Synthesis and biological activity of some novel thieno[2,3-b]quinoline, quinolino[3′,2′-4,5] thieno[3,2-d]pyrimidine and pyrido[2′,3′:4,5] thieno[2,3-b]quinoline derivatives

Article abstract of DOI:10.1080/104265090970322

Thieno [2,3-b] quinoline derivative 5 was synthesized by the cycloalkylation of compound bi 3a with chloro acetonitrile. Interaction of compound 5 with formic acid, formamide, and thioacetamide furnished the corresponding quinolino[3′,2′:4,5]thieno[3,2-d]

Full text of DOI:10.1080/104265090970322

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Phosphorus, Sulfur, and Silicon
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Synthesis and Biological
Activity of Some Novel
Thieno[2,3-b]quinoline,
Quinolino[3′,2′:4,5]
thieno[3,2-d]pyrimidine and
Pyrido[2′,3′:4,5] thieno[2,3-
b]quinoline Derivatives
M. S. A. El-Gaby a , S. M. Abdel-Gawad b , M. M.
Ghorab c , H. I. Heiba c & H. M. Aly c
a Department of Chemistry , Al-Azhar University at
Assiut , Assiut, Egypt
b Department of Chemistry , Al-Azhar University ,
Cairo, Egypt
c Department of Drug Radiation Research , National
Centre for Radiation Research and Technology , Nasr
City, Cairo, Egypt
Published online: 16 Aug 2006.
To cite this article: M. S. A. El-Gaby , S. M. Abdel-Gawad , M. M. Ghorab , H. I.
Heiba & H. M. Aly (2006) Synthesis and Biological Activity of Some Novel Thieno[2,3-
b]quinoline, Quinolino[3′,2′:4,5] thieno[3,2-d]pyrimidine and Pyrido[2′,3′:4,5]
thieno[2,3-b]quinoline Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 181:2, 279-297, DOI: 10.1080/104265090970322
To link to this article: http://dx.doi.org/10.1080/104265090970322
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Phosphorus, Sulfur, and Silicon, 181:279–297, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090970322
Synthesis and Biological Activity of Some Novel
Thieno[2,3-b]quinoline, Quinolino[3ꢀ,2ꢀ:4,5]
thieno[3,2-d]pyrimidine and Pyrido[2ꢀ,3ꢀ:4,5]
thieno[2,3-b]quinoline Derivatives
M. S. A. El-Gaby
Department of Chemistry, Al-Azhar University at Assiut, Assiut, Egypt
S. M. Abdel-Gawad
Department of Chemistry, Al-Azhar University, Cairo, Egypt
M. M. Ghorab
H. I. Heiba
H. M. Aly
Department of Drug Radiation Research, National Centre for Radiation
Research and Technology, Nasr City, Cairo, Egypt
Thieno [2,3-b] quinoline derivative
5 was synthesized by the cycloalkyla-
tion of compound bi 3a with chloro acetonitrile. Interaction of compound 5
with formic acid, formamide, and thioacetamide furnished the corresponding
quinolino[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine derivatives 7, 8, and 9, respectively.
Also, quinolinothienopyrimidine 11 was obtained in good yield by cyclization of
compound 5 with phenyl isothiocyanate under reflux in pyridine. Triethyl orthofor-
mate reacted with compound 5 to form the ethoxymethylene derivative 12. Reflux-
ing of 5 with acetic anhydride for a short time afforded acetamide derivative 16,
whereas when refluxed for a long time furnished the diacetyl derivative 17. Fusion of
compound 5 with urea and thiourea yielded the corresponding quinolinothienopy-
rimidines 19 and 20, respectively. When compound 5 was reacted with urea in the
presence of sodium ethoxide, the corresponding ureado derivative 18 was obtained.
Received December 1, 2004; accepted February 15, 2005.
Many thanks are due to Prof. Dr. A. I. El-Batal, Department of Drug Radiation Re-
search, National Centre for Radiation Research and Technology, Cairo, Egypt, for doing
the antimicrobial activity of some of the synthesized compounds.
Address correspondence to M. S. A. El-Gaby, Al-Azhar University at Assiut, De-
partment of Chemistry, Faculty of Science, Assiut, 71524 Egypt. E-mail: m-elgaby@
hotmail.com
279

