Synthesis and radiation stability of some new biologically active hydroquinoline and pyrimido[4,5-b]quinoline derivatives

Article abstract of DOI:10.1002/jccs.200500177

A new series of hydroqujnolines 6a-d, 10, 12, 15, 17b, 20 and pyrimidoquinolines 7, 8, 9a, 11, 14 and 16 were synthesized starting from 2-amino-4-(3-bromo-phenyl)-7,7-dimethyl-1-naphthalen-1-yl-5-oxo-1,4,5,6,7, 8-hexahydro-quinoline-3-carbonitrile 6b. The

Full text of DOI:10.1002/jccs.200500177

Journal of the Chinese Chemical Society, 2005, 52, 1227-1236
1227
Synthesis and Radiation Stability of Some New Biologically Active
Hydroquinoline and Pyrimido[4,5-b]quinoline Derivatives
S. M. Abdel-Gawad,a M. S. A. El-Gaby,b* H. I. Heiba,c H. M. Alyc and M. M. Ghorabc
aDepartment of Chemistry, Faculty of Science (Girls), Al-Azhar University, Cairo, Egypt
bDepartment of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
cDepartment of Drug Radiation Research, National Center for Radiation Research and Technology,
P.O. Box 29, Nasr City, Cairo, Egypt
A new series of hydroquinolines 6a-d, 10, 12, 15, 17b, 20 and pyrimidoquinolines 7, 8, 9a, 11, 14 and 16
were synthesized starting from 2-amino-4-(3-bromo-phenyl)-7,7-dimethyl-1-naphthalen-1-yl-5-oxo-1,4,5,6,7,8-
hexahydro-quinoline-3-carbonitrile 6b. The structures of the synthesized compounds were elucidated by ele-
mental analyses and spectral data. Compounds 6a, 10, 11 and 18 exhibited a remarkable antifungal activity
compared with fungicide Mycostatine. Radiosterilization of the biologically active compounds 6a, 10 and 11
in the dry state may prove to be applicable [retaining their structures unchanged up to (40 kGy)].
Keywords: Hydroquinoline; Pyrimido[4,5-b]quinoline and radiation stability.
INTRODUCTION
The chemistry of hydroquinoline derivatives has been
systems. Enaminone22 3 was obtained from condensation of
5,5-dimethyl-1,3-cyclohexandione 1 with a-naphthylamine
2. Treatment of enaminone 3 with cinnamonitriles 4a-d in the
presence of a catalytic amount of triethylamine resulted in
cycloaddition affording the hexahydroquinolines 6a-d, pre-
sumably via Michael type product 5.
increasing in interest because many of these compounds have
useful applications as chemotherapeutic agents against ma-
larial parasites and microbes.1-5 Encouraged by the above ob-
servations and as a further probe in this direction, we under-
took a study in which the aromatic system (a-naphthyl) with
a bromo group has been incorporated into a quinoline or
pyrimidoquinoline, all present in one molecule, with a view
to explore the possibility of achieving better antimicrobial ef-
fects.6 In recent years, considerable interest has been devel-
oped regarding the radiation sensitivity of various antibiot-
ics7-10 and synthetic biologically active heterocyclic com-
pounds.11-16 Studies, for the most part, have focused on the
correlation between chemical structure and biological func-
tion. Generally, data of these compounds indicate that, even
at a dose of 25 KGy, radiosterilization may be feasible.17,18
N-aryl substituent (a-naphthyl) decreases the nucleo-
philicity of enaminoketone 3 toward 2-arylidenemalono-
nitrile 4a-d; a base catalyst was required to achieve the for-
mation of N-a-naphthyl substituted hexahydroquinolines
6a-d. Presumably, the base generates the anion of the 3-ami-
nocyclohex-2-en-1-one 3, thus facilitating the addition to the
unsaturated nitrile 4a-d (Scheme II).
