had occurred as depicted (see Experimental).
The ester 3 reacted with hydrazine hydrate in refluxing ethanol (7 h)
to yield (4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-ylthio) acetic
acid hydrazide (6) in 85% yield (Scheme 3). The IR spectrum of 6
displayed bands at 3435 (NH), 3245, 3160 (NH/NH2), 1687 (C O
SCHEME 3

New Quinazolin Derivatives
415
quinazolinone), 1670 (C O amide carbonyl), and 1610 (C N) cm−1. The
1H NMR spectrum of 6 showed three singlet signals at δ 11.20, 9.52,
and 4.54 ppm related respectively to NH hydrazide, NH attached to
phenyl, and NH2 function. Also, the structure of 6 was confirmed by its
mass spectrum which shows a molecular ion peak M+ at m/z 341 (see
Experimental for details).
The hydrazide 6 reacted with benzoyl acetone, dibenzoyl methane,
and ethyl acetoacetate in ethanol containing a catalytic amount of
concentrated HCl to give 2-[2-(5-methyl-3-phenyl-pyrazol-1-yl)-2-oxo-
ethylthio]-3-phenylamino-3H-quinazolin-4-one (7), 2-[2-(3,5-diphenyl-
pyrazol-1-yl)-2-oxo-ethylthio]-3-phenylamino-3H-quinazolin-4-one (8),
and 2-[2-(3-methyl-5-oxo-4,5-dihydro-pyrazol-1yl)-2-oxo-ethylthio]-3-
phenylamino-3H-quinazolin-4-one (9) respectively (Scheme 3). The
structures 7–9 were supported by elemental analysis, IR, 1H NMR,
13C NMR and mass spectroscopic data (see Experimental). The IR
spectra of 7–9 showed disappearance of absorption peaks at 3245,
3160 cm−1 due to NH/NH2 and 1670 cm−1 due to amide carbonyl
function provided strong evidence that cyclization had occurred as
depicted. The mass spectrum of 7 was compatibic with molecular
1
formula C26H21N5O2S (M+ 467) and H NMR contained three singlet
signals at δ 9.78, 6.15 and 2.19 assigned to NH, pyrazole H-4 and
CH3 and showed a doblet-doublet signal at δ 4.65 ppm, assignable to
methylene protons ( SCH2). Structure 7 was indicated by 13C NMR
spectra which conclusive evidence for pyrazole structure. The spectrum
reveals low-field signals at δ 150.2 (pyrazole C-3), 103.4 (pyrazole C-4)
and 147.6 ppm (pyrazole C-5) in addition to signals at δ 162.7 and
168.4 ppm for C O group. The aromatic, methylene and methyl also
appeared at the expected field (see Experimental).
Reaction of hydrazide 6 with methanolic KOH and CS2 under
reflux condition gave 3-phenylamino-2-(5-thioxo-4,5-dihydro[1,3,4]-
oxadiazole-2-ylmethylthio)-3H-quinazolin-4-one (10) (Scheme 3).
Structure of 10 was established with basis of elemental analysis and
spectral data (see Experimental). Compound 10 displayed bands in
the IR spectrum at 3248 (NH), 3177 (NH C S), 1685 (C O quina-
zolinone), and 1185 (C S) cm−1 and the absence of bands at 3245,
3160 cm−1 due to NH/NH2 and 1670 cm−1 due to amide carbonyl
function stretching vibrations observed in 6, thus confirming that
heterocyclization occurred. The 1H NMR spectrum showed two singlet
signals at δ 11.72 and 9.64 ppm assignable to NH (oxadiazole) and
NH group at position 3 of quinazolinone, respectively, in addition a
doublet-doublet at δ 3.24 ppm corresponding to SCH2 group, where
as the mass spectrum showed the molecular ion peak (M+) at m/z 383
(see Expermental).

416
M. A. Saleh et al.
Compound
1
reacted namely with 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide, 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl
bromide and 2,3,4-tri-O-acetyl-α-D-xylopyranosyl bromide in the
presence of sodium hydride in dry dimethyl formamide to yield 3-
phenylamino-2-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-glucopyranosylthio)-3H-
quinazolin-4-one (11), 3-phenylamino-2-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-tetra-O-acetyl-β-D-
galactopyranosylthio)-3H-quinazolin-4-one (12), and 3-phenylamino-2-
(2ꢁ,3ꢁ,4ꢁ-tri-O-acetyl-β-D-xylopyranosylthio)-3H-quinazolin-4-one (13)
respectively (Scheme 4).
