Synthesis and antiviral evaluation of some new glycosylthioureas containing a quinazolinone nucleus

Article abstract of DOI:10.1081/NCN-120006534

A new synthesis of glycosylthioureas containing a quinazolinone nucleus is described utilizing per-O-acetylglycopyranosylisothiocyanates and several aminoquinazolinones as starting compounds. Structural proofs of these compounds are provided from elemental analyses, IR, ¹H and ¹³C NMR spectra and mass spectra. The biological activity of these compounds has been studied.

Full text of DOI:10.1081/NCN-120006534

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SYNTHESIS AND ANTIVIRAL EVALUATION OF SOME NEW
GLYCOSYLTHIOUREAS CONTAINING A QUINAZOLINONE
NUCLEUS
Mohamed A. Saleh a , Mohamed F. Adbel-Megged a , Mohamed A. Abdo a & Abdel-Basset M.
Shokr a
a Chemistry Department , Faculty of Science, Tanta University , Tanta, Egypt
Published online: 17 Aug 2006.
To cite this article: Mohamed A. Saleh , Mohamed F. Adbel-Megged , Mohamed A. Abdo & Abdel-Basset M. Shokr (2002)
SYNTHESIS AND ANTIVIRAL EVALUATION OF SOME NEW GLYCOSYLTHIOUREAS CONTAINING A QUINAZOLINONE NUCLEUS,
Nucleosides, Nucleotides and Nucleic Acids, 21:1, 93-106, DOI: 10.1081/NCN-120006534
To link to this article: http://dx.doi.org/10.1081/NCN-120006534
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NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS, 21(1), 93ꢀ106 (2002)
SYNTHESIS AND ANTIVIRAL EVALUATION
OF SOME NEW GLYCOSYLTHIOUREAS
CONTAINING A QUINAZOLINONE NUCLEUS
Mohamed A. Saleh,* Mohamed F. Abdel-Megged,
Mohamed A. Abdo, and Abdel-Basset M. Shokr
Chemistry Department, Faculty of Science,
Tanta University, Tanta, Egypt
ABSTRACT
A new synthesis of glycosylthioureas containing a quinazolinone nucleus
is described utilizing per-O-acetylglycopyranosylisothiocyanates and
several aminoquinazolinones as starting compounds. Structural proofs of
1
these compounds are provided from elemental analyses, IR, H and 13C
NMR spectra andmass spectra. The biological activity of these com-
pounds has been studied.
INTRODUCTION
Sugar isothiocyanates are versatile synthetic intermediates which
have been used as precursors of different sugar derivatives such as
glycosylthioureas1ꢀ3, glcosyl-aminoheterocycles,4ꢀ6 nucleosides7ꢀ9 andgly-
cosyl derivatives of b-cyclodextrines which have potential pharmacological
properties10ꢀ12. In addition several glcosyl-isothiocyanates are specific
enzyme inhibitors13,14. As a part of our program directed towards new,
simple andefficient procedures for synthesis of antimetabolites 15ꢀ21. We
report here synthesis of some new N-glycosyl- N0-(4-oxoquinazolinyl)
*Corresponding author.
93
Copyright # 2002 by Marcel Dekker, Inc.
www.dekker.com

94
SALEH ET AL.
thiourea derivatives and attempts to cause the ring closure of these com-
pounds with methyl cyanoacetate under acidic conditions.
RESULTS AND DISCUSSION
Treatment of 3-(4-aminophenyl)- 2-methyl- 4(3 H)- quinazolinone (1a)22
andits 6-bromo derivative 1b with 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl
isothiocyanate (2a),23 2,3,4,6-tetra-O-acetyl-b-D-galactopyranosyl iso-
24
thiocyanate (2b)
or 2,3,4-tri-O-acetyl-b-D-xylopyranosyl isothiocyanate
(2c)24 gave glycosyl thiourea derivatives 3aꢀd (Sch. 1), whose analytical and
spectroscopic data (see experimental) are in agreement with the proposed
structures. IR spectra of compounds 3aꢀd showedabsorptions at
3440ꢀ3433 (NH), 1753ꢀ1751 cmꢀ 1 (C¼O ester) andthe absence of the
characteristic isothiocyanate band(NCS) at 2100 ꢀ2000 cmꢀ1.
1
Proton assignments in H NMR spectra of compounds 3aꢀd, which
are listedin the experimental section, were made by 1H-1H homonuclear shift
correlated(COSY) 2D NMR, D O exchange anddouble resonance experi-
2
ments. The spin-spin coupling constant value (J ) are indicative of a pre-
ponderance of the C1 (D) conformation in solution. The chemical shifts
4
Scheme 1.