The IR spectrum of compound 6a showed bands at
3430, 3330 (NH2), 2920 (CH aliph.), 2190 (CºN), 1650 cm-1
(C=O). The mass spectrum of 6a exhibited a molecular ion
peak m/z at 339 (M+-NH2, 5.03%), with a base peak at 342,
and other significant peaks appeared at 343 (24.08%), 257
(5.09%), 207 (3.55%), 169 (4.28%), 127 (22.70%), 55
(10.24%). UV Spectrum of 6a showed lmax at 282 nm and
Log e at 3.64. The IR spectrum of 6b revealed bands at 3470,
3360 (NH2), 3090 (CH arom.), 2930 (CH aliph.), 2200 (CºN)
and 1650 cm-1 (C=O). 1H NMR spectrum of (6b in DMSO-d6)
showed signals at d 0.8, 1.3 [2s, 6H, 2CH3], 2.1, 2.3 [2s, 4H,
2CH2 cyclo], 4.6 [s, 1H, 4H pyridine], 5.6 [s, 2H, NH2 ex-
changeable D2O], and 7.4-8.3 [m, 11H, Ar-H]. The mass
spectrum of 6b revealed a molecular ion peak m/z at 498 (M+,
3.15%), with a base peak at 342, and other significant peaks
appeared at 497 (M-1, 8.15%), 499 (M+1, 5.84%), 500 (M+2,
CHEMISTRY
Enaminones are versatile reagents for the synthesis of
quinoline and pyrimidine derivatives.19-21 As a part of a pro-
gram directed towards the synthesis of new suitably function-
alised quinolines of potential biological activity, we report
here the possible utility of 5,5-dimethyl-3-(naphthalen-1-
ylamino)-cyclohex-2-enone (enaminone) 3 with its bulky
naphthyl moiety in the synthesis of N-Naphthylquinoline

1228 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Abdel-Gawad et al.
Scheme I
O
NH2
O
Me
Me
EtOH
+
Me
NH
O
Me
1
2
3
CN
Ar
Ar
CN
4a-d
O
H
Ar
CN
O
H
Me
Me
CN
NH2
CN
NH
Me
Me
N
5
6
6a, Ar = C6H3F2 - 2, 4
6b, Ar = C6H4Br - 3
6c, Ar = C6H2 (OCH3)-3,4,5
6d, Ar =
N
Scheme II
O
Ar
O
Ar
O
CN
CN
:
Me
Me
: B
HB+
Me
Me
Me
Me
NH
CN
..
C
N
N
:
N
4a-d
5
3
HB+
: B
Ar
N
O
H
CN
NH2
Me
Me
6

New Biologically Active Quinoline Derivative
J. Chin. Chem. Soc., Vol. 52, No. 6, 2005 1229
1.80%), 414 (0.88%), 258 (4.35%), 231 (1.03%), 127 (8.20%),
and 76 (2.14%). UV spectrum of 6b revealed lmax at 266, 327
nm and Log e at 3.86, 3.46. The IR spectrum of 6c exhibited
bands at 3480, 3370 (NH2), 3060 (CH arom.), 2950 (CH
aliph.), 2200 (CºN), 1660 cm-1 (C=O). 1H NMR spectrum of
(6c in DMSO-d6) revealed signals at d 0.8, 0.9 [2s, 6H,
2CH3], 2.1, 2.2 [2s, 4H, 2CH2 cyclo], 4.6 [s, lH, 4H pyridine],
5.5 [s, 2H, NH2, exchangeable D2O], and 6.6-8.2 [m, 9H,
Ar-H]. UV spectrum of 6c exhibited lmax at 283 nm and Log e
at 3.74. The IR spectrum of 6d showed bands at 3340, 3200
(NH2), 2200 (CºN), 1650 cm-1 (C=O). UV spectrum of 6d re-
vealed lmax at 291 nm and Log e at 3.56.
tablished through microanalyses and its IR spectrum, which
showed the absence of (CºN) and presence of (NH2) at 3340,
3200, (CH arom.) at 3100, (CH aliph.) at 2960, and (C=O) at
1630 cm-1. The mass spectrum of 7 exhibited a molecular ion
peak m/z at 525 (M+, 3.14%), with a base peak at 369, and
other significant peaks appeared at 526 (M+1, 8.86%), 527
(M+2, 2.38%), 441 (2.87%), 355 (10.75%), 285 (3.82%), 194
(8.55%), 143 (2.22%), 127 (10.38%), 77 (2.45%). UV spec-
trum of 7 showed lmax at 286 nm and Log e at 4.09. The be-
haviour of compound 6b towards acid derivatives was also
investigated. Thus, heating compound 6b with formic acid
caused cyclization to give pyrimidoquinoline derivative 8
(Scheme III). The IR spectrum of 8 showed the absence of
(CºN) band and presence of band at 3100 (NH), 2940 (CH
The pyrimidoquinoline derivative 7 was obtained by
the reaction of 6b with formamide. The structure of 7 was es-
Scheme III
Br
Br
Br
O
O
O
O
H
H
H
CN
NH
CH3
CN
NHCOCH3
Me
Me
Me
Me
Me
N(COCH3)2
N
N
N
Me
N
9a
9c
9b
Br
Br
O
Ac2O
NH2
O
H
O
H
N
Me
Me
NH
HCOOH
HCONH2
Me
Me
6b
N
N
N
N
PhN = C
S
7
8
Br
Br
O
H
O
NH
H
CN
N - Ph
S
Me
Me
Pyridine
EtOH
Me
Me
NHCSNHPh
N
N
N
H
10
11
Pyridine
D

1230 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Abdel-Gawad et al.