280
M. S. A. El-Gaby et al.
Treatment of 5 with sulfuric acid at r.t. furnished the novel thienoquinoline 6, while
on heating gave the acid derivative 21. Pyrido [2ꢀ,3ꢀ: 4,5]thieno [2,3-d] quinoline
23–25 were synthesized by the interaction of 5 with ethyl cyanoacetate, benzyli-
denemalononitrile, and acetaldehyde/malononitrile, respectively. On preliminary
screening, compounds 22 and 25 exhibited in vitro growth that was inhibitory activ-
ity against Saccharomyces Cerevisiae when compared with the standard fungicide
Mycostatine. The structure of the biologically active compounds 22 and 25 remain
unchanged when exposed to gamma irradiation up to 40 KGy.
Keywords Quinoline; thieno[2,3-b]quinoline; condensed quinoline derivatives
INTRODUCTION
Thieno [2,3-b] quinoline derivatives were reported to furnish in-
teresting biological properties that show antimicrobial1−3 and
antibiotics4 activities. In connection with our efforts to synthe-
size fused heterocycles5−12 from readily available starting mate-
rials, we report here on the synthesis of some novel thieno[2,3-
b]quinoline, quinolino[3ꢀ,2ꢀ:4,5]thieno[3,2-d] pyrimi-dine, and pyrido
[2ꢀ,3ꢀ;4,5]thieno[2,3-b] quinoline derivatives in order to investigate the
antimicrobial activity. In recent years considerable interest has been de-
veloped regarding the radiation sensitivity of various antibiotics13−16
and synthetic biologically active heterocyclic compounds.17−22 Studies,
for the most part, have focused on the correlation between chemical
structure and biological function. Generaly, data of these compounds
indicates that even at a dose of 25 KGy, the radiosterilization may be
feasible.23,24
CHEMISTRY
The starting materials 3a, b were synthesized by cyclocondensation25
of (4-flourophenyl and/or 4-pipronyl) methylenecyanothioacetamide 1a,
b with dimedone 2. The structure of 3a, b was established through
microanalyses, IR, 1H NMR, and mass spectral data. The IR spectrum
of 3a showed bands at 3300 (NH), 3050 (CH arom.), 2930 (CH aliph.),
2200 (C N), 1670 (C O), and 1630 cm−1 (C N). Its 1H NMR spectrum
(in DMSO-d6) exhibited signals at δ 0.9, 1.1 [2s, 6H, 2CH3], 2.2, 2.3 [2s,
4H, 2CH2], 4.5 [s,1H, pyridine CH], 7.0–7.5 [m, 4H, Ar-H], and 10.0
[s, 1H, NH]. Mass spectrum of 3a showed a molecular ion peak m/z at
328 (M+, 54.30%), 327 (M-1, 29.23%), and 326 (M-2, 84.10%) with a
base peak at 83, and other significant peaks appeard at 270 (80.0%),
244 (4.51%), 210 (23.08%), 182 (40.0%), and 95 (89.23 %). IR spectrum
of compound 3b revealed bands at 4380 (NH), 3100 (CH arom.), 2940
(CH aliph.), 2200 (C N), 1650 (C O), and 1580 cm−1 (C N). 1H NMR

Synthesis and Biological Activity of Some Derivatives
281
spectrum of (3b in DMSO-d6) exhibited signals at δ 1.5, 1.6 [2s, 6H,
2CH3], 2.1, 2.5 [2s, 4H, 2CH2], 4.5 [hump, 2H, pyridine CH + NH], 6.1 [s,
1H, O CH2 O], and 7.0–7.5 [m, 3H, Ar-H]. Its mass spectrum showed
a molecular ion peak m/z at 352 (M-2, 4.88%), with a base peak at 296,
and other significant peaks appeared at 266 (27.53%), 238 (21.25%), 178
(18.82%), 135 (44.60%), and 55 (93.73%). Cycloalkylation of compound
3a with chloroacetonitrile in the presence of sodium ethoxide in ethanol
under reflux yielded the novel thieno [2,3-b]-quinoline derivative 5 in
good yield. The structure of compound 5 was characterized by analytical
and spectral data. The IR spectrum of 5 showed bands at 3470, 3340,
3200 (NH, NH2), 2950 (CH aliph.), 2200 (C N), 1640 (C O), and 1600
cm−1 (C N). 1H NMR spectrum of (5 in DMSO-d6) revealed signals at
δ 0.9, 1.1 [2s, 6H, 2CH3], 2.2, 2.5 [2s, 4H, 2CH2], 5.0 [s, 1H, pyridine
CH], 6.2 [s, 2H, NH2], 6.9–7.4 [m, 4H, Ar-H], and 10.3 [s,1H, NH]. The
formation of thienoquinoline 5 is assumed to proceed through the initial
alkylation to form (4) followed by an intramolecular cyclization and
tautomerization to yield 5 (Scheme 1).
SCHEME 1

