Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.09.071

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4′,3′:-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4′,3′:1,2]- pyrimidoquinoline (5a,b, 10), imidazolo[3′,2′:1,2]pyrimido[4,5-b]- quinoline

Full text of DOI:10.1016/j.ejmech.2010.09.071

European Journal of Medicinal Chemistry 46 (2011) 21e30
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel
pyrimidoquinolines and its nucleoside derivatives
,
a
b
Hebat-Allah S. Abbas a , Hend N. Hafez , Abdel-Rahman B.A. El-Gazzar
*
a Photochemistry Department, National Research Centre, 12622 Dokki, Cairo, Egypt
b Al-Imam Muhammad Ibn Saud, Islamic University, Faculty of Science, Department of Chemistry, P.O. Box 90950, Riyadh 11623, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[40,30:-1,2]pyrimido[4,5-b]
quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[40,30:1,2]-pyrimidoquinoline (5a,b, 10),
imidazolo[30,20:1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline
(12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel
pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new
quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the
National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD50 values
in the low micromolar to nanomolar concentration range.
Article history:
Received 22 January 2010
Received in revised form
18 August 2010
Accepted 30 September 2010
Available online 8 October 2010
Keywords:
Pyrimidoquinoline
Tetrazolo-
Ó 2010 Elsevier Masson SAS. All rights reserved.
Triazolopyrimidoquinoline and its
N-nucleoside
Antimicrobial and antitumor activities
1. Introduction
be readily converted into a variety of other functionalities. On the
other hand, it was reported that dihydropyridine glycosides were
Quinolines and their derivatives are under constant investiga-
tion of the medicinal chemists in view of their profound range of
biological activities, antimalarial [1], antibacterial [2], anti-
asthmatic [3], antihypertensive [4] anti-inflammatory [5]. The
quinoline structural moiety is present in most of the antibacterials
introduced in the recent past namely, nalidixic acid [6], norfloxacin
[7], ciprofloxacene [8], ofloxacin [9]. Also imiquimed, clioquinol,
and enoxacin are antiviral, antifungal and antibacterial drugs which
contain pyrimidine and quinolines rings. Moreover, pyr-
imidoquinoline is present in a number of biologically active organic
compounds [10e14] which exhibit, antibacterial [15], anticancer
[16], medicinal [17,18], and anti-inflammatory activity.
N-Glycosides have received considerable attention, because
they are widely employed as biological inhibitors [19e23], inducers
[24] and ligands [25e27] for affinity chromatography of carbohy-
drate-processing enzymes and proteins. Moreover, they are
promising candidates in synthetic carbohydrate chemistry as
convenient and versatile glycosyl donors [28]. Among these
glycosyl donors are the N-glycosyl heterocycles that are sufficiently
stable under a variety of reaction conditions and have the ability to
used as P-glycoprotein (Pgp) substrates or inhibitors in the protein
glycosylation process [29]. Moreover, the increasing biological
importance of pyrimidoquinoline derivatives, particularly in the
field of chemotherapy, prompted us to develop and identify the
new molecules, such as tetrazolo[40,30:1,2]pyrimido[4,5-b]quino-
line, triazolo[40,30:1,2]pyrimido[4,5-b]quinoline, imidazolo[30,20:
1,2]pyrimido[4,5-b]-quinoline, and its N-glycosides derived from
pyrimido[4,5-b]quinoline-4,6-dione in order to investigate the
effect of such structural modification on the antimicrobial and
antitumor activities.
2. Results and discussion
2.1. Chemistry
As part of our programme of research on the synthesis of pyr-
idoquinolines and biological activity of these types of compounds,
we became interested in the synthesis of the corresponding glyco-
sides analogues [30e33] in order to study their antimicrobial
and antitumor activities. Thus, 5-aryl-8,8-dimethyl-2-methylthio-
5,8,9,10-tetrahydropyrimido[4,5-b]-quinoline-4,6-dione(1aec)were
prepared in good yield via the oneepot reaction of 6-amino-2-
methylthiopyrimidin-4-one with 5,5-dimethyl-cyclohexane-1,3-
dione and aryl-carboxal-dehydes [34]. Compounds (1aec) treated
* Corresponding author. Fax: þ20 2 33 370931.
E-mail address: hebanrc@yahoo.com (H.-A.S. Abbas).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.09.071

22
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
O
O
O
O
N
with hydrazine hydrate (99%) (Scheme 1), afforded 5-aryl-8,8-dim-
ethyl-2-hydrazino-5,8,9,10-tetrahdropyeimido[4,5-b]quinoline-4,6-
dione (2aec). Compound 2c could be used as a starting material for
the synthesis of new polynuclear heterocycles such as tetrazolopyr-
imido[4,5-b]quinoline. Thus treatment of 2c with nitrous acid led to
theformationof 5,8,9,10-tetrahydrotetrazolo-[40,30:1,2]pyrimido[4,5-
b]quinoline-4,6-dione derivative (3) (Scheme 1), which is the
tautomer of 2-azido-pyrimido[4,5-b]quinoline. The IR spectrum of 3
displayed absorption bands at 3254 (NH’s) and 1715,1683 cmꢀ1 (2C]
O) and characteristic absorption band for the azido group [35] at
Ar
Ar
H
H
H
CH3
MeI
N
N
N
H
N
SCH3
N
H
SCH3
11
1c
POCl3
POCl3
2318 cmꢀ1
.
Cl
O
Cl
O
Ar
Ar
H
H
According to the literature aminopyrimidines have biological
activities as anticancer, antibacterial, and antimalarial [36]. There-
fore, compound 3 was reduced into 2-amino-pyrimido[4,5-b]
quinoline 4 by zinc dust. Heating the hydrazine derivative 2c with
aliphatic acids, namely formic or acetic acid, resulted in the
formation of triazolo[40,30:1,2]pyrimido-[4,5-b]quinoline 5a,b
H
CH3
MeI
N
N
N
H
N
SCH3
N
H
N
SCH3
12
13
1c, 11, 12, 13, Ar= 4-NO2C6H4
Scheme 2.
O
O
N
Ar
H
H
N
Zn dust
acetic acid
N
H
NH2
4
O
N
O
Ar
Ar
H
H
H
N
N
N
NaNO2
O
O
N
Ar
H
N
H
N
N
H
N
H
N
N3
H
N
3
N
H
SCH3
O
O
Ar
H
R
1a-c
a, Ar= C6H5
N
b, Ar= 4-ClC6H4
c, Ar= 4-NO2C6H4
N
N
H
N
N
H
5
NH2.NH2
5a, R=H; b, R= CH3
Ar
O
N
O
O
O
Ar
H
O
H
O
O
O
N
Ar
H
O
O
O
O
O
O
HN
NH
H
6
N
N
N N
H
N
H
N
N
N
H
H
N
H
NHNH2
O
O
7
2a-c
O
O
N
a, Ar= C6H5
b, Ar= 4-ClC6H4
c, Ar= 4-NO2C6H4
Ar
H
N
N
H
N
R
NH2
8
8a, R=CH3;b, R=C6H5
O
O
Ar
H
H
N
ArCHO
N
H
N
H
N
N
H
Ar`
9a, Ar`= C6H5,
b, Ar`= 4-ClC6H4
9a-c
Cl
c, Ar`= 4-OCH3C6H4
O
O
Ar
H
Ac2O/ pyridine
N
N
N
H
N
N
H
3, 4, 5, 7, 8, 9, 10 Ar= 4-NO2C6H4
10
Scheme 1.

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
Ar
23
O
S
H
O
Ar
S
AcO
H
O
OAc
Br
NH
NH
AcO
14
N
N
SCH3
N
N
SCH3
AcO
O
O
AcO
OH
1
2
AcO
R
OH
16
R
HO
19a,b
NH3/MeOH
Ar = 4-NO2-C6H4
NH3/MeOH
1c
O
Ar
N
S
H
O
Ar
S
H
NH
NH
N
SCH3
N
N
SCH3
AcO
O
AcO
O
AcO
O
1
AcO
R
Br
2
AcO
R
1
2
AcO
R
AcO
AcO
18
R
15a,b
AcO
17a,b
15a, 17a, R1 = H, R2 = OAc 19a, R1 = H, R2 = OH
15b, 17b, R1 = OAc, R2 = H 19b, R1 = OH, R2 = H
Scheme 3.
(Scheme 1). 1H NMR spectrum of 5b, as an example, shows three
signals at 0.90, 1.01, 1.12 for (3CH3) and disappearance of signals at
12.0 (3NH).