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
95
(5.78ꢀ5.88) of H-10 andthe large values (8.6 ꢀ9.3 Hz) of J1 ,2 for compounds
3aꢀd are in accordwith b-configuration. The 13C NMR spectrum of 3c
revealeda signal at d 83.1 corresponding to C-10 of the b-anomer anda signal
at d 182.2 corresponding to C¼S of the thiourea moiety. The 13C NMR data
listedin the experimental section were assignedon the basis of comparing the
data obtained for 3c and 3d with those reportedin the literature for
0
0
26
2-methyl-3-aryl-4(3 H)-quinazolinone25 andper-O-acetylglycopyranose.
The FAB mass spectrum of 3c showedits M þ 23 andM þ 1 peaks at m=z
743 (for Br81) andat m =z 721 (for Br81) andat m =z 741 (for Br79) andat m =z
719 (for Br79), respectively. In addition to the fragment ions corresponding to
the loss of thiourea moiety (Mþ ꢀ 388) andthe characteristic loss of AcOH
27
in poly-O-acetylatedsugars were observed
(see experimental). The base
peak appearedat m =z 105 (100%) andcorresponsd to relative stable
C7H7Nþ , yet revealedthe characteristic fragments depictedin Sch. 5.
The reaction of 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl isothio-
cyanate (2a) with 6-amino-2-methyl-4(3H)-quinazolinone (4),28 3-amino-2-
phenyl-4(3 H)-quinazolinone(5),29 3-amino-2,4(1H,3H)-quinazolinedione
(6)30or 2-(b-aminoethylthio)-3-phenyl-4(3 H)-quinazolinone (7),31 gave the
corresponding N0-substituted N-glucopyranosylthiourea derivatives 8ꢀ11,
respectively (Sch. 2).
The structures 8ꢀ11 were supportedby I R, 1H and 13C NMR andmass
spectral data (see experimental). In the IR spectra of 8ꢀ11, the absorption
bands at 3356ꢀ3276 cmꢀ 1 are characteristic for NH groups of thiourea
derivatives. The strong bands at 1687ꢀ1660 and1778 ꢀ1740 cmꢀ 1 are
Scheme 2.

96
SALEH ET AL.
attributedto the quinazolinone andester C ¼O stretching vibrations,
1
respectively. The H NMR spectra of 8ꢀ11 shows triplets for the anomeric
protons at d 5.65ꢀ5.76 which were converted to the doublets upon addition
0
0
of D2O. The doublets exhibit a large J1 ,2 (8.5ꢀ9.5 Hz), which is in the range
for antiperiplanar protons and indicates that the new glucosidic bond has the
4
b-configuration in a C1(D) conformation (see experimental). The chemical
shifts of the acetoxy protons in the glucosyl residue provided further ver-
4
ification of the favored C1(D) conformation and b-configuration of 8ꢀ11,
since these signals fell within the range expectedfor equatorial secondary
acetoxy groups32 (see experimental). The 13C NMR spectrum of 11 is char-
acterizedby a signal at d 82.4 corresponding to C-10 (anomeric carbon atom),
which is also in agreement with the b-configuration of glucosyl residue33. The
FAB mass spectrum of 11 (Sch. 6) showed(M þ þ 1) at m=z 687 and709
(Mþ þ Na). Fragmentation of the molecular ion gave peaks at 356, 297,
281and253 due to sequential expulsion of sugar moiety, NHCS, NH
and
2
C2H4 fragments. Peaks were observedat m =z 331, 271 and229 due to loss of
thiourea derivatives, HOAc and CH2CO (see experimental). The base peak
appears at m=z 433 (100%) andcorresponds to N-þ(2,3,4,6-tetra-O-acetyl-b-
D-glucopyranosyl)-N0-ethylthiourea (C17H25N2O9S ).
Deacetylation of 3c and 9 by Zemplen’s method34 in the presence of
a catalytic amount of sodium ethoxide in absolute ethanol gave compounds
12 and 13 (Sch. 3). IR spectra of 12 and 13 show absorption bands at
3380ꢀ3345 (NH,OH) and1665 ꢀ1687 cmꢀ 1 (C¼O of quinazolinone moiety)
andthe absence of ester carbonyls at 1753 and1749 cm ꢀ 1. Because 3c and 9
4
have the C1(D) conformation andthe b-configuration, deacetylated com-
pounds 12 and 13 were expected to exist with the same conformation and
configuration, which was verifiedby their 1H NMR spectra.
The 13C NMR spectrum of 12 is characterizedby a signal at d 87.1
corresponding to C-10of the b-anomer anda signal at d 182.0 corresponding
to C¼S of the thiourea.
Scheme 3.