282
M. S. A. El-Gaby et al.
Heteroaromatic orthoaminocarbonitriles are versatile intermedi-
ates, which have been extensively utilized in the synthesis of condensed
heterocyclic compounds.26,27 Thus, the refluxing of 5 with formic acid
afforded the quinolino[3ꢀ,2ꢀ:4,5]thieno[3,2-d] pyrimidine derivative 7.
The IR spectrum of compound 7 showed bands at 3200 (NH), 2940 (CH
aliph.), 1680, 1660 (2C O), and 1640 cm−1 (C N). The mass spectrum
of 7 exhibited a molecular ion peak m/z at 395 (M+, 22.0 %), 396 (M + 1,
5.34%), 397 (M + 2, 18.41%), and 398 (M + 3, 6.52%), with a base peak at
393 and other significant peaks appeared at 337 (85.40%), 300 (44.8%),
254 (24.42%), 183 (10.80%), 109 (18.21%), and 83 (13.71%).
The formation of compound 7 is assumed to proceed via the amide
formation28 6 followed by an intramolecular cyclization with formic acid
to furnish 7 (Scheme 2).
Also, compound 5 was cyclocondensed with formamide under reflux
and afforded the quinolinothienopyrimidine 8. The IR spectrum of 8
showed bands at 3300, 3200 (br, NH, NH2), 2930 (CH aliph.), and 1670
cm−1 (C O). Its 1H NMR spectrum in (DMSO-d6) revealed signals at δ
1.1, 1.2 [2s, 6H, 2CH3], 2.1, 2.4 [2s, 4H, 2CH2], 4.6 [s, 1H, pyridine CH],
7.0–7.8 [m, 6H, Ar-H + NH2], 8.3 [s, 1H, CH pyrimidine], and 10.2 [s,
1H, NH]. Cyclocondensation of compound 5 with thioacetamide under
reflux in trifluoroacetic acid29 produced the novel quinolinothienopy-
rimidine 9 in a high yield. The IR spectrum of 9 showed bands at 3390,
3200 (2NH), 2930 (CH aliph.), 1640 (C O), 1600 (C N), and 1290 cm−1
(C S). Mass spectrum of compound 9 revealed a molecular ion peak
m/z 425 (M+, 53.22%) and 424 (M-1, 17.80%) with a base peak at 95,
and other significant peaks appeared at 340 (28.33%), 330 (88.53%),
300 (27.47%), and 75 (44.21%). Compound 5 was treated with phenyl
isothiocyanate under reflux in pyridine to give the corresponding con-
densed pyrimidinethione 11. Its IR spectrum showed bands at 3220,
3180 (NH), and 3100 (CH arom.), 1650 (C O), 1600 (C N), and 1310
cm−1 (C S). Mass spectrum of 11 exhibited a molecular ion peak m/z
at 501 (M-1, 41.48%) together with a base peak at 107, and other sig-
nificant peaks appeared at 252 (35.20%), 213 (55.88%), 202 (44.12%),
118 (41.48%), and 98 (55.88%). The formation of 11 was assumed to
proceed via the thiourea intermediate 10 followed by the intramolecu-
lar cyclization at the adjcent cyano function group to form 11. Reflux-
ing of compound 5 with triethylorthoformate in the presence of acetic
anhydride yielded the ethoxymethyleneamino derivative 12. The IR
spectrum of 12 showed bands at 3280 (NH), 2950 (CH aliph.), 2210
1
(C≡N), 1680(C O), and 1620 cm−1 (C N), the H NMR spectrum of
(12 in DMSO-d6) revealed signals at δ 0.9, 1.2 [2s, 6H, 2CH3], 1.8 [t,
3H, CH3 ethyl], 1.9, 2.1 [2s, 4H, 2CH2], 4.1 [s, 1H, pyridine CH], 5.1
[q, 2H, CH2 ethyl], 6.2 [s, 1H, N CH], 7.0–7.4 [m, 4H, Ar-H], and 9.9

Synthesis and Biological Activity of Some Derivatives
283
SCHEME 2
[s,1H, NH]. When compound 12 was treated with hydrazine hydrate in
benzene at r.t., the enaminonitrile 5 was recovered (m.p., m.m.p., and
TLC). The expected pyrimidine 13 formation was ruled out on the basis
of analytical and spectral data. The formation of 5 from the reaction
of 12with hydrazine hydrate was assumed to proceed via the addition