Cyclocondensation of compound 2c with acid anhydride (6)
affordedthecorresponding 2,6-bis{8,8-dimethyl-5-(4-nitrophenyl)-
3,4,5,6,7,8,9,10-octahydrpyrimido[4,5-b]quinoline-2-yl-amino-4,6-
dione}pyrrolo[3,4-f]isoindole-1,3,5,7-tetraone (7). In addition, the
reaction of 2c with -haloketones namely, chloroacetone or phe-
nacyl bromide in dry xylene, yielded the respective imidazolo
[30,20:1,2]pyrimido[4,5-b]quinoline 8a,b as shown in (Scheme 1). IR
spectrum of 8a displayed absorption bands around 3318, 1715,
1687 cmꢀ1 correspondingto(NH’s)and(2C]O)groups, respectively.
d
a
d
Table 1
Inhibition zone in mm as a criterion of antibacterial and antifungal activities of the newly synthesized compounds.
Compds.
Microorganism inhibition zone diameter (mm)
Gramþve bacteria
Gramꢀve bacteria
Fungi
Bacillus subtilis
Streptococcus lactis
Escherichia coli
Pseudomonas aeuroginosa
Candida albicans
Candida gabrata
1c
2c
3
4
5a
5b
7
8a
8b
9a
9b
9c
10
11
12
13
13
15
23
25
20
18
22
19
20
17
16
15
18
15
14
14
19
20
20
20
21
21
e
14
15
18
20
20
21
25
22
20
18
17
16
15
13
13
14
20
20
19
18
19
20
e
13
15
20
27
19
18
23
24
23
17
18
17
18
15
15
15
21
23
25
24
23
22
e
14
15
19
23
18
22
22
23
23
16
17
16
17
14
14
13
23
22
23
23
23
22
e
7
9
12
9
8
8
10
9
9
9
11
13
9
8
7
7
7
9
8
10
8
8
8
7
7
8
8
20
e
11
12
10
6
6
6
8
7
6
9
6
9
8
8
8
9
7
20
e
16
17a
17b
18
19a
19b
Nystatin
Nalidixic acid
25
25
25
25
Inhibition zone, 6e10 mm slight activity, 11e15 mm moderate activity, more than 15 mm high activity.

24
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
Table 2
MIC in mg/ml of the newly synthesized compounds.
Compds.
Gramþve bacteria
Gramꢀve bacteria
Fungi
Bacillus subtilis
Streptococcus lactis
Escherichia coli
Pseudomonas aeuroginosa
Candida albicans
Candida gabrata
3
4
30
20
40
30
30
30
30
20
20
20
30
30
30
30
30
30
30
30
20
40
30
30
30
30
20
20
20
30
30
30
30
30
30
30
30
20
40
30
30
30
30
20
20
20
30
30
30
30
30
30
30
30
20
40
30
30
30
30
20
20
20
30
30
30
30
30
30
30
40
40
40
40
40
50
50
40
40
40
30
30
30
30
30
30
30
40
40
40
40
40
50
50
40
40
40
30
30
30
30
30
30
30
5a
5b
7
8a
8b
9a
9b
9c
10
16
17a
17b
18
19a
19b
Also, 1H NMR spectrum of 8a, showed signals at
d
0.89 (s, 3H, CH3),
phosphorus oxychloride. Beside the correct values in elemental
analyses and spectral data (cf. Exp.), the structure of compound 12
was established chemically upon treatment of 1c with POCl3 to give
the corresponding 6-chloro derivative 13 which was alkylated with
methyl iodide in the presence of sodium ethoxide to give 12 as
shown in (Scheme 2).
1.09 (s, 3H, CH3),1.95 (m, 4H, 2CH2), 2.08 (s, 3H, CH3), 5.03 (s,1H, C5-
H), 7.46 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.97 (d, J ¼ 8.1 Hz, 2H, Ar-H), 8.16 (s,
1H, imidazole proton), 9.12, 9.84 (2br, 3H, NH, NH2, D2O
exchangeable).
According to El-Gazzar et al. [37] 2-hydrazino derivative 2c gave
the 2-(aryl-methylenehydrazone)pyrimido[4,5-b]quinoline deriv-
atives 9aec (Scheme 1) when treated with the appropriate alde-
hyde. Compounds 9aec gave compatible spectral and analytical
data (cf. Exp.). The arylhydrazone 9b could be cyclized into the
corresponding 1,2,4-triazolopyrimido[4,5-b]quinoline 10, when
reflexed in a mixture of acetic anhydride/pyridine (2:1). The
alkylation of 1c was carried out by treatment with one equivalent of
methyl iodide in the presence of sodium ethoxide to give 3,8,8-
trimethyl-2-methylthio-5-(4-nitrophenyl)-5,8,9,10-tetrahydropyr-
imido[4,5-b]quinoline-4,6-dione (11) (Scheme 2). The structure
was confirmed by spectroscopic data. 1H NMR spectrum of 11,
However the glycosylation of 1c with 2,3,5-tri-O-acetyl-
b-D-
arabinopyranosyl bromide 14 or 2,3,4,6-tetra-O-acetyl- -glycosyl
a-D
bromide 15a,b in acetone and in the presence of aqueous potassium
hydroxide afforded the corresponding acetylated nucleosides 16,
17a,b respectively in good yields (57e64%) (Scheme 3). Thin layer
chromatography (chloroform: methanol, 8:2) indicated the
formation of the pure compounds. The structures of 16, 17a,b were
confirmed by elemental analysis and spectral data (IR, 1H NMR, 13
C
NMR) (cf. Exp.). The 1H NMR spectrum of compound 17a as an
example, showed the anomeric proton of the glucose moiety as
0
0
a doublet at
indicating
protons of the glucopyranose ring resonated at
d
6.08 ppm with a coupling constant J1 e2 ¼ 10.9 Hz
-configuration of the anomeric center. The other
3.71e5.34 ppm,
showed signals at
d
0.93 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.04
b
(d, J ¼ 17.1 Hz, 2H, CH2), 2.15 (d, J ¼ 17.1 Hz, 2H, CH2), 2.56 (s, 3H,
SCH3), 3.26 (s, 3H, NCH3), 5.00 (s, 1H, C5-H), 7.45 (d, J ¼ 7.9 Hz, 2H,
Ar-H), 8.05 (d, J ¼ 8.0 Hz, 2H, Ar-H), 9.92 (br, 1H, NH, D2O
exchangeable). Compound 11 was converted into the correspond-
ing 6-chloro-pyrimido[4,5-b]quinoline-4,6-dione 12 by refluxing in
d
while the four acetoxy groups appeared as four singlets at
d
2.02e2.15 ppm. The 13C NMR revealed the signals at
169.35e170.45, 194.36 ppm due to the presence of (6CO), signals
d
at d
61.98, 68.67, 70.32, 71.03, 71.18, 71.52 ppm are assigned to C-60,
Table 3
Effect of treatment with different compounds on the survival of ascites tumor harboring mice inoculated with (HEPG2) or (HELA) cells line.
Conc. of Compds. (
m
g/kg b. w.)
Survival time
(days) HEPG2
% increase in life span
of animals HEPG2
Survival time
(days) HELA
% increase in life span
of animals HELA
Control
22.00 ꢁ 1.90
45.00 ꢁ 4.20a
28.00 ꢁ 2.30a
29.00 ꢁ 2.50a
35.00 ꢁ 1.90a
31.00 ꢁ 2.70a
38.00 ꢁ 2.50a
37.00 ꢁ 2.20a
37.00 ꢁ 2.70a
36.00 ꢁ 2.50a
34.00 ꢁ 2.50a
33.00 ꢁ 2.30a
33.00 ꢁ 1.90a
35.00 ꢁ 2.70a
36.00 ꢁ 1.90a
37.00 ꢁ 2.30a
38.00 ꢁ 2.50a
0
84
31
29
49
55
58
56
53
51
50
48
47
62
66
60
60
22.00 ꢁ 1.90
45.00 ꢁ 4.20a
29.00 ꢁ 2.50a
27.00 ꢁ 1.90a
31.00 ꢁ 2.70a
30.00 ꢁ 2.20a
29.00 ꢁ 2.20a
34.00 ꢁ 2.50a
32.00 ꢁ 2.70a
34.00 ꢁ 2.50a
28.00 ꢁ 2.30a
31.00 ꢁ 1.90a
30.00 ꢁ 2.70a
36.00 ꢁ 1.90a
37.00 ꢁ 2.80a
38.00 ꢁ 2.50a
36.00 ꢁ 2.70a
0
83
38
35
50
51
53
51
50
57
48
45
47
66
61
66
61
Cisplatine (2 mg/kg b. w.)
2c (10 g/kg b. w.)
m
3 (10
4 (10
m
m
g/kg b. w.)
g/kg b. w.)
5a (10
m
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
g/kg b. w.)
7 (10
m
8a (10
9b (10
10 (10
11 (10
m
m
m
m
g/kg b. w.)
g/kg b. w.)