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
97
Attempts to induce ring closure of glycosyl thiourea derivatives 3aꢀd
and 8ꢀ11 with methyl cyanoacetate to give compound 14, under either
thermal or acidic conditions were unsuccessful. Heating 9 with methyl cya-
noacetate in Ac2O under reflux gave N3-acetylamino-2-phenyl-4(3 H)-qui-
nazolinone (15) in 77% yieldand2,3,4,6-tetra-O-acetyl- b-D-glucopyranosyl
isothiocyanate (2a), as shown in Scheme 4.
The IR spectrum of compound 15 shows a characteristic bandat
3462 cmꢀ 1, corresponding to the stretching vibration of NH group, and
bands at 1716 and 1675 cmꢀ 1 which correspondto the stretching vibrations
1
for the acetyl andquinazolinone carbonyl groups, respectively. The H-NMR
spectrum of 15, shows a singlet peak at d 2.01 due to the N-acetyl group and
a singlet at d 10.45 due to the NH group, which is disappears upon addition
of D2O. The protons of the quinazolinone moiety appear as multiplets in the
d 8.35ꢀ7.63 region. Sugar isothiocyanate 2a was identified by comparing its
melting point with that of an authentic sample 22 andfrom the IR spectrum,
ꢀ 1
which shows a bandat 2101 cm
for the NCS group.
The compounds described in this manuscript showed no activity against
Human Immunodeficiency Virus (HIV). They were also devoid of any
activity against different types of tumor virus.
Scheme 4.

98
SALEH ET AL.
Scheme 5. Cleavage pathway of compound 3c.
EXPERIMENTAL
Melting points were determined on an electro- thermal melting MEL-
TEMP II apparatus and are reported uncorrected. IR spectra were recorded
on a UNICAM SP1200 spectrophotometer using pellet technique KBr discs.
Microanalyses were performedin Tanta University, Tanta, Egypt and

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
99
Scheme 6. Cleavage pathway of compound 11.
National Research Center (NRC) service of microanalysis, Cairo, Egypt. 1H
NMR and 13C NMR were recorded on a Bruker AC spectrometer operating
1
at 400 MHz for H NMR and100 MHz for 13C NMR measurement at
Department of Chemistry, Georgia State University, University Plaza,
Atlanta, USA. Chemical shifts are reportedin parts per million relatives to