284
M. S. A. El-Gaby et al.
of hydrazine at the imino function group to form the intermediate 14,
followed by the elimination of ethyl formate hydrazone30 (Scheme 3).
Attempts to synthesize the pyrimidine derivative 15 from compound
5 and acetic anhydride failed. Thus, the acetamide derivative 16 was
achieved by the refluxing of 5 with acetic anhydride for 5 min on the
basis of analytical and spectral data. Its IR spectrum showed the pres-
ence of (NH) at 3480 and 3350 (CH aliph.) at 2940, (C N) function group
1
at 2200 and (2C O) at 1660 and 1630 cm−1. The H NMR; spectrum
of 16 revealed signals at δ 0.9, 1.1 [2s, 6H, 2CH3], 2.1, 2.3 [2s, 4H,
SCHEME 3

Synthesis and Biological Activity of Some Derivatives
285
2CH2], 2.6 [s, 3H, COCH3], 4.9 [s, 1H, pyridine CH], 6.9–7.4 [m, 4H,
A-B system, Ar-H], and 10.2 [s, 2H, 2NH] (Scheme 4). Also, diacetyl
derivative 17 was obtained by the refluxing of compound 5 in acetic
anhydride for a long time. The IR spectrum revealed bands at 3250
(NH), 2950 (CH aliph.), 2200 (C N), 1710, 1700, and 1670 (3C O), and
1
1610 cm−1 (C N). The H NMR spectrum of (17 in DMSO-d6) showed
signals at δ 0.9, 1.1 [2s, 6H, 2CH3], 2.0, 2.1 [2s, 4H, 2CH2], 2.4, 2.6
[2s, 6H, 2COCH3], 4.8 [s, 1H, pyridine CH], and 7.0–7.5 [m, 5H, Ar-
H + NH].
When compound 5 was allowed to react with urea in the presence
of sodium ethoxide in ethanol, a product of the molecular formula
C21H19N4O2SF formed via the elimination of ammonia. Based on the
presence of CN absorption in the IR spectrum. Its IR spectrum showed
bands at 3490, 3320, 3200 (NH, NH2), 2940 (CH aliph.), 2200 (C≡N),
1660, and 1620 (2C O). The mass spectrum of compound 18 exhibited
a molecular ion peak m/z at 410 (M+, 33.11%), with a base peak at 272,
and other significant peaks appeared at 387 (31.78%) 368 (22.30%), 342
(53.38%), 282 (35.81%), 188 (28.38%), 170 (85.14%), 136 (50.88%), 88
(8.08%), and 76 (81.08%) (Scheme 5). While fusion of compound 5 with
urea furnished the condensed pyrimidine 19. Its IR spectrum exhibited
SCHEME 4

286
M. S. A. El-Gaby et al.
SCHEME 5
the disappearance of a band characteristic for the carbonitrile function
group and presence of bands at 3480, 3400, 3200 (NH, NH2), 3100 (CH
arom.), 1730, 1710 (2C O), and 1600 cm−1 (C N). The mass spectrum of
19 revealed a molecular ion peak m/z at 408 (M-2, 73.33%), with a base
peak at 330 and other significant peaks appeard at 379 (58.87%), 309
(88.87%), 272 (73.33%), 102 (50.22%), 71 (43.33%). Also the structure of
compound 19 was proved via another synthetic route through the fusion
of compound 18 at a high temperature. The formation of compound 19
was assumed to proceed through the elimination of ammonia followed
by intramolecular cyclization at the cyano group and tautomerization
to yield 19. In a similar manner compound 5 was cyclized with thiourea
under the condition of fusion to yield thiopyrimidine derivative 20. Its
IR spectrum showed bands at 3360, 3340, 3185 (NH,NH2), 2950 (CH
aliph.), 1640 (C O), 1610 (C N), and 1240 cm−1 (C S). The mass spec-
trum of compound 20 revealed a molecular ion peak m/z at 392 (M-H2S,
8.54%) with a base peak at 126, and other significant peaks appeared
at 313 (8.21%), 257(8.35%), 207 (17.24%), 88 (12.20%), and 76 (28.70%).
The treatment of compound 5 with sulfuric acid at r.t. furnished
the novel carboxamide derivative 6, via partially the hydrolysis of the