SCHEME 4
The IR spectra of 11–13 were characterized by the absence of
absorption band at 3242 (NH C S) and absorption band at 1220
(C S) cm−1 and the presence of acetoxy carbonyl stretching bands at
1
1747–1742 cm−1 that is associated with S-glycosylation. The H NMR
spectrum of 11 showed the signal for the anomeric proton (H-1ꢁ) of the
carbohydrate moiety in the form of a doublet at δ 5.78 ppm in spin-spin
ꢁ
ꢁ
coupling constant J1 ,2 = 10.6 Hz corresponds to the diaxial orientation
of H-1ꢁ and H-2ꢁ protons which indicates the β-configuration for 11 (see
Experimental).
The structure of S-glycosides 11–13 was further confirmed by close
inspection of mass spectral analysis (see Experimental). Fragmentation
pathway for 13 can be represented as in Scheme 5.
Oxidation of 11 with hydrogen peroxide in acetic acid afforded the
corresponding sulphone 14 confirms that glycosylation occurred on sul-
fur rather than nitrogen (Scheme 6). The IR spectrum of 14 showed
1
appearance of bands at 1185 and 1370 cm−1(SO2). The H NMR spec-
trum 14 showed signal at δ 5.93 for anomeric proton H-1ꢁ. The spin-spin
coupling constant at C1ꢁ and C2ꢁ of the carbohydrate residue (J1 ,2
=
ꢁ
ꢁ
8.5 Hz), indicates the β configuration of 14 (see Experimental).

New Quinazolin Derivatives
417
O
H
N
Ph
N
O
AcO
AcO
N
S
13
m/z
OAc
= 527 (2.2 %)
M
Dissociation of O- acetylated glycosides
at the glycosidic bond
O
N
-B
H
N
-Sugar moiety
N
Ph
+
O
HS
OAc
B + 1 m/z =269 (5.1%)
OAc
OAc
m /z = 259 (24.5 %)
-SH
-HOAc
+
O
H
N
+
O
N
Ph
+
O
- CH2CO
N
m/z = 236 (10.4 %)
OAc
OAc
OAc
NPh
O
m/z =199 (21.4 %)
m/z =157 (47.7 %)
-HOAc
+
+
O
O
-
+
CH2CO
O
H
N
N
O
m /z = 97 (100%)
+
m/z = 145(11.7 %)
OAc
- CO
O
m/z = 139 (51.6 %)
CN
m/z = 69 (13.9 %)
-CO
+
O
- NH
H
N
NH
m /z = 119 (3.0 %)
m /z = 92 (22.3 %)
m /z = 77 (28.0 %)
SCHEME 5 Proposed cleavage pathway of compound 13.
BIOLOGICAL RESULTS
All products were in vitro evaluated for antimicrobial activity against
Staphylococcus aureus, Escherichia coli, and for antifungal activity

418
M. A. Saleh et al.
O
H
N
O
N
OAc
H
N
N
Ph
OAc
N
Ph
O
AcO
AcO
O
N
H2O2
AcOH
S
O
AcO
AcO
S
OAc
11
OAc
O
14
SCHEME 6
against Candida albicans, using the cup-diffusion method.18 Each cup
(8 mm in diameter) was filled with two drops of 1% solution of the test
compound in dimethylsulfoxide. The results obtained indicated com-
pounds 1, 5, 7, 8, 9, 10, 13, and 14 are the only compounds that showed
antimicrobial activity. Compound 14 showed the most pronounced in-
hibitory effect when tested against S. aureus. Compound 13 came in the
second rank according to its inhibitory effect to S. aureus. Compounds
1, 5, 7, 8, 9, and 10 inhibited C. albicans while no compounds was found
to be posses marked activity against E. coli.
EXPERIMENTAL
All melting points are uncorrected. They were performed by open cap-
illary method using electrothermal melting MEL-TEMP II apparatus.
The IR spectra were recorded with Unicam SP 1200 spectrophotome-
ter using pellet technique KBr discs (υ in cm−1). The 1H NMR spectra
were recorded with Bruker AC 250 FT spectrometer (250 MHz). The
13C NMR spectra were recorded with Bruker AC-250 FT spectrometer
(62.9 MHz). TMS was used as an internal standard and chemical shifts
are expressed in δ ppm values. The mass spectral data were obtained
with micro mass spectrometer model 7070 at energy of 70 eV and in-
let temperature 90◦C. Elemental analyses (C, H, N) were performed
by the Microanalysis Centre, Cairo University and Central Laboratory
Service of Microanalysis Tanta University, Egypt.