100
SALEH ET AL.
tetramethylsilane. Low resolution mass spectra data were obtained with a
micromass spectrometer model 7070 at 70 ev and an inlet temperature 90ꢁC.
FAB (LSIMS) spectra were recorded on a VG- Autospec instrument at
University of Wales, Swansea, England. All analytical samples were homo-
geneous by thin layer chromatography, which was performedon EM silica
gel 60 F254 sheet (0.2 mm) with chloroform=acetone (5:2 V:V), benze-
ne=acetone (5:2 V:V) andisopropyl alcohol =benzene=ammonia solution
(10:5:2 V:V:V) as developing eluents A, B and C, respectively. The spots were
detected with UV lamp model UVGL-58. National Cancer Institute,
Bethesda, Maryland, U.S.A. did the biological evaluation studies. Anti- HIV
tests were determined according to the reported method literature.35
General Procedure for the Preparation of 3aꢀd
A mixture of D-glycosyl isothiocyanates 2aꢀc (0.005 mole) and3-(4-
aminophenyl)-2-methyl-4(3H )-quinazolinone (1a) or its bromo derivative 1b
(0.005 mole) in dry benzene (150 mL) was heated at reflux for 8ꢀ24 h. The
solvent was evaporated under diminished pressure. The residue was tritu-
ratedseveral times with chloroform to remove impurities andwas then
crystallizedfrom ethanol. The following compounds were preparedin this
manner.
N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-[4-(2-methyl-4-
oxoquinazolin-3-yl) phenyl]thiourea (3a)
After 16 h at reflux, 1.19 g (60%) of 3a was isolatedas fine, colorless
needles, m.p. 140-141ꢁC; IR(KBr): 3450ꢀ3440 (NH), 1752 (C¼O ester), 1654
(C¼O quinaz.), 122(C¼S), 1225 (C-O-C) and911 cm ꢀ 1 (glucopyranosyl); 1H
0
NMR (CDCl3): d 5.88 (t, 1H, H-10, J1 ,2 ¼ 9.0 Hz), 4.79 (t, 1H, H-2 ,
0
0
0
0
0
0
0
0
J2 ,3 ¼ 9.2 Hz), 5.33 (t, 1H, H-3 , J3 ,4 ¼ 9.2 Hz), 4.71(t, 1H, H-4 ), 4.18 (m,
1H, H-50), 4.27ꢀ3.86 (m, 2H, H-60,H-600), 1.97, 1.98, 2.02 and2.05 (4 s, each
0
3H, 4 Ac), 7.44 (d, 1H, exchangeable, NH, J1 ,NH ¼ 8.2 Hz), 8.65(br s., 1H,
N0H), 8.40(d, 1H, H-5 of quinaz.), 7.91 (t, 1H, H-6 of quinaz.), 7.67 (t, 1H,H-
7 of quinaz.), 7.87 (d, 1H, H-8 of quinaz.), 7.28-7.14 (m, 4H, Ph), and 2.11 (s,
3H, CH3).
Anal. Calcdfor C 30H32N4O10S: C, 56.25; H, 5.00; N, 8.75. Found: C,
56.61; H, 4.71; N, 9.01.
N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-[4-(6-bromo-2-methyl-4-
oxoquinazolin-3-yl) phenyl]thiourea (3b)
After 24 h at reflux, 2.53 g (70%) of 3b was isolatedas an amorphous
and hydroscopic solid, m.p. 158ꢀ160ꢁC; IR (KBr): 3445ꢀ3330 (NH), 1742

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
101
(C¼O ester), 1652 (C¼O quinaz.), and1228(C ¼S) cmꢀ 1. 1H NMR (CDCl3):
0