12(10
13 (10
16 (10
mg/kg b. w.)
m
m
g/kg b. w.)
g/kg b. w.)
17a (10
m
g/kg b. w.)
g/kg b. w.)
mg/kg b. w.)
18 (10
m
19a (10
Values are mean ꢁ SE.; n ¼ 10 mice; aP < 0.05 significant with respect to control.

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
25
Table 4
group. Compounds 3, 7, 8a, 8b and 16e19 exhibited good activity
towards Gram-negative and Gram-positive bacteria, but
compounds 1c, 2c, 5a, 5b and 9e13 exhibited moderate activity
towards Gram-negative and Gram-positive bacteria, while most of
the newly synthesized compounds exhibited moderate activity
against fungi as compared with the reference drug (Nystatin).
The MIC (minimum inhibitory concentration) of the most active
compounds toward the microorganism showed that the MICs
In vivo acute toxicity of prepared compounds LD50 mg/kg b.w.
Compounds
LD50
m
g/kg b.w. (HEPG2)
LD50 mg/kg b.w. (HELA)
2c
3
4
5a
7
8a
9b
10
11
12
13
16
17a
18
19a
89
90
95
100
99
93
96
95
98
100
101
104
109
110
115
100
90
90
98
99
90
90
89
111
103
110
114
111
116
119
ranged between 20 and 30
mg/disk. The activity is tested at
concentration of 50 g/disk. The minimum inhibitory concentra-
m
tions (MIC) for compounds with high activity are presented in
(Table 2) were in accordance with the results obtained in the
primary screening.
2.2.2. Antitumor activity
The synthesized compounds were tested and evaluated for
inhibition using human liver carcinoma cell line (HEPG2) and
Human cervix carcinoma cell line (HELA) Table 3. The administra-
tion of prepared compounds significantly increases (P < 0.05) the
life span of the animals as compared with control group [animals
injected with Human liver carcinoma cell line (HEPG2) or Human
cervix carcinoma cell line (HELA) alone]. There is a gradual increase
in life span using the prepared compounds. The increase in life span
was around 29%e66%. The standard reference drug (Cisplatine
2 mg/kg body weight) exhibited 84% (P < 0.05) increase in life span
of the animals. All the animals in the HEPG2 or HELA injected alone
group were dead after 25 or 30 days respectively.
The results of measurements of effect of treatment with tested
compounds on the survival of ascites tumor harboring mice inoc-
ulated with (HEPG2) cells line (Table 3) revealed that compound
17a was the most active exhibiting 66% increase in life span fol-
lowed by compounds 16, 18 and 19a (62e60%). Compounds 7, 8a,
9b, 10 and 11 (50e58%) showed moderate activity against the same
tumor cell lines. While the results with (HELA) cells line (Table 3)
showed that compounds 16 and 18 showed the highest activity
with an increase in life span 66% followed by compounds 17a and
19a (61%). Compounds 10, 7, 5a, 8a, 4 and 9b showed moderate
activity with increase in life span 50e57%.
C-40, C-20, C-30, C-50 and C-10 respectively. Also, the four signals at
20.81e20.99 ppm are assigned to the acetate methyl carbon
atoms.
Deacetylation of acetylated nucleosides 16, 17a,b using satu-
rated solution of ammonia in methanol at room temperature
afforded the corresponding deacetylated nucleosides 18, 19a,b
respectively. The structures of free nucleosides 18 and 19a,b have
been established on the basis of their spectral data and elemental
analyses. Thus, the 1H NMR spectrum of 19a showed the anomeric
d
0
0
proton as a doublet at
configuration. The signals of the other six glucose protons appeared
at 3.25e4.21 ppm, while the signals that disappear on rapid
d
6.10 ppm. J1 e2 ¼ 10.8 Hz indicating a
b-D-
d
exchange with D2O are observed at
as the four hydroxyl groups.
d 4.60e5.13 ppm, were assigned
2.2. Pharmacological screening
2.2.1. Antimicrobial activity
In vitro antimicrobial activity: In vitro antimicrobial screening of
the new synthesized bases and glycoside compound was evaluated
against two Gram-positive bacteria (Bacillus subtilis and Strepto-
coccus lactis), two Gram-negative bacteria (Escherichia coli and
Pseudomonas aeuroginosa) and two fungal strains (Candida albicans
and Candida gabrata). Activities of the tested compound (Table 1)
were evaluated by agar diffusion method. Compound 4 exhibited
excellent activity toward Gram-positive bacteria, while exhibited
highly activity toward Gram-negative bacteria as compared with
the reference drug (Nalidixic Acid) due to the presence of amino
On the other hand, the results of In vivo acute toxicity
measurements of synthesized compound with respect to ascites
tumor harboring mice inoculated with (HEPG2) cells (Table 4)
revealed that compound 19a exhibiting the highest LD50 with
115
(LD50 100e110
For the ascites tumor harboring mice inoculated with (HELA) cells,
mg/kg b.w. followed by compounds 18, 17a, 16, 13, 5a and 12
m
g/kg b.w.) among the tested series of compounds.
compound 19a also showed the highest LD50 with 119 mg/kg b.w.
140
120
100
80
LD50 (HEPG2)
LD50 (HELA )
60
40
20
0
2c
3
4
5a
7
8a
9b
10
11
12
13
16
17a
18
19a
Compounds
Fig. 1. Acute toxicity of synthesized compounds (LD50 mg/kg b.w.).

26
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
followed by compounds 18, 16, 17a, 11 and 13 with acute toxicities
(LD50 110e116 mg/kg b.w.) Fig. 1.
4.1.1.3. 2-Hydrazino-8,8-dimethyl-5-(4-nitrophenyl)-5,8,9,10-terahy-
dropyrimido[4,5-b] quinoline-4,6-dione (2c). t was obtained from 1c
(4.12 g, 0.01 mol), as a yellow powder, crystallized from DMF in
a 90% yield, mp 322e323 ꢂC; IR (cmꢀ1
,
y
): 3288 (br, NH’s), 1710,
3. Conclusion
1687 (2C]O); 1H NMR (DMSO-d6) (
d
, ppm) 0.88 (s, 3H, CH3), 1.06
d
(s, 3H, CH3), 2.01 (d, J ¼ 17.2 Hz, 2H, CH2), 2.22 (d, J ¼ 17.1 Hz, 2H,
CH2), 4.93 (s, 1H, C5-H), 7.47 (d, J ¼ 8.3 Hz, 2H, Ar-H), 8.09 (d,
J ¼ 8.2 Hz, 2H, Ar-H), 8.17, 9.92, 12.0 (3br, 5H, 3NH, NH2, D2O
The overall results indicated that, the tested compounds showed
promising antimicrobial activity against bacteria and Fungi. Among
the tested compounds, for gram-positive and gram-negative
bacteria, it was noticed compound 4 demonstrated inhibitory
activities more than compounds 3, 7, 8a, 8b and 16e19, while most
of the newly synthesized compounds exhibited moderate activity
against fungi as compared with the reference drug (Nystatin). On
the other hand, the antitumor activities revealed that the acetylated
sugar (16, 17a) and deacetylated sugar (18, 19a) most significant
activities than the other tested compounds.
exchangeable); 13C NMR (DMSO-d6) (
d, ppm) d 27.68, 29.90 (2CH3),
35.48, 39.82 (C-5 þ C-8), 41.07, 51.0 (2CH2), 91.58, 109.62, 123.80,
123.91, 129.60, 129.63, 146.35, 153.06, 154.99 (Ar-10C), 156.16 (C]
N), 157.12, 194.74 (2C]O); Its MS (m/z), 396 (Mþ, 51%); C19H20N6O4
(396.40); Requires (Found): C, 57.57 (57.50); H, 5.09 (4.99); N, 21.20
(21.28).
4.1.2. 8,8-Dimethyl-5-(4-nitrophenyl)-5,8,9,10-tetrahydrotetrazolo
[40,30:1,2]pyrimido[4,5-b] quinoline-4,6-dione (3)
4. Experimental
To an ice-cold solution of compound 2c (3.96 g, 0.01 mol) in
acetic acid (10 ml) was added drop wise a solution of sodium nitrite
(10.35 g, 0.15 mol) in a least amount of water in an ice bath at ꢀ5 ꢂC.
The reaction mixture was allowed to stand overnight at room
temperature, then poured onto water (100 ml). The solid precipi-
tated was filtered off and crystallized from ethanol to pꢀro1duce 3 as
4.1. Chemistry
All melting points were measured on ElectrothermalIA 9100
series digital melting point apparatus. Microanalytical data (in
accord with the calculated values) were performed by Vario, Ele-
mentar apparatus (Shimadzu). The IR spectra (KBr) were recorded
on a PerkineElmer 1650 spectrometer (USA). 1H and 13C NMR
spectra were determined on a JEOL EX-300 and JEOL ECA-500.