3-Phenylamino-2-thioxo-3H-quinazolin-4-one (1)
This compound was in 72% yield as previously described,19 m.p. 250–
252◦C (lit.19 248–250◦C); additional data, 1H NMR ([D6] DMSO): δH
=
6.26–7.12 (m, 5H, Ph), 7.33 (t, 1H, J = 7.8 Hz, H-6), 7.42 (d, J = 7.8 Hz,
1H, H-8), 7.76 (t, J = 7.8 Hz, 1H, H-7), 7.97 (d, J = 7.8 Hz, 1H, H-5),
8.72 (br s, 1H, exchangeable with D2O, NH), 10.00 (s, 1H, exchangeable
with D2O, NH). 13C NMR ([D6] DMSO): δC = 122.7 (2C, C-2 and C-6

New Quinazolin Derivatives
419
of phenyl), 116.4 (C-8), 116.6 (C-4 of phenyl), 119.5 (C-5), 120.4 (C-4a),
128.4 (C-6), 128.6 (2C, C-3 and C-5 of phenyl), 136.7 (C-7), 139.1 (C-1
of phenyl), 146.2 (C8a), 158.7 (C-4), 176.2 (C S).
2-Methylthio-3-phenylamino-3H-quinazolin-4-one (2).
To a solution of 1 (2.69 g, 10 mmol) in methanolic KOH (30 ml), methyl
iodide (0.56 g, 10 mmol) was slowly added with stirring at room temper-
ature. The reaction mixture was heated under reflux for 2 h and it was
allowed to stand at room temperature for 1 h. Then it was poured into
300 ml ice/water, whereby a precipitate was formed which was filtered
off, washed with water, dried, and recrystallized from methanol/water
(30%) to give 2. Yield, 1.98 g (70%); m.p., 164–165◦C. IR (KBr): 3425
(NH), 2849 (Ar-H), 1687 (C O quinazolinone), 1604, 1540, 1461 cm−1
(C N, C C). 1H NMR ([D6] DMSO): δH = 2.05 (s, 3H, CH3, J = 7.1 Hz),
6.65-7.16 (m, 5H, Ph), 7.42 (t, J = 7.8 Hz, 1H, H-6), 7.63 (d, J = 7.8
Hz, 1H, H-8), 7.81 (t, J = 7.8 Hz, 1H, H-7), 8.05 (d, J = 7.8 Hz, 1H,
H-5), 9.31 (s, 1H, exchangeable with D2O, NH). 13C NMR ([D6] DMSO):
δC = 13.9 (CH3), 112.6 (3C, C-8 and C-2, C-6 of phenyl), 119.4 (C-4
phenyl), 120.6 (C-6), 125.4 (C-5), 125.7 (C-4a), 129.0 (2C, C-3 and C-5
of phenyl), 132.0 (C-7), 145.1 (C-1 of phenyl), 145.9 (C-8a), 147.0 (C-2),
167.2 (C-4).
Anal. Calcd. for C15H13N3OS (283.34): C, 63.58; H, 4.62; N, 14.83.
Found: C, 63.78; H, 4.43; N, 14.48.
(4-Oxo-3-phenylamino-3H-quinazolin-2-ylthio) Acetic
Acid Ethyl Ester (3)
Compound 3 was prepared in the same manner as described for 2 us-
ing 1 (10 mmol) and α-chloroethylacetae (1.22 g, 10 mmol) and it was
recrystallized from methanol.
Yield, 2.31 g (65%); m.p., 138–140◦C. IR (KBr): 3427 (NH), 2923 (Ar-
H), 1735 (C O ester), 1694 (C O quinazolinone), 1605, 1542, 1467,
1402 cm−1 (C N, C C). 1H NMR ([D6] DMSO): δH = 2.51 (t, 3H, CH3,
J = 7.0 Hz), 3.67 (q, 2H, OCH2), 4.00 (s, 2H, SCH2), 6.66–7.20 (m, 5H,
Ph), 7.27 (t, 1H, H-6), 7.57 (d, 1H H-8), 7.86 (t, 1H, H-7), 8.07(d, 1H,
H-5), 9.48 (s, 1H, exchangeable with D2O, NH).13C NMR ([D6] DMSO):
δC = 14.4 (CH3), 38.2 (SCH2), 61.6 (OCH2), 117.3 (C-8), 114.0 (2C, C-2
and C-6 of phenyl), 119.7 (C-4 of phenyl), 121.6 (C-6), 125.3 (C-5), 125.8
(C-4a), 129.4 (2C, C-3 and C-5 of phenyl), 131.5 (C-7), 145.7 (C-1 of
phenyl), 146.1 (C-8a), 147.4 (C-2), 167.2 (C-4), 167.8 (C O ester).
EI MS, m/z (%) = 355 (M+, 28.4), 310 (M+ OC2H5, 16.8), 236 (310-
SCH2CO, 12.2), 145 (18.6), 119 (5.3), 77 (100).

420
M. A. Saleh et al.
Anal. Calcd. for C18H17N3O3S (355.41): C, 60.83; H, 4.82; N, 11.82.