Synthesis and Biological Activity of Some Derivatives
287
cyano function group, while the complete hydrolysis of the cyano group
occured when compound 5 was refluxing in sulfuric acid to give the
corresponding acid derivative 21. The IR spectrum of 6 showed bands
at 3480, 3310, 3190 (NH, NH2), 2950, 2820 (CH aliph.), 1650 (2C O),
1
and 1600 cm−1 (C N). Its H NMR spectrum in (DMSO-d6) revealed
signals at δ 0.9, 1.1 [2s, 6H, 2CH3], 2.0–2.2 [2s, 4H, 2CH2], 3.7 [s, 5H,
2NH2 + Pyridine CH], and 7.0–7.6 [m, 5H, Ar-H +NH]. The mass spec-
trum of 6 exhibited a molecular ion peak m/z at 385 (M+, 7.58%) with a
base peak at 109, and other significant peaks appeared at 368 (57.05%),
328 (18.0%), 286 (24.03%), 277 (8.21%), 188 (7.20%), 164 (70.47%),
and 83 (99.48%). The IR spectrum of compound 21 revealed bands at
3400–3300 (NH NH2), 3500–3000 (br, OH), 1690 (2C O), and 590 cm−1
(C N). The mass spectrum of compound 21 exhibited a molecular ion
peak m/z at 386 (M+, 2.71%) and 387 (M + 1, 0.83%) with a base peak at
113, and other significant peaks appeared at 341 (5.57%), 271 (2.70%),
229 (5.70%), 198 (7.81%), 149 (18.88%), and 69 (38.85%). Also compound
6 was obtained via the reaction of compound 3a with chloroacetamide
in methanol in the presence of sodium methoxide. The corresponding
condensed pyrimidine 7 was also obtained by the refluxing of 6 with
formic acid. When compound 5 was refluxed with hydroxylamine in
ethanol in the presence of sodium ethoxide, it gave the pyrazolothieno-
quinoline derivative 22. Compound 22 is assumed to be formed through
the addition of the amino group of hydroxylamine to the cyano function
group followed by intramolecular cyclization by the elimination of wa-
ter. The IR spectrum of 22 showed bands at 3490, 3330, 3215 (NH, NH2),
2930, 2820 (CH aliph.), 1640 (C O), and 1610 cm−1 (C N). The mass
spectrum of compound 22 exhibited a molecular ion peak m/z at 382
(M+, 13.87%) with a base peak at 55 and other significant peaks ap-
peared at 365 (27.31%), 309 (12.18%), 281 (10.50%), 170 (11.34%), and
95 (20.57%). The reaction of 5 with ethyl cyanoacetate in dimethylfor-
mamide in the presence of a few drops of piperidine under reflux yielded
the corresponding pyridothienoquinoline derivative 23. The formation
of compound 23 is assumed to take place via the elimination of ethanol
followed by an intramolecular cyclization at the cyano function group
and tautomerization to yield 23. IR spectrum of 23 showed bands at
3400, 3360, 3190 (NH,NH2), 2930 (CH aliph.), 2220 (C N), 1670, 1620
1
(2C O), and 1600 cm−1 (C N) H NMR spectrum of (23 in DMSO-
d6) revealed signals at δ 1.1, 1.3 [2s, 6H, 2CH3], 2.2 [s, 4H, 2CH2],
4.2 [s,1H, pyridine CH], 6.8–7.5 [m, 6H, Ar-H + NH2], and 8.3 [s, 2H,
2NH]. Compound 5 was cyclocondensed with benzylidenemalononitrile
in ethanol in the presence of a catalytic amount of piperidine under re-
flux and provided the corresponding pyridothienoquinoline derivative
24. IR spectrum of 24 showed bands at 3490, 3320, 3200 (NH, NH2),