aliph.), 1720, 1650 (2C=O), and 1620 cm-1 (C=N). The mass
spectrum of 8 revealed a molecular ion peak m/z at 526 (M+,
1.20%), with a base peak at 472, and other significant peaks
appeared at 518 (1.88%), 500 (47.73%), 446 (20.01%), 389
(1.12%), 290 (34.73%), 176 (52.39%), 127 (90.08%), and 77
(18.85%). UV spectrum of 8 showed lmax at 272, 281 nm and
Log e at 3.99, 3.94. When compound 6b was made to react
with acetic anhydride, the fused system pyrimidoquinoline
9a was isolated and the monoacetyl 9b or diacetyl derivative
9c was eliminated from consideration on the basis of elemen-
tal analyses and 1H-NMR spectroscopy. The IR spectrum of
9a showed the disappearance of (CºN) band and presence of
bands at 3100 (NH), 2930 (CH aliph.), 1700, 1650 (2C=O),
and 1600 cm-1 (C=N). 1H NMR spectrum of (9a in DMSO-d6)
showed signals at d 0.7, 0.8 [2s, 6H, 2CH3], 1.8 [s, 3H, CH3],
1.9, 2.0 [2s, 4H, 2CH2 cyclo], 5.1 [s, 1H, CH pyridine], 7.2-
7.6 [m, 11H, Ar-H], and 12.2 [s, 1H, NH]. Mass spectrum of
compound 9a revealed a molecular ion peak m/z 540 (M+,
1.84%), 541 (M+1, 4.41%), 542 (M+2, 1.50%) with a base
peak at 384 and other significant peaks appeared at 456
(0.31%), 328 (2.58%), 300 (5.04%), 201 (2.76%), 180 (0.42%),
127 (5.85%), and 77 (1.12%). UV spectrum of 9a exhibited
lmax at 278, 288 nm and Log e at 4.24, 4.26.
and 11 seemed possible. Structure 10 was established for the
reaction product on the basis of its IR spectrum, which showed
the presence of (CºN) band. Compound 6b was also reacted
with phenyl isothiocyanate in pyridine to give pyrimidoquin-
oline derivative 11. Compound 11 was also obtained by heat-
ing 10 in pyridine (Scheme III). The IR spectrum of 10
showed bands at 3400, 3300 (2NH), 3070 (CH arom.), 2960
1
(CH aliph.), 2200 (CºN), and 1650 cm-1 (C=O). H NMR
spectrum of (10 in DMSO-d6) revealed signals at d 0.6, 0.7
[2s, 6H, 2CH3], 0.8, 1.2 [2s, 4H, 2CH2 cyclo], 4.6 [s, 1H, CH
pyridine], 7.3-7.8 [m, 16H, Ar-H], 8.1, and 8.2 [2s, 2H,
2NH]. UV spectrum of 10 showed lmax at 276, 284 nm and
Log e at 3.74, 3.75. The IR spectrum of 11 showed the ab-
sence of (CºN) band and presence of bands at 3210 (NH),
3070 (CH arom.), 2950 (CH aliph.), 1630 (C=O), and 1600
cm-1 (C=N). Mass spectrum of 11 revealed a molecular ion
peak m/z at 633 (M+, 12.43%), with a base peak at 127, and
other significant peaks appeared at 617 (17.01%), 538
(13.51%), 460 (28.85%), 347 (37.84%), 294 (48.73%), 230
(57.03%), and 86 (34.58%). UV spectrum of 11 showed lmax
at 270, 290 nm and Log e at 3.78. The enaminonitrile 6b was
reacted with triethylorthoformate in acetic anhydride to yield
the ethoxymethylideneamino derivative 12. On using trieth-
ylorthoformate only without acetic anhydride the same prod-
uct 12 was obtained in good yield. The IR spectrum of 12
showed bands at 3080 (CH arom.), 2970 (CH aliph.), 2210
In addition, the behaviour of 6b towards phenyl isothio-
cyanate under different conditions was also studied. Thus, re-
action of 6b with phenyl isothiocyanate in boiling ethanol af-
forded a product (C35H29N4OSBr) for which two structures 10
1
(CºN), 1680 (C=O), and 1620 cm-1 (C=N). H NMR spec-
Scheme IV
Br
O
H
CN
Me
N = C-OC2H5
N
Me
9a
CH3
Ac2O
C (OC2H5)3
CH3
13
Br
Br
O
H
CO2C2H5
CO2C2H5
OC2H5
N
O
CN
H
Me
CH(OC2H5)3
Ac2O
6b
N = CHOC2H5
N
Me
Me
Me
CO2C2H5
N
N
12
14

New Biologically Active Quinoline Derivative
J. Chin. Chem. Soc., Vol. 52, No. 6, 2005 1231
trum of (12 in DMSO-d6) revealed signals at 0.65, 0.8 [2s,
6H, 2CH3 cyclo], 0.9 [t, 3H, CH3 ethyl], 2.1, 2.5 [2s, 4H,
2CH2 cyclo], 4.8 [q, 2H, CH2 ethyl], 5.1 [s, 1H, CH pyridine],
7.4-7.8 [m, 11H, Ar-H], and 8.1 [s, 1H, N=CH]. UV spectrum
of 12 revealed lmax at 270 nm and Log e at 3.97.