Chemical shifts were expressed in ppm relative to SiMe4 as internal
standards and DMSO-d6 as solvent. Mass spectra were recorded on
70 ev EI Ms-QP 1000 EX (Shimadzu, Japan). Antimicrobial activities
were measured at pharmacology department, National Research
Center, Cairo, Egypt. Antitumor activities were measured at the
National Cancer Institute, Cairo University, Cairo, Egypt.
orange powder in a 60% yield, mp 335e337 ꢂC; IR (cm
,
y
): 3254
(br, NH’s), 1715, 1683 (2C]O); 1H NMR (DMSO-d6) (
d
, ppm) 0.90
d
(s, 3H, CH3), 1.03 (s, 3H, CH3), 2.02 (d, J ¼ 16.8 Hz, 2H, CH2), 2.14 (d,
J ¼ 16.9 Hz, 2H, CH2), 5.01 (s, 1H, C5-H), 7.47 (d, J ¼ 8.2 Hz, 2H, Ar-H),
8.08 (d, J ¼ 8.3 Hz, 2H, Ar-H), 9.79, 10.14 (2br, 2H, 2NH, D2O
exchangeable); Its MS (m/z), 407 (Mþ, 45%); C19H17N7O4 (407.38);
Requires (Found): C, 56.01 (56.12); H, 4.21 (4.18); N, 24.07 (24.11).
4.1.3. 2-Amino-8,8-dimethyl-5-(4-nitrophenyl)-5,8,9,10-
tetrahydropyrimido[4,5-b] quinoline-4,6-dione (4)
To a well-stirred solution of the appropriate tetrazolo-pyrimido
[4,5-b]quinoline 3 (4.07 g, 0.01 mol) in glacial acetic acid (30 ml)
was added portionwise activated zinc dust (5.0 g) at room
temperature over a period of 30 min. Stirring was continued for
additional 3 h. Then the reaction mixture was heated on water bath
(80e90 ꢂC) for 3 h. The progress of reduction was monitored by TLC.
After allowing the reaction mixture to cool to room temperature, it
was poured onto cold water (100 ml). The insoluble solid which
separated was filtered, washed with water, and dried. The crude
solid was extracted with hot diethyl ether and the solid obtained
after the removal of ether under reduced pressure was crystallized
from ethanol, as brown powder in a 41% yield, mp 301e302 ꢂC; IR
4.1.1. 5-Aryl-8,8-dimethyl-2-hydrazino-5,8,9,10-
tetrahydropyrimido[4,5-b]quinoline-4,6-dione (2aec)
General procedure. A suspension of compound 1aec (0.01 mol)
in hydrazine hydrate (99%, 20 ml) was stirred under reflux for 10 h.
The reaction mixture was allowed to cool to room temperature. The
solid precipitate was filtered off, washed with ethanol, dried and
crystallized from dimethylformamide to produce 2aec in high
yields.
4.1.1.1. 2-Hydrazino-8,8-dimethyl-5-phenyl-5,8,9,10-tetrahydropyr-
imido[4,5-b]quinoline-4,6-dione (2a). It was obtained from 1a
(3.7 g, 0.01 mol), as a yellow powder, crystallized from DMF in a 75%
(cmꢀ1
,
y
): 3325 (br, NH’s), 1700, 1680 (2C]O); 1HNMR (DMSO-d6)
0.92 (s, 3H, CH3), 0.99 (s, 3H, CH3), 2.10 (m, 4H, 2CH2),
yield, mp 319e320 ꢂC; IR (cmꢀ1
,
y
): 3280 (br, NH’s), 1703, 1682
(d, ppm) d
(2C]O); 1H NMR (DMSO-d6) (
d, ppm) 0.82 (s, 3H, CH3), 0.93 (s,
d
5.04 (s, 1H, C5-H), 7.56 (d, J ¼ 8.2 Hz, 2H, Ar-H), 8.02 (d, J ¼ 8.2 Hz,
2H, Ar-H), 8.50, 9.90, 11.03 (3br, 4H, 2NH, NH2, D2O exchangeable);
Its MS (m/z), 381 (Mþ,12%); C19H19N5O4 (381.39); Requires (Found):
C, 59.84 (59.79); H, 5.02 (4.98); N, 18.36 (18.33).
3H, CH3), 2.12 (d, J ¼ 17.0 Hz, 2H, CH2), 2.33 (d, J ¼ 17.0 Hz, 2H,
CH2), 4.96 (s, 1H, C5-H), 7.42 (m, 2H, Ar-H), 7.76 (m, 3H, Ar-H), 8.55,
9.95, 12.30 (3br, 5H, 3NH, NH2, D2O exchangeable); Its MS (m/z),
351 (Mþ, 78%); C19H21N5O2 (351.40); Requires (Found): C, 64.94
(65.01); H, 6.02 (5.98); N, 19.93 (19.85).
4.1.3.1. 8,8-Dimethyl-5-(4-nitrophenyl)-5,8,9,10-tetrahydro[1,2,4]tri-
azolo[40,30:1,2]pyrimido [4,5-b]quinoline-4,6-dione (5a). A mixture
of 2c (3.96 g, 0.01 mol), formic acid (10 ml), and 1 ml of concen-
trated hydrochloric acid was heated under reflux for 6 h. The
reaction mixture was allowed to cool to room temperature and
poured onto water (100 ml). The formed solid was collected by
filtration, washed with ethanol (20 ml), dried, and crystallized from
4.1.1.2. 5-(4-Chlorophenyl)-2-hydrazino-8,8-dimethyl-5,8,9,10-tetra-
hydropyrimido[4,5-b] quinoline-4,6-dione (2b). It was obtained
from 1b (4.0 g, 0.01 mol), as a yellow powder, crystallized from DMF
in a 78% yield, mp 310e311 ꢂC; IR (cmꢀ1
,
y
): 3290 (br, NH’s), 1712,
d
1675 (2C]O); 1H NMR (DMSO-d6) (
d
, ppm) 0.95 (s, 3H, CH3), 1.00
(s, 3H, CH3), 1.96 (d, J ¼ 16.9 Hz, 2H, CH2), 2.14 (d, J ¼ 17.0 Hz, 2H,
CH2), 5.05 (s, 1H, C5-H), 7.44 (d, J ¼ 8.1 Hz, 2H, Ar-H), 8.03 (d,
J ¼ 8.1 Hz, 2H, Ar-H), 8.15, 9.90, 12.27 (3br, 5H, 3NH, NH2, D2O
exchangeable); Its MS (m/z), 385 (Mþ, 90%), 386 (Mþ þ 1, 18%), 387
(Mþ þ 2, 31%); C19H20ClN5O2 (385.85); Requires (Found): C, 59.14
(59.10); H, 5.22 (5.30); N, 18.15 (18.20).
ethanol, as yellow powder in a 76% yield, mp 299e300 ꢂC; IR (cmꢀ1
,
y
): 3290 (br, NH’s),1698,1679 (2C]O); 1H NMR (DMSO-d6) (
d, ppm)
d
0.98 (s, 3H, CH3),1.14 (s, 3H, CH3),1.99 (d, J ¼ 17.3 Hz, 2H, CH2), 2.15
(d, J ¼ 17.3 Hz, 2H, CH2), 5.11 (s, 1H, C5-H), 7.43 (d, J ¼ 7.9 Hz, 2H, Ar-
H), 8.03 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.64 (s, 1H, azomethine proton),
9.90, 10.0 (2br, 2H, 2NH, D2O exchangeable); Its MS (m/z), 406 (Mþ,

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
27
43%); C20H18N6O4 (406.39); Requires (Found): C, 59.11 (59.05); H,
4.46 (4.40); N, 20.68 (20.73).
(8b). It was obtained from compound 2c (3.96 g, 0.01 mol) and
phenacylbromide (1.97 g, 0.01 mol), crystallized from methanol, as
yellow powder in a 66% yield, mp 308e310 ꢂC; IR (cmꢀ1
,
y
): 3305 (br,
4.1.3.2. 3,8,8-Trimethyll-5-(4-nitrophenyl)-5,8,9,10-tetrahydro[1,2,4]
NH’s), 1712, 1679 (2C]O); 1H NMR (DMSO-d6) (
d, ppm) 0.95
d
triazolo[40,30:1,2]
pyrimido[4,5-b]quinoline-4,6-dione
(5b). A
(s, 3H, CH3), 1.00 (s, 3H, CH3), 1.96 (d, J ¼ 16.9 Hz, 2H, CH2), 2.15 (d,
J ¼ 16.8 Hz, 2H, CH2), 4.95 (s, 1H, C5-H), 7.30 (m, 3H, Ar-H), 7.39 (d,
J ¼ 8.2 Hz, 2H, Ar-H), 8.05 (s,1H, imidazole proton), 8.13 (d, J ¼ 8.2 Hz,
2H, Ar-H), 8.22 (m, 2H, Ar-H), 9.10, 9.87 (2br, 3H, NH, NH2, D2O
exchangeable); Its MS (m/z), 496 (Mþ, 28%); C27H24N6O4 (496.52);
Requires (Found): C, 65.31 (65.25); H, 4.87 (4.92); N, 16.93 (16.85).
mixture of 2c (3.96 g, 0.01 mol) and glacial acetic acid (30 ml) was
stirred under reflux for 6 h (TLC). The reaction mixture was allowed
to cool to room temperature and then poured onto water (100 ml).