d 5.85 (t, 1H, H-10, J1 ,2 ¼ 8.7 Hz), 4.96 (t, 1H, H-2 , J2 ,3 ¼ 8.5 Hz), 5.34 (t,
0
0
0
0
0
1H, H-30, J3 ,4 ¼ 8.3 Hz), 4.90ꢀ3.82 (m, 4H, H-4 , H-5 , H-6 , H-6 ), 1,97,
0
0
00
0
0
0
1.98, 2.04 and2.06 (4s, each 3H, 4Ac), 8.23 (d, 1H, NH, J1 , NH ¼ 8.5 Hz),
9.20 (br s., 1H, N0H), 8.41 (s, 1H, H-5 of quinaz.), 8.21 (d, 1H, H-7 of qui-
naz.), 7.82(d, 1H, H-8 of quinaz.), 8.21-7.02 (m, 4H, Ph) and 2.13 (s, 3H,
CH3).
Anal Calcd. For C30H31N4BrO10S: C, 50.10; H, 4.30; N, 7.79. Found:
C, 49.98; H, 4.14; N, 7.52.
N-(2,3,4,6-Tetra-O-acetyl-b-D-galactopyranosyl)-N0-[4-(6-bromo-2-methy-4-
oxoquinazolin-3-yl) phenyl]thiourea (3c)
After 10 h at reflux, 2.35 g (65%) of 3c was isolatedas colorless crystals,
m.p. 128-130-130ꢁC; IR(KBr):3445-3350 (NH), 1753(C¼O ester), 1229
ꢀ 1
(C¼S), 1654(C¼O quinaz.), 1225(C-O-C) and912 cm
(galactopyranose).
1
H NMR(CDCl3): d 5.78 (t, 1H, H-10, J1 ,2 ¼ 8.6 Hz), 5.22 (t, 1H, H-20), 5.49
0
0
(t, 1H, H-30), 4.91(m, 1H, H-40), 4.24-3.99 (m, 3H, H-50, H-60,H-600), 2.04,
0
2.06, 2.07 and2.13(4s, each 3H, 4Ac), 7.92(d, 1H, NH, J1 ,NH ¼ 8.5 Hz),
8.95(br s., 1H, N0H), 8.56(s, 1H, H-5 of quinaz.), 8.15(d, 1H, H-7 of quinaz.),
7.85 (d, 1H, H-8, of quinaz.), 7.85-6.75(m, 4H, Ph) and 2.16(s, 3H, CH3). 13
C
NMR(CDCl3):d 83.1(b C-10), 72.7, 73.7, 68.8, 70.5 and61.7(C-2 0, C-30, C-40,
C-50andC-6 0 of sugar moiety),170.9, 170.8, 169.9 and169.7(4CO ester), 20.5,
20.6, 20.6 and20.7(4 CH ), 182.2 (C¼S), 166.4, 167.6, 121.6, 129.0, 127.3,
3
132.4, 122.1 and138.4 (C-2, C-4, C-5, C-6, C-7, C-8 andC-8a of quinaz.
moiety), 23.1(CH3 at position 2), 126.3(2C, C-2,6 of Ph), 127.8(2C, C-3,5 of
Ph), 132.2(C-1 of Ph) and137.5(C-4 of Ph). FAB Mass spectrum: m =z 743
(32.32, M þ Na, for Br81), 721(64.55, M þ 1, for Br81), 741 (31.51, M þ Na,
for Br79), 719 (55.28, M þ 1, for Br79 ), 705 (6.25, 720 - CH3) 703(6.32, 718 -
CH3), 688(10.65, 721-SH), 390( 8.68, thiourea moiety, C16H13Br81N4OSþ ),
388 (10.50, thiourea moiety, C16H13Br79N4OSþ ), 331(8.22, galactosyl moi-
ety), 271(2.53, 331-AcOH), 229(3.16, 271-CH2O), 211(3.79, 271-AcOH), 169
(72.78, 211-CH2O), 127 (17.72, 169-AcOH) and105 (100, C H7Nþ ).
7
Anal. Calcd. for C30H31BrN4O10S: C, 50.10; H, 4.30; N, 7.79. Found: C,
50.31; H, 4.50; N, 7.51.
N-(2,3,4-Tri-O-acetyl-b-D-xylopyranosyl)-N0-[4-(6-bromo-2-methyl-4-
oxoquinazolin-3-yl) phenyl]thiourea (3d)
After 8 h at reflux, 2.43 g (75%) of 3d was isolatedas an amorphous and
hydroscopic solid, m.p. 140-142ꢁC. IR (KBr): 3446-3ꢀ3510 (NH), 1752 (C¼O
1
(C-O-C). H NMR
ester), 1654 (C¼O quinaz.) 1228 (C¼S) and1223 cm
0
(CDCl3): d 5.84 (t, 1H, H-10, J1 ,2 ¼ 9.2 Hz), 5.35(t, 1H , H- 2 ), 5.64 (t, 1H,
0
0