tion of 6b with ethylacetoacetate under conditions of fusion
gave a product which was formulated as quinoline derivative
15 (Scheme V). The IR spectrum of 15 showed bands at 3380
(NH), 3100 (CH arom.), 2940 (CH aliph.), 2220 (CºN),
1710, 1700, 1680 cm-1 (3C=O). 1H NMR spectrum of (15 in
DMSO-d6) exhibited signals at d 0.7, 0.8 [2s, 6H, 2CH3], 2.1,
2.2 [2s, 4H, 2CH2], 2.5 [s, 3H, COCH3], 4.6 [s, 1H, CH
pyridine], 5.6 [s, 2H, CH2CO], 7.4-8.1 [m, 11H, Ar-H], and
8.4 [s, 1H, NH]. UV spectrum of 15 revealed lmax at 273, 285
nm and Log e at 4.19, 4.24. Interaction of compound 6b with
benzoylchloride afforded the pyrimido-quinoline derivative
16 (Scheme V). The IR spectrum showed the absence of
(CºN) band and presence of bands at 3100 (NH), 3080 (CH
arom.), 2930 (CH aliph.), 1690, 1660 cm-1 (2C=O). 1H NMR
spectrum of compound (16 in DMSO-d6) exhibited signals at
d 0.8, 0.9 [2s, 6H, 2CH3], 2.3, 2.4 [2s, 4H, 2CH2], 5.4 [s, 1H,
CH pyridine], 7.4-8.2 [m, 17H, Ar-H+NH]. UV spectrum of
16 showed lmax at 286 nm and Log e at 4.17.
Also, interaction of 6b with triethylorthoacetate in ace-
tic anhydride produced compound 9a, instead of the expected
product 13. This result was proved using IR spectrum which
showed the absence of (CºN) band, and, 1H NMR data, which
exhibited the absence of a triplet and a quartet due to the ethyl
group. Cyclocondensation of 6b with diethyloxalate in etha-
nol containing sodium ethoxide yielded the corresponding
pyrimidoquinoline derivative 14; its IR spectrum showed
bands at 1760, 1720 (2C=O), and 1660 cm-1 (C=N). 1H NMR
spectrum of (14 in DMSO-d6) revealed signals at d 0.6, 0.8
[2s, 6H, 2CH3], 1.1 [m, 6H, 2CH3 ethyl], 2.1, 2.3 [2s, 4H,
2CH2 cyclo], 4.0, 4.4 [m, 4H, 2CH2 ethyl], 5.0 [s, 1H, CH
pyridine], and 7.4-8.1 [m, 11H, Ar-H]. Mass spectrum of
compound 14 exhibited a molecular ion peak m/z at 626 (M+,
0.9%), with a base peak at 368 and other significant peaks ap-
peared at 599 (9.17%), 499 (3.37%), 442 (35.12%), 342
(17.88%), 256 (4.48%), 155 (7.81%), 127 (22.03%), and 77
(2.88%). UV spectrum of 14 revealed lmax at 285 nm and Log
e at 4.10. This work was extended to cover the reactivity of
compound 6b toward carbonyl compounds. Thus, condensa-
Fusion of compound 6b with succinic anhydride yielded
the unexpected pyrrolidine derivative 17b through the initial
formation of the expected intermediate 17a based on elemen-
tal analysis and IR spectrum which showed the absence of
(NH) band and presence of bands at 3070 (CH arom.), 2960
(CH aliph.), 2220 (CºN), 1750, 1700, 1670 (3C=O), and
1620 cm-1 (C=N). Mass spectrum of compound 17b exhibited
Scheme V
Br
O
O
Br
O
H
O
O
CN
H
CN
NHCOCH2CH2COOH
Me
Me
PhCOCl
6b
NHCOPh
Me
Me
N
D
Fusion
N
17a
Fusion
CH3COCH2COOEt
Br
Br
Br
O
O
H
O
O
NH
H
H
Me
Me
CN
CN
NH
O
Ph
N
N
Me
Me
Me
Me
N
O
N
N
O
CH3
O
16
17b
15

1232 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Abdel-Gawad et al.