Found: C, 61.00; H, 4.54; N, 12.10.
2-(4-Oxo-3-phenylamino-3,4-dihydroquinazolin-2-ylthio)-
1,3-diphenyl-propane-1,3-dione (4)
It was prepared by reacting 1 (2.69 g, 10 mmol) with α-bromobenzo-
ylacetophenone (3.3 g, 11 mmol) under the same condition. The product
was recrystallized from ethanol to give compound 4.
Yield, 3.34 g (68%); m.p., 220–221◦C. IR (KBr): 3425(NH), 3058, 2919
(Ar-H), 1683 (C O quinazolinone), 1602, 1543, 1505, 1459 cm−1 (C N,
C C). 1H NMR ([D6] DMSO): δH = 4.52 (s, 1H, CH), 6.68–7.18 (m,
5H, Ph), 7.37–7.86 (m, 10H, 2Ph), 7.42 (t, 1H, H-6), 7.52 (d, 1H H-8),
7.68 (t, 1H, H-7), 8.26(d, 1H, H-5), 9.48 (s, 1H, exchangeable with D2O,
NH).
13C NMR ([D6] DMSO): δC = 38.2 (CH), 113.8 (Ph), 119.0 (Ph), 120.8
(C-6), 120.9 (C-8), 125.8 (Ph), 125.9 (Ph), 126.3 (C-4a), 128.2 (Ph), 128.6
(C-5 and Ph), 129.0 (Ph), 133.3 (C-7), 135.0 (Ph), 136.5 (Ph), 145.8 (Ph),
146.4 (C-8a), 159.3 (C-2), 160.3 (C-4), 194.3 (2C, C O aliphatic).
Anal. Calcd. for C29H21N3O3S (491.56): C, 70.86; H, 4.31; N, 8.55.
Found: C, 70.52; H, 4.23; N, 8.21.
3-Hydroxy-10-oxo-4-phenyl-4H,10H-1-thia-4,4a,9-triaza-
anthracene-2-carbonitrile (5)
α-Bromo-α-cyano ethylacetate (1.92 g, 10 mmol) was added dropwise
to a stirred suspension compound 1 (2.69 g, 10 mmol) and KOH (10
mmol) in 50% aqueous ethanol (30 ml) at room temperature and stir-
ring is continued for 1 h. The reaction mixture was refluxed for 3 h
then was cooled to room temperature. The precipitate was filtered,
washed with cold water, dried, and crystallized from methanol to
give 5.
Yield, 2.0 g (60%); m.p., 273–274◦C. IR (KBr): 3425 (OH), 3053 (Ar-
H), 2225 (CN), 1687 (C O quinazolinone), 1608, 1563, 1461 cm−1 (C N,
1
C C). H NMR ([D6] DMSO): δH = 6.96–7.44 (m, 5H, Ph), 7.38 (t, J =
8.0 Hz, 1H, H-6), 7.48 (d, J = 8.0 Hz, 1H, H-8), 7.96 (t, J = 8.0 Hz, 1H,
H-7), 8.26 (d, J = 8.0 Hz, 1H, H-5), 9.75 (s, 1H, exchangeable with D2O,
OH).
13C NMR ([D6] DMSO): δC = 114.9 (CN), 120.1 (2C, C-2 and C-6 of
phenyl), 121.6 (C-5), 121.7 (C-4 of phenyl), 126.3 (C-7), 126.6 (C-10a),
128.3 (C-8), 129.1 (2C, C-3 and C-5 of phenyl), 135.4 (C-6), 145.5
(C-9a), 145.7 (C-1 of phenyl), 146.7 (C-8a), 157.2 (C-3), 157.3 (C-2), 159.1
(C-10).

New Quinazolin Derivatives
421
MS, m/z (%) = 334 (M+, 27.24), 257 (M+-Ph, 14.40), 178 (C8H6N2SO+,
100).
Anal. Calcd. for C17H10N4O2S (334.35): C, 61.07; H, 3.01; N, 16.76.
Found: C, 61.30; H, 3.10; N, 16.83.
(4-Oxo-3-phenylamino-3,4-dihydroquinazolin-
2-ylthio)acetic Acid Hydrazide (6)
To a suspension of 3 (1.8 g, 5 mmol) in ethanol (20 ml), hydrazine hy-
drate 1.5 ml (30 mmol) was added and the reaction mixture was refluxed
for 7 h. After cooling, the resulting crystalline product was filtered,
washed with little ethanol, dried, and recrystallized from ethanol to
give 6.