The solid formed was collected by filtration, washed with ethanol
(20 ml), dried and crystallized from ethanol, as yellow powder in
a 69% yield, mp 276e278 ꢂC; IR (cmꢀ1
,
y
): 3291 (br, NH’s),1709,1681
0.90 (s, 3H, CH3), 1.01 (s, 3H,
(2C]O); 1H NMR (DMSO-d6) (
d, ppm)
d
4.1.6. 2-(Arylmethylenhydrazone)-5-(4-nitrophenyl)-8,8-dimethyl-
5,8,9,10-tetrahydro-pyrimido[4,5-b]quinoline-4,6-dione (9aec)
General procedure. A mixture of 2c (3.96 g, 0.01 mol), the
appropriate aromatic aldehyde (0.01 mol) was stirred under reflux
in glacial acetic acid (30 ml) for 50 min. The reaction mixture was
allowed to cool to room temperature; the formed solid was filtered
off and crystallized from appropriate solvent to produce 9aec.
CH3), 1.12 (s, 3H, CH3), 2.02 (d, J ¼ 16.9 Hz, 2H, CH2), 2.22
(d, J ¼ 16.9 Hz, 2H, CH2), 4.94 (s,1H, C5-H), 7.44 (d, J ¼ 8.0 Hz, 2H, Ar-
H), 8.08 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.84, 9.71 (2br, 2H, 2NH, D2O
exchangeable); 13C NMR (DMSO-d6) (
d, ppm) d 21.38, 27.74, 29.83
(3CH3), 33.05, 39.78 (C-5 þ C-8), 41.04, 50.99 (2CH2), 93.15, 109.63,
123.98, 129.65, 129.84, 146.43, 153.03, 154.59, 155.79 (Ar-10C),
159.9, 162.56 (2C]N), 168.94, 194.82 (2C]O); Its MS (m/z), 420
(Mþ, 46%), 421 (Mþ þ 1, 14%); C21H20N6O4 (420.42); Requires
(Found): C, 59.99 (60.03); H, 4.79 (4.72); N, 19.99 (20.02).
4.1.6.1. 2-[N0-(Phenylmethylen)-hydrazone]-8,8-dimethyl-5-(4-nitro-
phenyl)-5,8,9,10-tetra-hydropyrimido[4,5-b]quinoline-4,6-dione
(9a). It was obtained from compound 2c (3.96 g, 0.01 mol) and
benzaldehyde (1.06 g, 0.01 mol), crystallized from acetic acid, as yellow
4.1.4. 2,6-Bis{8,8-dimethyl-5-(4-nitrophenyl)-3,4,5,6,7,8,9,10-
octahydropyrimido[4,5-b] quinoline-2-yl-amino-4,6-dione}pyrrolo
[3,4-f]isoindole-1,3,5,7-tetraone (7)
powder in a 58% yield, mp 323e325 ꢂC; IR (cmꢀ1
,
y
): 3298 (br, NH’s),
0.83 (s, 3H, CH3),
1710, 1687 (2C]O); 1H NMR (DMSO-d6) (
d, ppm)
d
A mixture of compound 2c (7.38 g, 0.02 mol) and 1,2,4,5-
benzene-tetracarboxylic dianhydride 6 (2.18 g, 0.01 mol) in glacial
acetic acid (30 ml) was heated under reflux for 6 h. The residue
formed was filtered off and crystallized from ethanol, as yellow
0.96 (s, 3H, CH3), 1.89 (d, J ¼ 16.8 Hz, 2H, CH2), 2.16 (d, J ¼ 16.8 Hz, 2H,
CH2), 4.98 (s, 1H, C5-H), 7.42 (m, 3H, Ar-H), 7.57 (d, J ¼ 8.2 Hz, 2H, Ar-
H), 7.94 (d, J ¼ 8.2 Hz 2H, Ar-H), 8.08 (m, 2H, Ar-H), 8.20 (s, 1H, azo-
methine proton), 9.30, 9.68, 10.05 (3br, 3H, 3NH, D2O exchangeable);
Its MS (m/z), 484 (Mþ, 9.6%), 483 (Mþ ꢀ 1, 11.5%); C26H24N6O4 (484.51);
Requires (Found): C, 64.45 (64.40); H, 4.99 (4.90); N, 17.35 (17.40).
powder in a 68% yield, mp 323e325 ꢂC; IR (cmꢀ1
,
y
): 3339 (br, NH’s),
1711e1675 (8C]O); 1H NMR (DMSO-d6) (
d
, ppm) 0.89 (s, 6H,
d
2CH3), 1.01 (s, 6H, 2CH3), 1.96 (d, J ¼ 17.3 Hz, 4H, 2CH2), 2.46 (d,
J ¼ 17.3 Hz, 4H, 2CH2), 4.94 (s, 2H, 2C5-H), 7.44 (d, J ¼ 8.2 Hz, 4H, Ar-
H), 8.01 (d, J ¼ 8.2 Hz, 4H, Ar-H), 8.10 (d, J ¼ 7.9 Hz, 2H, Ar-H), 8.80,
4.1.6.2. 2-[N0-(4-Chlorophenylmethylen)-hydrazone]-8,8-dimethyl-
5-(4-nitrophenyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6-
dione (9b). It was obtained from compound 2c (3.96 g, 0.01 mol)
and 4-chlorobenzaldehyde (1.40 g, 0.01 mol), crystallized from
acetic acid, as yellow powder in a 70% yield, mp 330e331 ꢂC; IR
9.65, 11.3 (3br, 6H, 6NH, D2O exchangeable); 13C NMR (DMSO-d6) (
d,
ppm)
d 21.83, 21.99, 27.75, 29.83 (4CH3), 33.06, 36.01, 39.77, 39.98
(2C-5 þ 2C-8), 40.81, 41.02, 49.95,50.00 (4CH2), 109.63, 123.99,
124.12, 129.66, 130.09, 130.56, 135.65, 146.44, 153.03, 154.32 (Ar-
26C), 155.98, 156.21 (2C]N), 168.23, 168.35, 168.49, 169.92, 194.83
(8C]O); Its MS (m/z), 974 (Mþ, 58%); C48H38N12O12 (974.89);
Requires (Found): C, 59.14 (59.10); H, 3.93 (3.98); N, 17.24 (17.29).
(cmꢀ1
,
y
): 3320 (br, NH’s), 1710, 1689 (2C]O); 1H NMR (DMSO-d6)
0.92 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.10 (m, 4H, 2CH2),
(d, ppm) d
5.04 (s, 1H, C5-H), 7.45 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.80 (d, J ¼ 8.0 Hz,
2H, Ar-H), 7.96 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.12 (d, J ¼ 8.0 Hz, 2H, Ar-
H), 8.26 (s, 1H, azomethine proton), 8.99, 9.60, 10.85 (3br, 3H, 3NH,
D2O exchangeable); Its MS (m/z), 518 (Mþ, 66%), 519 (Mþ þ 1, 19%),
520 (Mþ þ 2, 22%); C26H23ClN6O4 (518.94); Requires (Found): C,
60.17 (60.25); H, 4.47 (4.50); N, 16.19 (16.12).
4.1.5. 1-Amino-8,8-dimethyl-2-(methyl or phenyl)-5-
(4-nitrophenyl)-5,8,9,10-tetrahydro-imidazolo[30,20:1,2]pyrimido
[4,5-b]quinoline-4,6-dione (8a,b)
General procedure. A mixture of compound 2c (3.96 g, 0.01 mol)
and chloroacetone or phenacylbromide (0.01 mol) was heated
under reflux for 5 h in dry xylene (30 ml). The solid that separated
upon cooling was filtered off and crystallized from appropriate
solvent to produce 8a and 8b respectively in high yields.