a molecular ion peak m/z at 580 (M+, 4.33%), 581 (M+1,
9.51%), 582 (M+2, 4.01%) with a base peak at 424, and
other significant peaks appeared at 579 (M-1, 10.04%), 479
(8.14%), 312 (3.63%), 290 (20.83%), 207 (11.32%), 127
(83.82%), and 55 (34.58%). UV spectrum of 17b showed
lmax at 274, 282 nm and Log e at 4.23, 4.24. The reaction of
enaminone 3 with ethyl-a-cyano-b-ethoxyacrylate by reflux-
ing in ethanol afforded a high yield of 2-cyano-3-[4,4-di-
methyl-2-(naphthalen-1-ylamino)-6-oxo-cyclohex-1-enyl]-
acrylic acid ethyl ester 18 instead of its expected isomer 19
(Scheme VI). The structure of 18 was established by elemen-
tal analysis and IR spectrum which showed the presence of
(NH) band at 3220 cm-1 and (CH aliph.) at 2940 cm-1, (CºN)
at 2210 cm-1, and (2C=O) at 1690, 1640 cm-1. 1H NMR spec-
trum of compound (18 in DMSO-d6) showed signals at d 1.0
[s, 6H, 2CH3], 1.2 [t, 3H, CH3 ethyl], 2.1, 2.5 [2s, 4H, 2CH2
cyclo], 4.2 [q, 2H, CH2 ethyl], 7.3-8.0 [m, 7H, Ar-H], 8.2 [s,
1H, NH], and 9.1 [s, 1H, CH]. Mass spectrum of compound
18 exhibited a molecular ion peak m/z at 388 (M+, 1.85%)
with a base peak at 180, and other significant peaks appeared
at 341 (0.24%), 314 (0.31%), 265 (71.70%), 209 (83.50%),
127 (38.27%), and 77 (17.39%). UV spectrum of 18 showed
lmax at 327 nm and Log e at 4.02. The structure of compound
18 was further confirmed upon conducting it to an intra-
molecular cyclization reaction. Thus, when compound 18
was heated in glacial acetic acid, cyclization occured and the
corresponding quinoline 20 was obtained. The IR spectrum
of 20 showed bands at 3050 (CH arom.), 2960 (CH aliph.),
2210 (CºN), 1680, 1660 cm-1 (2C=O). Mass spectrum of
compound 20 exhibited a molecular ion peak m/z at 342 (M+,
2.54%), with a base peak at 265 and other significant peaks
appeared at 333 (4.70%), 313 (8.23%), 295 (3.53%), 209
(87.57%), 180 (74.84%), 127 (28.58%), 115 (23.21%), and
55 (23.21%). UV spectrum of 20 showed lmax at 274 nm and
Log e at 3.77.
EXPERIMENTAL
Melting points are uncorrected and were determined on
a Stuart melting point apparatus. IR spectra were recorded on
a Pye-Unicam SP 3-100 spectrophotometer using the KBr
1
technique. H NMR spectra were recorded on a BRUKER
proton NMR-Avance 300 (300 MHz), in DMSO-d6 as a sol-
vent, using tetramethylsilane (TMS) as internal standard.
Mass spectra were run on an HP Model MS-5988. Elemental
analyses were carried out at the microanalytical laboratories
of the Faculty of Science, Cairo University. The samples
Scheme VI
O
Me
Me
CN
CO2Et
N - CH
O
19
EtO
H
CN
CO2C2H5
Me
Me
NH
H
O
CN
Me
Me
CO2Et
NH
3
H
N
18
O
CN
O
Me
Me
AcOH
D
20

New Biologically Active Quinoline Derivative
J. Chin. Chem. Soc., Vol. 52, No. 6, 2005 1233
were irradiated with gamma radiation (60Co) at the National
Center for Radiation Research and Technology. Powder sam-
ples were irradiated at room temperature conditions in poly-
carbonate vials at a dose rate of (10 KGy/h). UV spectra were
recorded using an ATI unicam. UV/Vis AURORA SCAN.
in an oil bath for 6 h. The reaction mixture was cooled, di-
luted with ethanol and the resulting solid was crystallized
from dioxane to give 11.
Method (B):
A solution of 10 (6.33 g, 0.01 mol) in pyridine (5 mL)
was refluxed for 5 h. The reaction mixture was then cooled
and diluted with ethanol/H2O to give 11.