Yield, 1.45 g (85%); m.p., 192–194◦C. IR (KBr): υ = 3435 (NH), 3245,
3160 (NH / NH2), 1687 (C O), 1670 (C O), 1600, 1556, 1511, 1465 cm−1
1
(C N, C C), 695 (C-S-C); H NMR ([D6] DMSO): δH = 4.25 (br s, 2H,
exchangeable with D2O, NH2), 4.70 (s, 2H, SCH2), 6.63–7.13 (m, 5H,
Ph), 7.24 (t, 1H, H-6), 7.46 (d, 1H, H-8), 7.72 (t, 1H, H-7), 7.92 (d, 1H,
H-5), 8.72 (s, 1H, exchangeable with D2O, NH), 9.85 (s, 1H, exchange-
able with D2O, NH).
EI MS, m/z (%) = 341 (M+, 54.21), 310 (M+-NH-NH2, 23.54), 282
(310-CO, 18.60), 268 (310-CH2CO, 100), 236 (310-SCH2CO, 22.40), 145
(9.21), 119 (6.00), 92 (18.52), 77 (38.62).
Anal. Calcd. for C16H15N5O2S (341.39): C, 56.29; H, 4.43; N, 20.51.
Found: C, 56.57; H, 4.22; N, 20.34.
2-[2-(5-Methyl-3-phenyl-pyrazol-1-yl)-2-oxo-ethylthio]-
3-phenylamino-3H-quinazolin-4-one (7)
and 2-[2-(3,5-Diphenyl-pyrazol-1-yl)-2-oxo-ethylthio]-
3-phenylamino-3H-quinazolin-4-one (8)
The hydrazide 6 (3.41 g, 10 mmol) was dissolved in ethanol (20 ml),
then benzoyl acetone or dibenzoyl methane (10 mmol) was added, fol-
lowed by the addition 2–4 drops perchloric. The mixture was heated
under reflux for 8 h and cooled to room temperature. The product
was collected by filtration, washed with little ethanol, dried, and crys-
tallized from a mixture ethanol and ethyl acetate (3: 1) to give 7
or 8.
Compound 7
Yield, 3.36 g (72%); m.p., 214–216◦C. IR (KBr): υ = 3442 (NH), 1730
(C O), 1678 (C O quinazolinone), 1607, 1595, 1511, 1462 (C N, C C),

422
M. A. Saleh et al.
1
691 cm−1 (C-S-C). H NMR ([D6] DMSO): δH = 2.19 (s, 3H, CH3, J =
7.1 Hz), 4.65 (dd, 2H, SCH2), 6.15 (s, 1H, pyrazole H-4), 6.69–8.32 (m,
14H, 2Ph and quinazolinone), 8.78 (s, 1H, exchangeable with D2O, NH).
13C NMR ([D6] DMSO): δC = 13.4 (CH3), 37.6 (SCH2), 102.9 (pyrazole
C-4) 112.8 (2C, C-2, C-6 of Ph), 118.3 (C-8), 120.7 (C-4 Ph), 121.4 (C-6),
125.2 (2C, C-2 and C-6 of Ph), 125.5 (C-5), 126.0 (C-4a), 127.5 (C-4 of
Ph), 128.4 (2C, C-3 and C-5 of Ph), 129.2 (2C, C-3 and C-5 of Ph), 132.0
(C-7), 134.4 (C-1 of Ph), 142.4 (C-1 of Ph), 145.9 (C-8a), 147.4 (pyrazole
C-5), 149.0 (C-2), 150.3 (pyrazole C-3), 164.7 (C-4), 168.4 (C O). EI MS,
m/z (%) = 467 (M+, 38.75).
Anal. Calcd. for C26H21N5O2S (467.55): C, 66.79; H, 4.53; N, 14.98.
Found: C, 67.02; H, 4.42; N, 14.67.
Compound 8
Yield, 4.23 g (80%); m.p., 242–244◦C. IR (KBr): υ = 3438 (NH), 1725
(C O), 1685 (C O quinazolinone), 1605, 1592, 1536, 1490 (C N, C C),
1
695 cm−1 (C-S-C). H NMR ([D6] DMSO): δH = 4.60 (dd, 2H, SCH2),
6.25 (s, 1H, pyrazole H-4), 7.12–8.40 (m, 19H, 3Ph and quinazolinone),
9.21 (s, 1H, exchangeable with D2O, NH).
Anal. Calcd. for C31H23N5O2S (529.63): C, 70.30; H, 4.38; N, 13.22.
Found: C, 70.08; H, 4.57; N, 13.49.
2-[2-(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)-2-oxo-
ethylthio]-3-phenylamino-3H-quinazolin-4-one (9)
A mixture of hydrazide 6 (3.41 g, 10 mmol) and ethyl acetoacetate (1.30
g, 10 mmol) was refluxed in methanol (25 ml) containing 3–4 drops
perchloric acid for 5 h. The reaction mixture was cooled to room tem-
perature and separated solid filtered off, washed with little methanol,
dried, and crystallized from methanol to give 9.