102
SALEH ET AL.
H-30), 4.97-3.47 (m, 3H, H-40, H-50 andH-5 00), 8.20 (d, 1H, NH,
0
0
J1 ,NH ¼ 8.3 Hz), 9.05 (br s, 1H, N H), 8.42 (d, 1H, H-5 of quinaz.), 8.02 (d,
1H, H-7 of quinaz.) 7.89 (d, 1H, H-8 of quinaz.), 7.88ꢀ6.75 (m, 4H, ph) and
2.16(s, 3H, 3H). 13C NMR (CDCl3): d 84.9 (b C-10), 167.3, 169.7 and170.1(3
C¼O ester), 20.6, 20.7 and20.8 (each CH 3, 3 Ac), 72.5, 71.3, 69.3 and63.5(C-
20, C-30, C-40 andC-5 of xylosyl moiety, respectively), 143.9, 166.0, 121.9,
0
130.2, 128.9 138.9. 122.7 and141.9(C-2, C-4, C-4a, C-5, C-6, C-7, C-8 andC-
8a of quinaz. residue, respectively), 23.9 (CH3 at position 2), 126.3 (2C, C2,6
of Ph), 127.8 (2C, C3,5 of Ph), 132.2(C-1 of Ph) and137.5 (C-4 of Ph).
Anal. Calcdfor C 27H27 BrN4O8S: C, 50.07; H, 4.17; N, 8.65. Found: C,
50.06; H, 4.21; N, 8.31.
N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-[(2-methyl-3-phenyl-4-
oxoquinazolin-6-yl)]thiourea (8)
Compound 8 was obtainedsimilarly to compound 3b from 6-amino-2-
methyl-4(3H)-quinazolinone (4) (0.251 g, 0.001 mole) and 2a (0.390 g, 0.001
ꢁ
mole). Yield(0.38 g, 60%) , m.p. 135 C. IR(KBr): 3356 (NH), 1745 (C¼O
ꢀ 1
ester), 1660 (C¼O, quinaz.), 1229 (C¼S) and1224 cm
(C-O-C). 1H
NMR(CDCl3): 5.47 (t, 1H, H-10, J1 ,2 ¼ 9.5 Hz), 5.02 (t, 1H, H-2 ,
0
0
0
0
0
0
0
0
0
J2 ,3 ¼ 9.2 Hz), 5.29 (t, 1H, H-3 , J3 ,4 ¼ 9.2 Hz), 4.76 (t, 1H, H-4 ), 4.07 (m,
1H, H-50), 4.31 (q, 1H, H-60), 3.80 (m, 1H, H-600), 1.98, 2.00, 4.04 and20.06
0
(4s, each 3H, 4 Ac), 6.84 (d, 1H, NH, J1 , NH ¼ 8.5 Hz), 8.49 (br s, 1H, N H),
7.79 (s, 1H, H-5 of quinaz.), 7.69(d, 1H, H-7 of quinaz.), 7.54 (d, 1H, H-8 of
quinaz.), 7.23ꢀ7.50 (m, 5H of Ph) and2.22 (s, 3H, of CH at position 2).
3
Anal. Calcd. for C30H32N4O10S: C, 56.25; H, 5.00; N, 8.75. Found: C,
56.41; H, 4.78; N, 8.32.
N-(2, 3, 4, 6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-[(2-phenyl-4-
oxoquinazolin-3-yl)]thiourea (9)
Thiourea 9 was obtainedsimilarly to compound 3d from 3-amino-2-
phenyl-4(3H)-quinazolinone (5) (0.24 g, 0.001 mole) and 2a (0.39 g, 0.001
mole). Yield(0.28 g, 45%), m.p. 119 ꢀ120ꢁC. IR (KBr): 3297 (NH), 1749
(C¼O ester), 1608 (C¼O quinaz.), 1229 (C¼S) and1225 cm ꢀ 1 (C-O-C). 1H-
0
NMR (CDCl3): d 5.69 (t, 1H, H-10, J1 ,2 ¼ 8.5 Hz), 5.04 (t, 1H, H-2 ,
0
0
0
0
0
0
0
0
J2 ,3 ¼ 8.3 Hz), 5.23 (t, 1H, H-3 , J3 ,4 ¼ 9.0 Hz), 4.92 (t, 1H, H-4 ), 3.80ꢀ4.82
(m, 3H, H-50, H-60 andH-6 00), 1.97, 1.99, 2.04 and2.06 (4s, each CH 3, 4 Ac),
6.97(d, 1H, NH), 8.26(br s, 1H, N0H), 7.80 (d, 1H, H-5 of quinaz.), 7.75 (t,
1H, H-6 of quinaz.) and7.41 ꢀ7.53 (m, 7H, H-7, H-8 of quinaz andof Ph).
FAB Mass spetrum: m=z 649 (< 1, M^ þ Na), 627 (1.57, M þ 1), 331 (12.06,
glucosyl moiety, Sþ ), 296 ( 14.34, thiourea moiety, C15H12N4OSþ ), 271