2-Amino-4-substituted-7,7-dimethyl-1-naphthalen-1-yl-5-
oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (6a-d)
A mixture of 3 (2.63 g, 0.01 mol), appropriate cinna-
monitrile 4a-d (0.01 mol) and triethylamine (3 drops) in etha-
nol (15 mL) was refluxed for 30 min. The solid obtained upon
cooling was crystallized from ethanol to give 6a-d.
N-[4-(3-Bromo-phenyl)-3-cyano-7,7-dimethyl-1-naphthalen-
1-yl-5-oxo-1,4,5,6,7,8-hexahydro-quinolin-2-yl]formimidic
acid ethyl ester (12)
A mixture of 6b (4.98 g, 0.01 mol), triethylorthofor-
mate (2 mL) and acetic anhydride (10 mL) was refluxed for 8
h. The reaction mixture was left to cool overnight and the
solid formed was crystallized from ethanol to give 12.
4-Amino-5-(3-bromo-phenyl)-8,8-dimethyl-10-naphthalen-
1-yl-5,8,9,10-tetrahydro-7H-pyrimido[4,5-b]quinolin-6-one
(7)
A solution of 6b (4.98 g, 0.01 mol) in formamide (5
mL) was refluxed for 5 h. The solid obtained was crystallized
from dioxane to give 7.
5-(3-Bromo-phenyl)-4-ethoxy-8,8-dimethyl-10-naphthalen-
1-yl-6-oxo-5,6,7,8,9,10-hexahydro-pyrimido[4,5-b]quino-
line-2-carboxylic acid ethyl ester (14)
A mixture of 6b (4.98 g, 0.01 mol) and diethyloxalate
(0.01 mol) in ethanol containing (0.01 mol) sodium ethoxide
was refluxed for 3 h. The obtained product was crystallized
from ethanol to give 14.
5-(3-Bromo-phenyl)-8,8-dimethyl-10-naphthalen-1-yl-
5,8,9,10-tetrahydro-3H,7H-pyrimido[4,5-b]quinoline-4,6-
dione (8)
A solution of 6b (4.98 g, 0.01 mol) in formic acid (5
mL), was refluxed for 4 h. The solid obtained was crystal-
lized from ethanol to give 8.
N-[4-(3-Bromo-phenyl)-3-cyano-7,7-dimethyl-1-naphthalen-
1-yl-5-oxo-1,4,5,6,7,8-hexahydro-quinolin-2-yl]-3-oxo-bu-
tyramide (15)
5-(3-Bromo-phenyl)-2,8,8-trimethyl-10-naphthalen-1-yl-
5,8,9,10-tetrahydro-3H,7H-pyrimido[4,5-b]quinolin-4,6-
dione (9a)
A mixture of 6b (4.98 g, 0.01 mol) and ethylaceto-
acetate (15 mL) was fused at 180 °C for 1 h. The obtained
solid was crystallized from acetic acid to give 15.
A solution of 6b (4.98 g, 0.01 mol) in acetic anhydride
(10 mL) was refluxed for 3 h. After cooling the solid obtained
was crystallized from ethanol to give 9a.
5-(3-Bromo-phenyl)-8,8-dimethyl-10-naphthalen-1-yl-2-
phenyl-5,8,9,10-tetrahydro-3H,7H-pyrimido-[4,5-b]quino-
line-4,6-dione (16)
1-[4-(3-Bromo-phenyl)-3-cyano-7,7-dimethyl-1-naphthalen-
1-yl-5-oxo-1,4,5,6,7,8-hexahydro-quinolin-2-yl]-3-phenyl-
thiourea (10)
A mixture of 6b (4.98 g, 0.01 mol) and benzoylchloride
(1.40 g, 0.01 mol) in pyridine (20 mL) was refluxed for 12 h.
The obtained product was crystallized from dioxane to give
16.
A mixture of 6b (4.98 g, 0.01 mol), phenyl isothio-
cyanate (1.35 g, 0.01 mol) and absolute ethanol (10 mL) was
refluxed for 5 h. The solid obtained was crystallized from eth-
anol to give 10.
4-(3-Bromo-phenyl)-2-(2,5-dioxo-pyrrolidin-1-yl)-7,7-di-
methyl-1-naphthalen-1-yl-5-oxo-1,4,5,6,7,8-hexahydro-
quinoline-3-carbonitrile (17)
5-(3-Bromo-phenyl)-4-imino-8,8-dimethyl-2-thioxo-10-
naphthalen-1-yl-3-phenyl-2,3,4,5,7,8,9,10-octahydro-1H-
pyrimido[4,5-b]quinolin-6-one (11)
A mixture of 6b (4.98 g, 0.01 mol) and succinic anhy-
dride (1 g, 0.01 mol) was fused at 220 °C for 15 min. The ob-
tained product was cooled, ground to a fine powder in an mor-
tar to give 17, and treated with NaOH (4%, 100 mL); the fil-
trate was acidified with dil HCl. The obtained product was
crystallized from acetic acid to give 17.