Yield, 2.65 g (65%); m.p., 287–288◦C. IR (KBr): υ = 3452 (NH), 1732
(C O), 1682 (C O quinazolinone), 1665 (C O pyrazolone), 1604, 1598,
1532, 1485(C N, C C), 698 cm−1 (C-S-C). 1H NMR ([D6] DMSO): δH
=
2.25 (s, 3H, CH3), 4.63 (dd, 2H, SCH2), 5.02 (s, 2H, pyrazole H-4),
6.75–8.16 (m, 9H, Ph and quinazolinone), 8.82 (s, 1H, exchangeable
with D2O, NH). 13C NMR ([D6] DMSO): δC = 14.6 (CH3), 38.2 (SCH2),
41.8 (pyrazole C-4), 118.7 (C-8), 116.3 (2C, C-2 and C-6 of Ph), 120.4
(C-4 of Ph), 123.0 (C-6), 126.0 (C-5), 127.2 (C-4a), 129.8 (2C, C-3 and
C-5 of Ph), 134.4 (C-7), 144.3 (C-1 of Phl), 145.6 (C-8a), 147.4 (pyra-
zole C-4), 149.4 (C-2), 164.5 (C-4), 167.6 (C O), 170.2 (C O pyrazole
C-5).
Anal. Calcd. for C20H17N5O3S (407.45): C, 58.96; H, 4.21; N, 17.19.
Found: C, 58.75; H, 3.94; N, 17.35.

New Quinazolin Derivatives
423
3-Phenylamino-2-(5-thioxo-4,5-dihydro[1,3,4]oxadiazol-
2-ylmethylthio)-3H-quinazolin-4-one (10)
A mixture of hydrazide 6 (3.41 g, 10 mmol), potassium hydroxide
(10 mmol), and carbon disulphide (3 ml) in ethanol (25 ml) was heated
under reflux for 12 h. The solvent was evaporated to dryness and
the residue dissolved in cold water. The resulting clear solution fil-
tered and the filtrate was acidified with dilute hydrochloric acid. The
separated solid was filtered, dried, and crystallized from ethanol to
give 10.
Yield, 2.83 g (74%); m.p., 172–174◦C. IR (KBr): υ = 3436 (NH), 3177
(NH-C S), 1685(C O quinazolinone), 1608, 1590, 1530, 1482 (C N,
C C), 1185 (C S), 697 cm−1 (C-S-C). 1H NMR ([D6] DMSO): δH = 3.24
(dd, 2H, SCH2), 5.02 (s, 2H, pyrazole H-4), 6.62–8.25 (m, 9H, Ph and
quinazolinone), 11.72 (s, 1H, exchangeable with D2O, pyrazole NH),
9.52 (s, 1H, exchangeable with D2O, NH).
EI MS, m/z (%) = 383 (M+, 45.21), 269 (26.41), 145 (14.95), 119 (5.94),
116 (C3H4N2SO+, 38.45), 102 (C2H2N2SO+, 100).
Anal. Calcd. for C17H13N5O2S2 (383.45): C, 53.25; H, 3.42; N, 18.26.
Found: C, 53.54; H, 3.28; N, 18.29.
3-Phenylamino-2-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-
β-D-glucopyranosylthio)-3H-quinazolin-4-one (11)
To a solution of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide
(4.1 g, 10 mmol) in DMF (15 ml) was added a solution of compound
1 (2.69 g, 10 mmol) in DMF (5 ml) and a suspension of sodium hydride
(0.24 g, 10 mmol) in DMF (15 ml). The reaction mixture was stirred for
3 h and left to stand at room temperature over night. TLC detected
completion of the reaction (system: petroleum ether/ethylacetate, 3:
1, V: V). The reaction mixture was poured onto crushed ice and the
precipitate that formed, was filtered, washed with cold water, dried,
and crystallized from ethanol to afford 11 in 64% yield (3.83 g); m.p.,
169–170◦C.
IR (KBr): υ = 3427 (NH), 2925 (Ar-H), 1744 (C O acetoxy), 1697(C O
quinazolinone), 1584, 1562, 1460 (C N, C C), 915 cm−1 (β pyranoside).
1H NMR (CDCl3): δH = 1.96, 2.02, 2.06, 2.12 (4 s, 12H, each CH3), 3.99
(m, 1H, H-5ꢁ ), 4.15 (q, 1H, H-6ꢁꢁ ), 4.24 (q, 1H, H-6ꢁ ), 4.28 (t, 1H, H-2ꢁ
), 5.12 (t, 1H, H-4ꢁ), 5.40 (t, 1H, H-3ꢁ), 5.78 (d, 1H, H-1ꢁ, J1 ,2 = 10.6
Hz) ), 6.74–7.18 (m, 5H, Ph), 7.39 (t, 1H, H-6), 7.61 (d, 1H, H-8), 7.74
(t, 1H, H-7), 8.15 (d, 1H, H-5), 8.93 (s, 1H, exchangeable with D2O,
NH).