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
103
(16.64, 331-AcOH), 229 (1.52, 271-CH2CO), 169 (99.52, 229-AcOH), 109
(61.79, 169-AcOH), 81 (8.53, 109-CO) and60 (62.02, AcOH).
Anal. Calcd. For C29H30N4O10S: C, 55.59; H, 4.79; N, 8.94. Found: C,
55.81; H, 4.38; N, 8.81.
N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-[2,4-dioxo-(1H,3H)-
quinazolin-3-yl]thiourea (10)
Compound 10 was obtainedsimilarly to compound 3b from 3-amino-
2,4(1H, 3H )quinazolinedione (6) (0.18 g, 0.001 mole) and 2a (0.39 g, 0.001
mole). Yield(0.28 g, 50%), m.p. 128 ꢀ130ꢁC; IR (KBr): 32769 (NH), 1778
ꢀ 1
1
(C¼O ester), 1676 (C¼O quinaz.), 1229 (C¼S) and1224 cm
(C-O-C). H
NMR (CDCl3): d 5.76 (t, 1H, H-10, J1 ,2 ¼ 9.0 Hz), 4.93 (t, 1H, H-2 ), 5.15 (t,
0
0
0
1H, H-30, J3 ,4 ¼ 9.0 Hz), 3.24ꢀ4.21 (m, 4H, H-4 , H-5 , H-6 andH-6 ), 1.87,
0
0
0
00
0
0
1,89, 1.94 and1.96 (4s, 3H, each 3H, 4 Ac), 11.15(br s, 1H , CONH), 6.41 (d,
0
0
1H, NH, J1 ,NH ¼ 8.3 Hz),9.75 (br s., 1H, N H), 8.32 (d, 1H, H-5 of quinaz.),
7.89 (t, 1H, H-6 of quinaz.), 7.45(t, 1H, H-7 of quinaz.) and7.24(d, 1H, H-8
of quinaz.).
Anal. Calcd. for C23H26N4O11S: C, 48.76; H, 4.59; N, 9.89. Found: C,
48.36; H, 4.71; N, 9.61.
N-(2,3,4,6-Tetra-O-acetyl-b-D-glucopyranosyl)-N0-2-[b-(3-phenyl-4-
oxoquinazolin-2-yl)thioethyl]thiourea (11)
A mixture of 2a (0.39 g, 0.001 mole) and2-( b-aminoethyl)-3-phenyl-
4(3H)quinazolinone (7) (0.297 g, 0.001 mole) in dry xylene (100 mL) was
heatedon a water bath (at 60 ꢀ70ꢁC) for 8 h andallowedto standat room
temperature for 2 h. After collection of the separatedcrystals by filtration, the
product was crystallized from benzene. Yield (0.52 g, 75%), m.p. 140ꢀ141ꢁC.
IR (KBr): 3354 (NH), 1752 (C¼O, ester), 1687 (C¼O of quinaz.), 1228
(C¼S), 1223(C-O-C) and2927 (CH 2) cmꢀ 1. 1H NMR (DMSO-d6): d 5.65 (t,
0
0
1H, H-10, J1 ,2 ¼ 9.2 Hz), 5.05 (t, 1H, H-2 ), 5.21(t, 1H, H-3 ), 3.82ꢀ4.80(m,
0
0
4H, H-40, H-50, H-60 andH-6 ) 2.00, 2,04, 2.06 and20.07(4s, each 3H, 4 Ac),
00
0
6.49(d, 1H, NH, J1 ,NH ¼ 8.7 Hz), 7.29 (br s., 1H, N H), 8.33 (d, 1H, H-5 of
quinaz.), 7.73(t, 1H, H-6 of quinaz.), 7.56(t, 1H, H-7 of quinaz.), 7.31-
7.41(m, 6 H, H-8 andof Ph), 4.17(q, 2H, N-CH ) and3.25(q, 2H, -SCH ).
2
2
13C NMR (DMSO-d6): d 82.4(b C-10), 170.8, 169.8, 167.5 and165.8 (4 C ¼O),
20.5, 20.6, 20,6 and20.8 (4 CH 3), 183.5 (C¼S), 70.7, 72.8, 68.3, 72.3 and61.8
(C-20, C-30, C-40, C-50 andC-6 0 of glucosyl residue, respectively), 157.5, 161.8,
119.8, 129.7, 130.1, 135.2, 126.1 and147.4 (C-2, C-4, C-4a, C-5, C-6, C-7, C-8
andC-8a of quinaz., respectively), 129.8 (2C, C-2,6 of Ph), 126.4(2C,C-3,5 of
Ph), 128.9 (C-4 of Ph), 135.2(C-1 of ph), 31.1 (-SCH2) and40.6 (-NHCH ).
2
FAB mass spectrum: m/z 709 (7.59, M þ Na), 687 (83.54, M þ 1), 655