Method (A):
A mixture of 6b (4.98 g, 0.01 mol), phenyl isothio-
cyanate (1.35 g, 0.01 mol) and pyridine (20 mL) was refluxed

1234 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Abdel-Gawad et al.
2-Cyano-3-[4,4-dimethyl-2-(naphthalen-1-yl-amino)-6-
oxo-cyclohex-1-enyl]acrylic acid ethyl ester (18)
ANTIMICROBIAL ACTIVITY
A mixture of 3 (2.63 g, 0.01 mol) and ethyl-a-cyano-
b-ethoxyacrylate (1.69 g, 0.01 mol) in ethanol (30 mL) was
refluxed for 5 h. The precipitate that separated after cooling
was collected and crystallized from ethanol to give 18.
Fourteen compounds were screened in vitro for their anti-
microbial activities against Gram positive bacteria Staphylo-
coccus aureus [29213], Gram negative bacteria Escherichia
coli (ATCC 25922) and one yeast fungus Saccharomyces
Cerevisiae by the agar diffusion technique.22 A 1 mg/mL so-
lution in dimethylformamide was used. The bacteria and
fungi were maintained on nutrient agar and Czapek’s-Dox
agar media, respectively. DMF showed no inhibition zones.
The agar media were inoculated with different microorgan-
ism’s culture tested after 24 hrs. of incubation at 30 °C for
bacteria and 48 hrs. of incubation at 28 °C for fungi; the diam-
eter of inhibition zone (mm) was measured (Table 2). Ofloxacin
Cyclization of 18: formation of 7,7-dimethyl-1-naph-
thalen-1-yl-2,5-dioxo-1,2,5,6,7,8-hexahydro-quinoline-3-
carbonitrile (20)
A solution of 18 (3.88 g, 0.01 mol) in glacial acetic acid
(15 mL) was heated under reflux for 4 h. The solid that sepa-
rated after cooling was collected by filtration and crystallized
from acetic acid to give 20.
Table 1. Characterization data for newly synthesized compounds (6a-20)
Elemental Analyses
Calculated /Found.
Compound
No.
M.P.
(°C)
Yield
(%)
Mol. Formula
(Mol.Wt)
C %
H %
N %
6a
6b
6c
6d
7
262-264
266-268
216-218
279-281
170-172
98-100
91
63
59
55
57
76
68
74
81
76
79
69
75
81
77
72
C28H23N3OF2
(455)
C28H24N3OBr
(498)
C31H31N3O4
(509)
C27H24N4O
(420)
C29H25N4OBr
(525)
C29H24N3O2Br
(526)
C30H26N3O2Br
(540)
C35H29N4OSBr
(633)
C35H29N4OSBr
(633)
C31H28N3O2Br
(554)
C34H32N3O4Br
(626)
C32H28N3O3Br
(582)
C35H28N3O2Br
(602)
C32H26N3O3Br
(580)
C24H24N2O3
(388)
C22H18N2O2
(342)
73.85
73.60
67.47
67.80
73.08
73.30
77.14
77.40
66.29
66.50
66.16
66.40
66.67
66.40
66.35
66.60
66.35
66.10
67.15
67.30
65.18
65.50
65.98
65.70
69.77
69.90
66.21
66.50
74.23
74.50
77.19
77.50
5.05
4.90
4.82
4.60
6.09
6.30
5.71
5.50
4.76
4.40
4.56
4.70
4.81
4.90
4.58
4.80
4.58
4.30
5.05
5.30
5.11
5.30
4.81
4.60
4.65
4.80
4.48
4.70
6.19
6.40
5.26
5.50
9.23
9.50
8.43
8.20
8.25
8.50
13.330
13.100
10.670
10.400
7.98
7.70
7.78
7.50
8.85
8.60
8.85
9.10
7.58
7.80
6.71
6.40
7.22
7.50
6.98
6.70
7.24
7.50
7.22
7.10
8.19
8.40
8
9a
10
11
12
14
15
16
17b
18
20
334-336
113-115
166-168
218-220
200-202
153-155
91-93
213-215
128-130
158-160

New Biologically Active Quinoline Derivative
J. Chin. Chem. Soc., Vol. 52, No. 6, 2005 1235
Table 2. Antimicrobial activity of the newly synthesized compounds
Compound
No.