4.1.6.3. 2-[N0-(4-methoxyphenylmethylen)-hydrazone]-8,8-dimethyl-
5-(4-nitrophenyl)-5,8,9, 10-tetrahydropyrimido[4,5-b]quinoline-4,6-
dione (9c). It was obtained from compound 2c (3.96 g, 0.01 mol)
and 4-methoxybenzaldehyde (1.36 g, 0.01 mol), crystallized from
acetic acid, as yellow powder in a 43% yield, mp 319e320 ꢂC; IR
4.1.5.1. 1-Amino-2,8,8-trimethyl-5-(4-nitrophenyl)-5,8,9,10-tetrahy-
droimidazolo[30,20:1,2] pyrimido[4,5-b]quinoline-4,6-dione (8a). It
was obtained from compound 2c (3.96 g, 0.01 mol) and chlor-
oacetone (0.92 g, 0.01 mol), crystallized from ethanol, as white
(cmꢀ1
,
y
): 3328 (br, NH’s), 1714, 1683 (2C]O); 1H NMR (DMSO-d6)
0.89 (s, 3H, CH3), 0.93 (s, 3H, CH3), 1.89 (d, J ¼ 17.2 Hz, 2H,
(d, ppm) d
CH2), 2.15 (d, J ¼ 17.2 Hz, 2H, CH2), 3.33 (s, 3H, OCH3), 4.95 (s,1H, C5-
H), 7.49 (d, J ¼ 7.9 Hz, 2H, Ar-H), 7.52 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.69 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 8.01 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.36 (s, 1H,
azomethine proton), 9.50, 10.23, 10.41 (3br, 3H, 3NH, D2O
exchangeable); Its MS (m/z), 514 (Mþ, 23%); C27H26N6O5 (514.53);
Requires (Found): C, 63.02 (63.10); H, 5.09 (5.01); N, 16.33 (16.39).
crystals in a 62% yield, mp 298e299 ꢂC; IR (cmꢀ1
,
y
): 3318
(br, NH’s), 1715,1687 (2C]O); 1H NMR (DMSO-d6) (
d, ppm) d 0.89 (s,
3H, CH3), 1.09 (s, 3H, CH3), 1.95 (m, 4H, 2CH2), 2.08 (s, 3H, CH3), 5.03
(s, 1H, C5-H), 7.46 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.97 (d, J ¼ 8.1 Hz, 2H, Ar-
H), 8.16 (s, 1H, imidazole proton), 9.12, 9.84 (2br, 3H, NH, NH2, D2O
exchangeable); Its MS (m/z), 434 (Mþ, 12%); C22H22N6O4 (434.45);
Requires (Found): C, 60.82 (60.78); H, 5.10 (5.05); N, 19.34 (19.40).
4.1.7. 3-(4-Chlorophenyl)-8,8-dimethyl-5-(4-Nitrophenyl)-5,8,9,10-
tetrahydro[1,2,3] triazolo [40,30:1,2]pyrimido[4,5-b]quinoline-4,6-
dione (10)
4.1.5.2. 1-Amino2-phenyl-5-(4-nitrophenyl)-8-dimethyl-5,6,7,8,9,10-
hexahydro[1,3] imidazolo[30,20:1,2]pyrimido[4,5-b]quinoline-4,6-dione
A solution of compound 9b (5.18 g, 0.01 mol) in acetic anhydride
(30 ml) was stirred under reflux 8 h poured onto water (100 ml)

28
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
and the solid formed was collected by filtration and crystallized
from ethanol, as yellow powder in a 52% yield, mp 298e299 ꢂC; IR
J ¼ 16.9 Hz, 2H, CH2), 2.15 (d, J ¼ 17.0 Hz, 2H, CH2), 2.55 (s, 3H, SCH3),
4.93 (s, 1H, C5-H), 5.56 (s, 1H, C7-H), 7.40 (d, J ¼ 8.1 Hz, 2H, Ar-H),
8.04 (d, J ¼ 8.1 Hz, 2H, Ar-H), 9.90, 10.75 (2br, 2H, 2NH, D2O
(cmꢀ1
, y
): 3310 (br, NH’s), 1705, 1690 (2C]O); 1H NMR (DMSO-d6)
(
d
, ppm)
d
0.91 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.98 (d, J ¼ 16.9 Hz, 2H,
exchangeable); 13C NMR (DMSO-d6) (
d, ppm) d 14.54 (SCH3), 27.74,
CH2), 2.25 (d, J ¼ 16.9 Hz, 2H, CH2), 5.01 (s, 1H, C5-H), 7.45
(2d, overlap, J ¼ 8.2 Hz, 4H, Ar-H), 7.93 (d, J ¼ 8.2 Hz, 2H, Ar-H), 8.08
(d, J ¼ 8.2 Hz, 2H, Ar-H), 9.54, 11.48 (2br, 2H, 2NH, D2O exchange-
29.71 (2CH3), 33.12, 41.05 (C-5 þ C-8), 50.96 (CH2), 110.34, 124.09,
130.25, 146.62, 152.29, 152.68, 154.88, 157.25 (Ar-12C), 159.73 (C]
N), 170.91 (C]O); Its MS (m/z), 308 (MþꢀC6H4NO2, 100%), 309
able); 13C NMR (DMSO-d6) (
d, ppm)
d
27.71, 29.95 (2CH3), 33.06,
(Mþ
þ
1-C6H4NO2, 18%), 310 (Mþ
þ
2-C6H4NO2, 35%);
39.83 (C-5 þ C-8), 41.09, 50.99 (2CH2), 93.77, 109.72, 123.98, 129.47,
129.72, 130.09, 134.11, 135.03, 14.45, 146.44 (Ar-16C), 154.34, 155.77
(2C]N), 162.60, 194.83 (2C]O); Its MS (m/z), 516 (Mþ, 29%), 517
(Mþ þ 1, 6%), 518 (Mþ þ 2, 9%); C26H21ClN6O4 (516.93); Requires
(Found): C, 60.41 (60.37); H, 4.09 (3.99); N, 16.26 (16.30).
C20H19ClN4O3S (430.91); Requires (Found): C, 55.75 (55.70); H, 4.44
(4.49); N, 12.99 (12.91).
4.1.11. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(20,30,50-
tri-O-acetyl-b-D-arabino-furanosyl)-5,8,9,10-tetrahydropyrimido
[4,5-b]quinoline-4,6-dione (16)
4.1.8. 3,8,8-Trimethyl-2-methylthio-5-(4-nitrophenyl)-5,8,9,10-
tetrahydro-pyrimido[4,5-b] quinoline-4,6-dione (11)
To a solution of 1c (4.12 g, 0.01 mol) in aqueous potassium
hydroxide (0.56 g, 0.01 mol) in distilled water (5 ml) was added
To a warm ethoxide solution (prepared by dissolving (0.23 g,
0.01 mol) of sodium in 30 ml absolute ethanol) was added
compound 1c (4.12 g, 0.01 mol), the heating was continued for
30 min, the mixture was allowed to cool to room temperature and
methyl iodide (17.04 g, 0.12 mol) was added. The mixture was
stirred under reflux for 3 h, cooled to room temperature, and
poured onto cold water (100 ml). The solid precipitated was filtered
off, washed with water and dried. The compound was crystallized
from ethanol, as brown powder in a 60% yield, mp 280e282 ꢂC; IR
a solution of 2,3,5-tri-O-acetyl-b-D-arabinofuranosyl bromide 14
(4.17 g, 0.011 mol)inacetone (30ml). Thereactionmixturewasstirred
at room temperature for 24 h (under TLC control). The solvent was
evaporated under reduced pressure at 40 ꢂC, and the crude product
was filtered off and washed with distilled water to remove KBr
formed. The product was dried, and crystallized from diethyl ether as
pale yellow powder in a 64% yield, mp 313e314 ꢂC; IR (cmꢀ1
,
y
): 3333
(br, NH), 1710e1675 (5C]O); 1H NMR (DMSO-d6) (
d, ppm)
d
0.90
(s, 3H, CH3), 1.09 (s, 3H, CH3), 2.05 (m, 4H, 2CH2), 2.12e2.33 (3s, 9H,
(cmꢀ1
, y
): 3290 (br, NH’s), 1700, 1682 (2C]O); 1H NMR (DMSO-d6)
3COCH3), 2.65(s, 3H, SCH3), 3.50(m, 2H, H-50, H-500), 3.68 (m, 2H, H-40,
H-30), 4.20 (m,1H, H-20), 5.02 (s,1H, C5-H), 5.99 (d, J1 e2 ¼10.2 Hz,1H,
H-10), 7.48 (d, J ¼ 8.0 Hz, 2H, Ar-H), 8.05 (d, J ¼ 8.0 Hz, 2H, Ar-H), 11.02
(br, 1H, NH, D2O exchangeable); C31H34N4O11S (670.67); Requires
(Found): C, 55.51 (55.50); H, 5.11 (5.08); N, 8.35 (8.30).