ꢁ
ꢁ

424
M. A. Saleh et al.
EI MS, m/z (%) = 599 (M+, 6.4), 331 (sugar+, 17.9), 268 (B, 21.4),
270 (B+2,17.5) 236 (15.5), 229 (4.7), 211 (6.0), 187 (5.3), 169 (32.1), 145
(13.7), 119 (2.6), 109 (25.0), 93 (100).
Anal. Calcd. for C28H29N3O10S (599.61): C, 56.09; H, 4.87; N, 7.01.
Found: C, 56.40; H, 4.64; N, 7.36.
3-Phenylamino-2-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-
β-D-glucopyranosylthio)-3H-quinazolin-4-one (12)
Compound 12 was prepared in the same manner as described for 11,
using compound 1 (2.69 g, 10 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-
galactopyranosyl bromide (4.1 g, 10 mmol). The product was crystallized
from aqueous ethanol (30%) to afford 12 in 58% yield (3.47 g); m.p., 157–
159◦C.
IR (KBr): υ = 3462 (NH), 2927 (Ar-H), 1747 (C O acetoxy), 1695(C O
quinazolinone), 1592, 1525, 1438 (C N, C C), 860 cm−1 (β pyranoside).
1H NMR (CDCl3): δH = 1.87, 1.94, 2.04, 2.16 (4 s, 12H, each CH3), 4.11
(m, 1H, H-5ꢁ), 4.15 (q, 1H, H-6ꢁꢁ), 4.20 (q, 1H, H-6ꢁ), 4.21 (t, 1H, H-2ꢁ),
5.26 (t, 1H, H-4ꢁ), 5.37 (t, 1H, H-3ꢁ), 5.77(d, 1H, H-1ꢁ, J1 ,2 = 9.5 Hz) ),
6.74–7.26 (m, 5H, Ph), 7.38 (t, 1H, H-6), 7.63 (d, 1H, H-8), 7.74 (t, 1H,
H-7), 8.14 (d, 1H, H-5), 8.90 (s, 1H, exchangeable with D2O, NH).
EI MS, m/z(%) = 599 (M+, 3.9), 331 (sugar+, 70.5), 271 (2.9), 269 (B+1,
8.9), 236 (10.4), 229 (6.0), 211 (3.4), 187 (3.1), 169 (100), 145 (11.7), 119
(3.0), 109 (87.3), 92 (22.3), 81 (19.5), 77 (23.0).
ꢁ
ꢁ
Anal. Calcd. for C28H29N3O10S (599.61): C, 56.09; H, 4.87; N, 7.01.
Found: C, 56.30; H, 4.70; N, 7.32.
3-Phenylamino-2-(2ꢀ,3ꢀ,4ꢀ-tri-O-acetyl-
β-D-xylopyranosylthio)-3H-quinazolin-4-one (13)
Compound 1 (2.69 g, 10 mmol) was reacted with 2,3,4-tri-O-acetyl-α-
D-xylopyranosyl bromide (3.9 g, 10 mmol) to give compound 13 as de-
scribed for 11. The product was crystallized from chloroform / petroleum
ether to give 13 in 60% yield (3.16 g); m.p., 180–181◦C.
IR (KBr): υ = 3422 (NH), 2923 (Ar-H), 1742 (C O acetoxy), 1681
(C O quinazolinone), 1596, 1528, 1482 (C N, C C), 928 cm−1 (β pyra-
noside). 1H NMR (CDCl3): δH = 1.95, 2.03, 2.08 (3 s, 9H, each CH3), 3.64
(q, 1H, H-5ꢁ), 4.25 (m, 1H, H-5ꢁꢁ), 4.97 (t, 1H, H-4ꢁ), 5.03 (t, 1H, H-2ꢁ),
5.27 (t, 1H, H-3ꢁ), 5.95 (d, 1H, H-1ꢁ, J1 ,2 = 7.5 Hz) ), 6.73–7.21 (m, 5H,
Ph), 7.36 (t, 1H, H-6), 7.44 (d, 1H, H-8), 7.64 (t, 1H, H-7), 8.13 (d, 1H,
H-5), 8.86 (s, 1H, exchangeable with D2O, NH).
ꢁ
ꢁ
EI MS, m/z (%) = 527 (M+, 2.2), 259 (sugar+, 24.5), 269 (B+1, 5.1),
236 (10.4), 199 (21.4), 157 (47.7), 145 (11.7), 139 (51.6), 119 (3.0), 97
(100), 92 (22.3), 77 (23.0), 69 (13.9).