Staphylococcus aureus
(29213)
Escherichia coli
(ATCC 25922)
Saccharomyces
Cerevisiae
6a
6b
6c
++
0
0
0
+
0
+++
0
0
6d
+
0
0
7
+
0
+
8
9a
++
+
0
0
+
0
10
11
12
0
0
0
0
0
0
+++
++++
+
14
+
0
+
15
16
0
0
0
+
++
+
18
++
++++
0
+++
+++
0
Ofloxacina
(Tarivid)
SXTa
Mycostatineb
DMF
++++
0
0
+++
0
0
0
+++
0
a Ofloxacin and SXT (Trimethoprime + Sulfamethoxazole) were supplied from Oxoid Lab.,
England.
b Manufactured by Bristol Myers Squibb, Giza, Egypt.
Well diameter 1 cm
Inhibition values = 0.1-0.5 cm beyond control = +,
Inhibition values = 0.6-1.0 cm beyond control = ++,
Inhibition values = 1.1-1.5 cm beyond control = +++,
Inhibition values = 1.6-2.0 cm beyond control = ++++,
0 = Not detected.
Table 3. UV data of biologically active compounds before and after gamma-irradiation
Compound
Dose (KGy) Conc. (Mol) lmax(1) Abs. (O.D.) lmax(2) Abs. (O.D.)
Control
05
10
15
20
25
30
40
282
282
282
282
282
282
282
282
0.892
0.938
0.982
1.041
1.042
1.072
1.081
1.086
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
6a
5 ´ 10-5
5 ´ 10-5
5 ´ 10-5
Control
05
10
15
20
25
30
40
276
276
276
276
276
276
276
276
1.101
1.107
1.123
1.128
1.134
1.152
1.156
1.150
284
284
284
284
284
284
284
284
1.142
1.163
1.212
1.230
1.274
1.249
1.250
1.255
10
11
Control
05
10
15
20
25
30
40
270
270
270
270
270
270
270
270
1.214
1.218
1.231
1.236
1.238
1.230
1.248
1.256
290
290
290
290
290
290
290
290
1.209
1.211
1.222
1.225
1.220
1.234
1.241
1.244
Abs. = Absorbance.

1236 J. Chin. Chem. Soc., Vol. 52, No. 6, 2005
Abdel-Gawad et al.
and SXT in a concentration of 30 mg mL-1 and Mycostatine 30
mg mL-1 were used as a reference for antibacterial and anti-
fungal activities, respectively. The minimal inhibitory con-
centration (MIC) of the biologically active compounds was
measured by a two fold serial dilution method. The data ob-
tained are summarized in Table 2. The quinoline derivative
6a containing 2,4-difluorophenyl in position four, quinoline
derivative 10 having thiourea and 3-bromophenyl moieties
and quinolinopyrimidine derivative 11 containing thioxo
moiety and cyclo derivative 18 were found to be the most ac-
tive compounds against Saccharomyces Cerevisiae, whereas
compounds 6a, 8 and 18 showed a moderate activity against
Staphylococcus aureus (29213). From these results it can be
concluded that the biologically active compounds 6a, 10, 11
and 18 (MIC values were < 50 mg/mL) are nearly as active as
the standared Mycostatine.
ment of Drug Radiation Research, National Center for Radia-
tion Research and Technology, Cairo, Egypt, for doing the
antimicrobial activity of some synthesized compounds.
Received October 13, 2004.
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RADIOSTABILITY OF THE BIOLOGICALLY
ACTIVE COMPOUNDS
The aim of the present work is to investigate the stabil-
ity of the chemical structure of the biologically active com-
pounds 6a, 10 and 11 after irradiation. These compounds, in
the dry state, were exposed to doses of gamma irradiation
ranging from 5-40 KGy. Ultraviolet measurements (UV spec-
tra) and thin layer chromatography (TLC) were run before
and after irradiation to probe any change after irradiation.
The UV spectra of unirradiated (control) and irradiated com-
pounds in DMF as solvent are listed in Table 3. The results
showed that all of the biologically active compounds 6a, 10
and 11 remain radioresistant, retaining their structure un-
changed up to 40 KGy (Table 3).
Further, thin layer chromatographic analyses (Rf) were
made on precoated silica gel G sheets 1B-F and were detected
by use of a UV Lamp at 254 nm. The Rf values of the un-
irradiated compounds 6a, 10 and 11 were 0.37, 0.46 and 0.39,
respectively [eluent benzene/ethylacetate 8.5/1.5]. After irra-
diation, the irradiated compounds gave identical Rf values as
before irradiation. This means that the structures of these
compounds remain radioresistant, and sterilization of these
compounds in dry form by gamma irradiation may prove to
be applicable.
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ACKNOWLEDGMENTS
Many thanks are due to Prof. Dr. A. I. El. Batal Depart-