0
0
(
d
, ppm)
d
0.93 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.04 (d, J ¼ 17.1 Hz, 2H,
CH2), 2.15 (d, J ¼ 17.1 Hz, 2H, CH2), 2.56 (s, 3H, SCH3), 3.26 (s, 3H,
NCH3), 5.00 (s, 1H, C5-H), 7.45 (d, J ¼ 7.9 Hz, 2H, Ar-H), 8.05 (d,
J ¼ 8.0 Hz, 2H, Ar-H), 9.92 (br, 1H, NH, D2O exchangeable); 13CNMR
(DMSO-d6) (d, ppm) d 15.38 (SCH3), 27.75, 29.78, 30.73 (3CH3),
33.11, 39.84 (C-5 þ C-8), 41.09, 50.96 (2CH2), 96.94, 109.56, 124.02,
129.93, 146.63, 151.39, 152.59, 154.87 (Ar-10C), 161.16 (C]N),
162.78, 194.86 (2C]O); Its MS (m/z), 426 (Mþ, 11.6%), 427 (Mþ þ 1,
3.6%); C21H22N4O4S (426.49); Requires (Found): C, 59.14 (59.18); H,
5.20 (5.19); N, 13.14 (13.10).
4.1.12. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-
(20,30,40,60-tetra-O-acetyl-
b-D-gluco- or galactopyranosyl)-5,8,9,10-
tetrahydropyrimido[4,5-b]quinoline-4,6-dione (17a,b)
General procedure. To a solution of 1c (4.12 g, 0.01 mol) in
aqueous potassium hydroxide (0.56 g, 0.01 mol) in distilled water
(5 ml) was added a solution of 2,3,4,6-tetra-O-acetyl-a-D-gluco- or
4.1.9. 6-Chloro-3,8,8-trimethyl-2-methylthio-5-(4-nitrophenyl)-
5,8,9,10-tetrahydro-pyrimido[4,5-b]quinoline-4,6-dione (12)
galactopyranosyl bromide 15a,b (0.011 mol) in acetone (30 ml). The
reaction mixture was stirred at room temperature for 24 h (under
TLC control). The solvent was evaporated under reduced pressure at
40 ꢂC, and the crude product was filtered off and washed with
distilled water to remove KBr formed. The product was dried, and
crystallized from diethyl ether.
A mixture of compound 10 (4.26 g 0.01 mol) in phosphorus
oxychloride (20 ml) was heated under reflux for 12 h. The solution
was cooled and poured into ice-water (100 ml). The solid was
filtered off, washed several times with water and dried. The
compound was crystallized from ethanol, as pale brown powder in
a 80% yield, mp 301e302 ꢂC; IR (cmꢀ1
,
y
): 3278 (br, NH’s), 1680 (C]
4.1.12.1. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(2,30,40,60-
O); 1H NMR (DMSO-d6) (
d, ppm)
d
0.92 (s, 3H, CH3),1.07 (s, 3H, CH3),
tetra-O-acetyl-
b]quinoline-4,6-dione (17a). It was obtained from compound 1c
(4.12 g, 0.01 mol) and 2,3,4,6-tetra-O-acetyl- -glucopyranosyl
bromide 15a (4.5 g, 0.011 mol), crystallized from diethyl ether, as
pale yellow powder in a 57% yield, mp 297e298 ꢂC; IR (cmꢀ1
):
3324 (br, NH), 1718e1667 (6C]O); 1H NMR (DMSO-d6) (
, ppm)
b-D-glucopyranosyl)-5,8,9,10-tetrahydropyrimido[4,5-
1.89 (d, J ¼ 17.2 Hz, 2H, CH2), 2.05 (d, J ¼ 17.2 Hz, 2H, CH2), 2.58 (s,
3H, SCH3), 3.30 (s, 3H, NCH3), 4.95 (s, 1H, C5-H), 5.77 (s, 1H, C7-H),
7.47 (d, J ¼ 8.1 Hz, 2H, Ar-H), 8.02 (d, J ¼ 8.1 Hz, 2H, Ar-H), 9.90 (br,
a-D
1H, NH, D2O exchangeable); 13C NMR (DMSO-d6) (
d
, ppm)
d
14.81
, y
(SCH3), 16.80, 20.82, 22.14 (3CH3), 39.84, 41.10 (C-5 þ C-8), 42.26
(CH2), 110.72, 112.76, 124.83, 128.24, 130.83, 131.09, 134.42, 147.62
(Ar-12C), 162.19 (C]N), 168.26 (C]O); Its MS (m/z), 444 (Mþ, 9.9%),
445 (Mþ þ 1, 2.6%); C21H21ClN4O3S (444.94); Requires (Found): C,
56.69 (56.66); H, 4.76 (4.78); N, 12.59 (12.51).
d
d
0.85 (s, 3H, CH3), 0.96 (s, 3H, CH3), 1.86 (d, J ¼ 17.1 Hz, 2H, CH2),
1.94 (d, J ¼ 17.1 Hz, 2H, CH2), 2.02e2.15 (4s, 12H, 4COCH3), 2.43 (s,
3H, SCH3), 3.71 (m, 2H, H-60, H-600), 3.86 (m, 1H, H-50), 3.98 (m, 2H,
H-40, H-30), 5.05 (s, 1H, C5-H), 5.34 (m, 1H, H-20), 6.08
(d, J1 e2 ¼ 10.9 Hz, 1H, H-10), 7.29 (d, J ¼ 8.0 Hz, 2H, Ar-H), 7.98 (d,
0
0
4.1.10. 6-Chloro-8,8-dimethyl-2-methylthio-5-(4-nitrophenyl)-
5,8,9,10-tetrahydropyrimido [4,5-b]quinoline-4,6-dione (13)
J ¼ 8.1 Hz, 2H, Ar-H), 10.44 (br, 1H, NH, D2O exchangeable); 13C NMR
(DMSO-d6) (d, ppm) d 14.08 (SCH3), 20.81e20.99 (4COCH3), 27.18,
A mixture of compound 1c (4.12 g, 0.01) in phosphorus oxy-
chloride (20 ml) was heated under reflux for 2 h. The solution was
cooled and poured into ice-water (100 ml). The solid was filtered
off, washed several times with water and dried. The compound was
crystallized from ethanol, as pale yellow powder in a 85% yield, mp
29.37 (2CH3), 32.70, 39.94 (C-5 þ C-8), 39.95, 50.38 (2CH2), 61.98
(C60), 68.67 (C40), 70.32 (C20), 71.03 (C30), 71.18 (C50), 71.52 (C10),
93.37, 94.45, 96.51, 97.26, 109.50, 123.62, 123.96, 129.11, 129.63,
146.37, 152.31, 156.65, 164.26, (Ar-10C), 164.84 (C]N), 169.35,
170.09, 170.31, 170.32, 170.45, 194.36 (6C]O); C34H38N4O13
S
325e326 ꢂC; IR (cmꢀ1
,
y
): 3319 (br, NH’s), 1675 (C]O); 1H NMR
d 0.83 (s, 3H, CH3), 0.95 (s, 3H, CH3), 1.98 (d,
(742.70); Requires (Found): C, 54.98 (55.00); H, 5.15 (5.18); N, 7.54
(7.50).
(DMSO-d6) ( , ppm)
d

H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
29
4.1.12.2. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(20,30,40,60-
tetra-O-acetyl- -galactopyranosyl)-5,8,9,10-tetrahydropyrimido[4,5-
b]quinoline-4,6-dione (17b). It was obtained from compound 1c
(4.12 g, 0.01 mol) and 2,3,4,6-tetra-O-acetyl- -galactopyranosyl
bromide 15b (4.5 g, 0.011 mol), crystallized from diethyl ether, as
pale yellow powder in a 59% yield, mp 311e312 ꢂC; IR (cmꢀ1
):
3350 (br, NH), 1705e1669 (6C]O); 1HNMR (DMSO-d6) (
, ppm)
OH), 4.79 (t, 1H, J ¼ 5.0 Hz, OH), 4.098 (s, 1H, C5-H), 5.19 (m, 2H,
0
0
b-D
2OH), 6.11 (d, J1 e2 ¼ 10.9 Hz, 1H, H-1 ), 7.49 (d, J ¼ 8.0 Hz, 2H, Ar-H),
7.98 (d, J ¼ 8.0 Hz, 2H, Ar-H), 10.95 (br, 1H, NH, D2O exchangeable);
C26H30N4O9S (574.60); Requires (Found): C, 54.35 (54.30); H, 5.26
(5.28); N, 9.75 (9.80).
a-D
,
y
d
4.2. Pharmacological screening
d
0.89 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.01 (m, 4H, 2CH2), 2.08e2.28
(4s, 12H, 4COCH3), 2.39 (s, 3H, SCH3), 3.88 (m, 2H, H-60, H-600), 4.18
4.2.1. Antimicrobial screening
(m, 1H, H-50), 4.40 (m, 2H, H-40, H-30), 5.00 (s, 1H, C5-H), 5.27 (m,
The bacterial isolates representing Gram-negative and Gram-
positive bacteria were recovered on Nutrient and MacConkey agar.