New Quinazolin Derivatives
425
Anal. Calcd. for C25H25N3O8S (527.54): C, 56.92; H, 4.78; N, 7.97.
Found: C, 57.10; H, 4.90; N, 8.20.
3-Phenylamino-2-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-tetra-O-acetyl-
β-D-glucopyranosylsulphonyl)-3H-quinazolin-4-one (14)
To a solution of the S-glucoside 11 (1.0 g) in glacial acetic acid (7.5 ml),
an excess of hydrogen peroxide 30% (1.4 g) was added with stirring for
about 6 h at room temperature and poured onto an ice-water (200 ml).
The separated solid was collected by filtration, washed with cold water,
dried, and crystallized from methanol to afford 14 in 65% yield (0.68 g);
m.p., 90–91◦C.
IR (KBr): υ = 3433 (NH), 2942 (Ar-H), 1749 (C O acetoxy),1694
(C O quinazolinone), 1586, 1563, 1473 (C N, C C), 1370, 1185 (SO2),
1
922 cm−1 (β pyranoside). H NMR (CDCl3): δH = 1.85, 1.91, 1.97, 2.00
(4 s, 12H, each CH3), 4.09 (m, 1H, H-5ꢁ), 4.10 (q, 1H, H-6ꢁꢁ), 4.27 (q, 1H,
H-6ꢁ), 5.01 (t, 1H, H-2ꢁ), 5.06 (t, 1H, H-4ꢁ), 5.52 (t, 1H, H-3ꢁ), 5.93 (d, 1H,
H-1ꢁ, J1 ,2 = 8.5 Hz) ), 6.67–7.24 (m, 5H, Ph), 7.37 (t, 1H, H-6), 7.63 (d,
1H, H-8), 7.74 (t, 1H, H-7), 8.15 (d, 1H, H-5), 9.38 (s, 1H, exchangeable
with D2O, NH).
ꢁ
ꢁ
Anal. Calcd. for C28H29N3O12S (631.61): C, 53.25; H, 4.63; N, 6.65.
Found: C, 53.63; H, 4.50; N, 6.95.
REFERENCES
[1] C. Parkanyi and D. Duran, J. Heterocycl., Chem., 37, 725 (2000).
[2] G. Honda, M. Tabata, and M. Tsuda, Planta Med., 37, 172 (1979).
[3] R. K. Saksena and M. Amin Khan, Ind. J. Chem., 28B, 443 (1989).
[4] S. Johne, Pharamazie, 36, 583 (1981).
[5] M. J. Kornet, Eur. J. Med. Chem., 21, 529 (1986).
[6] A. M. Mahmoud, H. A. H. El-Sherief, G. M. El-Naggar, and A. E. Abdel-Rahman,
Ind. J. Chem., 22B, 491 (1983).
[7] P. Mitta and A. S. Mittra, Acta Cienc. Indica, [Ser] Chem., 9, 109 (1983); Chem.
Abstr., 101, 90813 (1984).
[8] K. R. Agarwal, S. R. Nautiyal, and D. D. Mukerji, Ind. Drugs, 23, 458 (1986); Chem.
Abstr., 105, 54126 (1986).
[9] I. Mir and M. T. Siddqui, Tetrahedron, 26, 5235 (1970).
[10] Y. Hamoda, T. Matsuno, T. I. Shii, K. Imai, and M. Mano, Jap. Patent, 7563119
(1975).
[11] R. M. De Marinis, J. R. E. Hoover, G. L. Dunn, P. Actor, J. V. Uri, and J. A. Weisbach,
J. Antibiot., 28, 463 (1975).
[12] F. Russo, G. Romeo, S. Guccione, et al., Pharmazie, 45, 242 (1990).
[13] M. F. Abdel-Megeed, M. A. Saleh, Y. L. Aly, and I. M. Abdo, Nucleos. & Nucleot., 14,
1985 (1995).
[14] A. Santagati, J. Longmore, S. Guccione, et al., Eur. J. Med. Chem., 32, 937 (1997).

426
M. A. Saleh et al.
[15] M. A. Saleh, Sulfur Lett., 23(6), 265 (2000).
[16] M. A. Saleh, Sulfur Lett., 25(6), 235 (2002)
[17] J. Fischer Petriodou and E. P. Papdopoulos, J. Heterocycl. Chem., 19, 123 (1982).
[18] U. S. P. XXII, United States Pharmacopeial Convention, Inc., Rockville, MD 20852,
1493 (1990).
[19] H. K. Gakhar, S. C. Gupta, and N. Kumar, Ind. J. Chem., 20B, 14 (1981).