104
SALEH ET AL.
(11.39, 687-S), 433 (100, C17H25N2O9Sþ ), 356 (2.53, thiourea moiety,
C17H16N4OS2 þ ), 340 (33.54, 356-NH2), 297 (8.86, 356-NHCS), 281 (29.74,
297-NH2), 253 (18.35, 281 - C2H4), 221 (20.25, 253 -S ), 145 (14.55, 221-Ph),
331 (7.59, glucosyl moiety), 271 (3.79, 331-AcOH), 229 (4.43, 271-CH2CO),
169 (62.02, 229-AcOH), 109 (72.15, 169-AcOH), 187 (4.40, 229-CH2CO), 127
(29.74, 187-AcOH) and60 (45.80, AcOH).
Anal. Calcdfor C 31H34N4O10S2: C, 54.23; H, 4.96; N, 8.16. Found: C,
54.31; H, 5.32;N, 8.51
N-(b-D-Galactopyranosyl)-N0-[4-(6-bromo-2-methyl-4-oxoquinazolin-3-yl)
phenyl] thiourea(12)
To a suspension of 3c (1.14 g, 0.002 mole) in absolute methanol (25 mL),
0.6 mL of 1 M sodium methoxide was added, and the reaction mixture stirred
over night. The clear solution was neutralizedwith Dowex 50 (H þ ) filtered,
concentrated to dryness, and freeze-dried. The solid foam obtained was
crystallized from ethanol to give 0.44 g (40%Yield) of deacetylated product
12, m.p. 172ꢀ173ꢁC. IR (KBr): 3300ꢀ3060 (NH, OH), 1665 (C¼O quinaz.)
and1226 (C ¼S) cmꢀ 1
.
1H NMR (DMSO-d6): d 5.25 (t, 1H, H-10,
0
0
J1 ,2 ¼ 8.3 Hz), 3.30ꢀ5.22 (m, 6H, galactosyl protons), 10.56 (d, 1H, NH),
11.81(br s, 1H, N0H), 8.52 (d, 1H, H-5 of quinaz.), 7.25ꢀ8.21 (m, 6H, H-7, H-
8 of quinaz. andPh) and2.18 (s, 3H, CH 3). 13C NMR( DMSO-d6): d 84.1(b
C-10), 72.6, 77.5, 69.8, 78.1 and60.8 (C-2 , C-30, C-40, C-50 andC-6 ,
respectively), 182.0 (C¼S), 145.5, 167.4, 128.9, 120,9, 134.1,122.9, 128.9 and
135.49 (C-2, C-4, C-4a, C-5, C-6, C-7, C-8 andC-8a of quinaz., respectively),
134.5 (C-1, of Ph), 126.9 (C-2,6 of Ph), 129.8 (C-3 of Ph), 139.1(C-4 of Ph)
0
0
and22.8 (CH ).
3
Anal. Calcd. for C22H23BrN4O6S: C, 47.91; H, 4.17; N, 10.16. Found:
C, 47.61; H, 4.31; N, 10.61.
N-(b-D-Glucopyranosyl)-N0-[3-(2-phenyl-4-oxoquinazolin-3-yl)] thiourea (13)
Compound 13 was obtainedsimilarly to compound 12 from compound
10 (1.25 g, 0.002 mole) and sodium methoxide in methanol to give 0.48 g
(52% yield) of compound 13, m.p. 119ꢀ120ꢁC. IR(KBr): 3061ꢀ3268
(NH,OH), 1687 (C¼O quinaz.) and1228 (C ¼S) cmꢀ 1. 1H HNMR (DMSO-
d6): d 5.46 (t,1H, H-10, J1 ,2 ¼ 7.5 Hz), 3.18ꢀ5.15 (m, 6H, glucosyl protons),
6.77 (d, 1H, NH), 9.23 (brs, 1H, N0H) and7.47 ꢀ8.30 (m, 9 H, quinaz. andPh
protons).
0
0
Anal.Calcd. for C21H22N4O6S: C, 55.02; H, 4.80; N, 12.22. Found: C,
55.12; H, 4.79; N, 12.02.

GLYCOSYLTHIOUREAS WITH QUINAZOLINONE NUCLEUS
105
Attempted Ring of Closure of Compound 9
A mixture of compound 9 (0.63 g, 0.001 mole) andmethyl cyanoacetate
(0.099 g, 0.001 mole) in acetic anhydride (10 mL) was heated at reflux for 3 h
andpouredonto ice water (100 mL). The reaction mixture was extractedwith
chloroform (50 mL). The organic layer was washedwith saturatedsolution of
sodium bicarbonate and dried over anhydrous MgSO4. Removal of the
solvent by evaporation left a brown residue. Ether was added to the residue
andthe separatedcrystals were collectedby filtration. They were identified
with starting material 2a. The filtrate was concentrated under reduced
3
pressure to give 0.11 g (77%) yieldof N -acetylamino-2-phenyl-4(3H )-qui-
nazolinone 15, m.p. 112ꢀ113ꢁC (lit.36 m.p 112ꢀ113ꢁC).
ACKNOWLEDGMENT
Our thanks are due to Dr. John P. Bader at Department of Health and
Human Services, National Institute of Health (USA) for performing anti-
cancer andanti-HIV activities.
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ReceivedDecember 30, 2000
AcceptedDecember 7, 2001