The two fungal isolated on Sabouraud dextrose agar (Oxoid). They
are isolated from clinical samples and identified to the species level
according to different AOI systems (Biomerilux). The selected
compounds were tested in vitro using the agar disk diffusion
method taking Nalidixic acid [38] and Nystatin [39] as reference
drugs for bacteria and fungi, respectively. The antimicrobial
potentialities of the tested compounds were estimated by placing
pre-sterilized filter paper disks (5 mm in diameter) impregnated
1H, H-20), 6.08 (d, J1 e2 ¼ 9.9 Hz, 1H, H-10), 7.44 (d, J ¼ 8.0 Hz, 2H,
Ar-H), 8.08 (d, J ¼ 8.1 Hz, 2H, Ar-H), 10.52 (br, 1H, NH, D2O
exchangeable); C34H38N4O13S (742.70); Requires (Found): C, 54.98
(55.05); H, 5.15 (5.10); N, 7.54 (7.48).
0
0
4.1.13. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(b-D-
arabinopyranosyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-
4,6-dione (18)
Dry gaseous ammonia was passed through a solution of pro-
tected arabinosides 17 (0.5 g) in dry methanol (20 ml) at room
temperature for 10 min. The mixture was stirred overnight (fol-
lowed by TLC). The resulting mixture was then evaporated under
reduce pressure to afford a solid residue that was crystallized from
diethyl ether as pale yellow in a 42% yield, mp 287e289 ꢂC; IR
with 50 mg/disk using dimethylsulfoxide (DMSO) as solvent which
showed no inhibition zones. The inhibition zones of the tested
compounds were measured after 24e28 h incubation at 37 ꢂC for
bacteria and at 28 ꢂC after 5 days for fungi. The minimal inhibitory
concentration (MIC) determination method of the biologically
active compounds (Table 2) was applied using different concen-
trations per disk against G (ꢀve) and G (þve) bacteria, and fungi.
Reference Nystatin and Nalidixic acid disks were supplied by Pas-
(cmꢀ1
, y
): 3339e3287 (br, OH, NH), 1711, 1685 (2C]O); 1H NMR
(DMSO-d6) (
d
, ppm) d 0.82 (s, 3H, CH3), 0.99 (s, 3H, CH3), 2.00 (m,
4H, 2CH2), 2.68 (s, 3H, SCH3), 3.50 (m, 2H, H-50, H-500), 3.74 (m, 2H,
H-40, H-30), 4.28 (m, 1H, H-20), 4.63 (m, 1H, OH), 4.86 (t, J ¼ 4.6 Hz,
teur laboratory in Egypt of concentration 100 U and 30
respectively.
mg,
0
0
1H, OH), 5.02 (s, 1H, C5-H), 5.13 (m, 1H, OH), 6.10 (d, J1 e2 ¼ 10.1 Hz,
1H, H-10), 7.49 (d, J ¼ 7.9 Hz, 2H, Ar-H), 8.10 (d, J ¼ 7.9 Hz, 2H, Ar-H),
10.79 (br, 1H, NH, D2O exchangeable); C25H28N4O8S (544.58);
Requires (Found): C, 55.14 (55.20); H, 5.18 (5.08); N, 10.29 (10.30).
4.2.2. Antitumor screening
4.2.2.1. Animals. Male Swiss albino mice (body weight 20 ꢁ 2 g).
They were kept for a week under environmentally controlled
conditions (constant temperature 25e27 ꢂC, with 12 h light/dark
cycle) for one week prior to starting the experiments, and they
were provided with tap water and commercial diets.
4.1.14. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(b-D-
gluco- or galactopyranosyl)-5,8,9,10-tetrahydro-pyrimido[4,5-b]
quinoline-4,6-dione (19a,b)
General procedure. Dry gaseous ammonia was passed through
a solution of protected glycosides 18a,b (0.5 gm) in dry methanol
(20 ml) at room temperature for 10 min. The mixture was stirred
overnight (followed by TLC). The resulting mixture was then
evaporated under reduce pressure to afford a solid residue that was
crystallized from appropriate solvent, as pale yellow.
4.2.2.2. Cell line. Human liver carcinoma cell line (HEPG2) and
Human cervix carcinoma cell line (HELA). The cells were main-
tained by intraperitoneal inoculation of 1 ꢃ106 viable cells in mice.
4.2.2.3. Ascites tumor model. Animals were divided into groups
of 10 animals in each group. All the animals were injected i.p.
with 1 ꢃ 106 viable (HEPG2) or (HELA) cells. After 24 h of tumor
inoculation the prepared compounds were administered i.p. at
4.1.14.1. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(b-D-glu-
copyranosyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6-dione
(19a). It was obtained from glucosides 18a and crystallized from
dose of 10 mg/kg body weight and continued for 10 consecutive
diethyl ether, as pꢀal1e yellow powder in
(2C]O); 1H NMR (DMSO-d6) (
d, ppm) d 0.95 (s, 3H, CH3), 1.08 (s,
a
58% yield, mp
days. The group administered with vehicle alone (DMSO) was
maintained as control. Cisplatine (2 mg/kg body weight, i.p., for
10 days) was used as the standard reference drug. The mortality
rate was noted in each group and the percent increase in life span
(ILS) was calculated as described by Ahluwalia et al. [40] and Joy
et al. [41].
294e295 ꢂC; IR (cm
, y): 3410e3358 (br, OH, NH), 1705, 1691
3H, CH3), 1.98e2.15 (m, 4H, 2CH2), 2.59 (s, 3H, SCH3), 3.25 (m, 2H,
H-60, H-600), 3.47 (m, 1H, H-50), 3.65 (m, 2H, H-40, H-30), 4.21 (m, 1H,
H-20), 4.60 (m, 1H, OH), 4.86 (t, J ¼ 4.8 Hz, 1H, OH), 5.08 (s, 1H, C5-
H), 5.13 (m, 2H, 2OH), 6.10 (d, J1 e2 ¼ 10.8 Hz, 1H, H-10), 7.41 (d,
J ¼ 8.2 Hz, 2H, Ar-H), 8.08 (d, 2H, J ¼ 8.1 Hz, Ar-H), 11.0 (br, 1H, NH,
D2O exchangeable); C26H30N4O9S (574.60); Requires (Found): C,
54.35 (54.30); H, 5.26 (5.28); N, 9.75 (9.80).
0
0
4.2.2.4. Assay of acute toxicity. The acute toxicity of the prepared
compounds was determined in vivo according to Prieur et al. [42]
and Ghosh [43]. Adult Swiss albino mice fasted for 12 h, were
randomly divided into groups of 10 per group. Each group was
separately administrated once with gradual doses of the compounds
intraperitoneal (i.p.) in a value of 1 ml/kg body weight. Control
animals received the vehicle alone. The fasted mice in both test and
control groups were then provided with food and water immedi-
ately after the administration. Mortality of the animals was
observed up to two week post-treatment. LD50 (the median lethal
doses) of each extract was determined (the dose resulted in 50%
mortality of the animals) (Table 4).
4.1.14.2. 8,8-Dimethyl-2-methylthio-5-(4-nitrophenyl)-10-(b-D-gal-
actopyranosyl)-5,8,9,10-tetrahydropyrimido[4,5-b]quinoline-4,6-dione
(19b). It was obtained from galactosides 18b and crystallized from
diethyl ether, as pale yellow powder in a 58% yield, mp 301e302 ꢂC;
, y
IR (cmꢀ1 ): 3395e3318 (br, OH, NH), 1718, 1668 (2C]O); 1H NMR
(DMSO-d6) (
d
, ppm) d 0.90 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.89e2.11
(m, 4H, 2CH2), 2.62 (s, 3H, SCH3), 3.30 (m, 2H, H-60, H-600), 3.39 (m,
1H, H-50), 3.74 (m, 2H, H-40, H-30), 4.09 (m, 1H, H-20), 4.56 (m, 1H,

30
H.-A.S. Abbas et al. / European Journal of Medicinal Chemistry 46 (2011) 21e30
[17] D. Carclunescu, A.D. Lopez, E.G. Iriarte, G. Tina, G. Gomez, R. Tana, C. Ghirvu,
Ann. Real Acad. Farm. 51 (1985) 241.
[18] Newberry, R.A.; Bushell, B.J. US 3,979,402 (Cl.269e302R; Co7 D227122), 07
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4.2.2.5. Statistical analysis. Values are recorded as mean ꢁ SE. The
data were analyzed by Student’s t-test; differences below the 0.5
level (P < 0.05) was considered as statistically significant.
[19] M.Yu. Gavrilov, I.G. Mardanova, V.E. Kolla, M.E. Konshin, Pharmceut. Chem. J.
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