288
M. S. A. El-Gaby et al.
2950, 2840 (CH aliph), 2200 (C≡N), 1670 (C O), and 1600 cm−1 (C N).
1
The H NMR spectrum of (24 in DMSO-d6) revealed signals at δ 1.2,
1.3 [2s, 6H, 2CH3], 2.4, 2.5 [2s, 4H, 2CH2], 4.5 [s, 1H, pyridine CH], 6.1
[s, 2H, NH2], 7.0–7.6 [m, 9H, Ar-H], and 7.9 [s,1H, NH]. The formation
of compound 24 can be explained on the basis of an initial Michael ad-
dition of the amino function group in compound 5 to double the bond of
benzylidinemalononitrile followed by intramolecular cyclization, which
loses hydrogen cyanide and tautomerization to give 24 (Scheme 6). Fi-
nally compound 25 was obtained also in good yield via the reaction of
5 with acetaldehyde and malononitrile in refluxing ethanol containing
pyridine. The IR spectrum of compound 25 showed bands at 3480, 3360,
3220 (NH, NH2), 2930, 2870 (CH aliph.), 2195 (C N), 1625 (C O), and
1600 cm−1 (C N). The mass spectrum of 25 revealed a molecular ion
peak m/z at 430 (M+-2, 12.88%) with a base peak at 101, and other
significant peaks appeared at 385 (22.14%), 352 (80.0%), 325 (45.0%),
266 (58.57%), 194 (57.88%), 125 (89.20%), and 83 (0.71%).
EXPERIMENTAL
Melting points are uncorrected and were determined on a stuart melt-
ing point apparatus. IR spectra were recorded on a Pye-unicam SP
1
3-100 spectrophotometer using the KBr technique. H NMR spectra
were recorded on a BRUKER Proton NMR-Avance 300 (300 MHz),
in DMSO-d6 as a solvent, using tetramethylsilane (TMS) as inter-
nal standard. Mass spectra were run on the HP Model MS-5988. El-
emental analyses were carried out at the microanalytical laborato-
ries of the Faculty of Science, Cairo University, Cairo, Egypt. The
samples were irradiated with gamma radiation (60Co) at the Na-
tional Center for Radiation Research and Technology. A powder sample
was irradiated at r.t. condition in polycarbonate vials at a dose rate
(10 KGy/h). UV spectra were recorded using an ATI unicam. UV is
AURORA SCAN. Physical data is collected in Table 1.
4-(4-Fluoro-phenyl)-2-mercapto-7,7-dimethyl-5-oxo-1,4,5,6,7,8
-hexahydro-quinoline-3-carbonitrile 3a and 4-Benzo[1,3]-
dioxo-5-yl-2-mercapto-7,7-dimethyl-5-oxo-1,4,5,6,7,8-
hexahydroquinoline-3-carbonitrile 3b
A mixture of 1a, b (0.01 mole) and dimedone (0.01 mole) in ethanol
containing few drops of pipredine was heated under reflux for 4 h. The
solid obtained was recrystalized from ethanol to give 3a, b, respectively.

Synthesis and Biological Activity of Some Derivatives
289
SCHEME 6

290
M. S. A. El-Gaby et al.
3-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-
hexahydro-thieno [2,3-b]quinoline-2-carbonitrile (5)
A mixture of compound 3a (0.01 mole), chloroacetonitrile (0.01 mole),
and sodium ethoxide (0.01 mole) in absolute ethanol (50 mL) was heated
under reflux for 2 h. The solid product, which was produced on heating,
was collected and recrystallized from ethanol to give 5.
3-amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-
hexahydro-thieno[2,3-b]quinoline-2-carboxylic acid amide (6)
Method A
A sample of compound 5 (0.01 mole) was dissolved in conc. sulfuric
acid (10 mL) and stirred at r.t. for 2 h. The reaction mixture was diluted
with ice-cold water and neutralized with ammonium hydroxide. The
resulting precipitate was collect by filtration and recrystallized from
ethanol to give 6.
Method B
A mixture of compound 3a (0.01 mole), sodium methoxide (0.01 mole),
and chloroacetamide (0.01 mole) in (50 mL) methanol was refluxed for 2
h. The reaction mixture then cooled and poured into cold water (60 mL)
and acidified with HCl. The solid product was collected and recrystal-
lized from ethanol to give 6.
8,8-Dimethyl-11-(4-fluorophenyl)-4,7,8,9,10,11-hexahydro-
4,10-dioxo-quinolino [3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine (7)
A mixture of compound 5 (0.01 mole) and formic acid (10 mL) was heated
under reflux for 24 h. After cooling the precipitate was filtered and
recrystallized from dioxane to give 7.
4-Amino-8,8-dimethyl-11-(4-fluorophenyl)-7,8,9,10,11-pent-
ahydro-10-oxo-quinolino[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine (8)
Compound 5 (0.01 mole) in formamide (10 mL) was heated under reflux
for 24 h and left to cool. The crystalline product thus formed was filtered,
washed with ether, and recrystallized from dioxane to give 8.
2,8,8-Trimethyl-11-(4-fluorophenyl)-4,7,8,9,10,11-hexahydro-4-
thioxo-10-oxo-quinolino[3‘,2‘:4,5]thieno[3,2-d]pyrimidine (9)
A mixture of compound 5 (0.01 mole), thioacetamide (0.01 mole), and
trifluoroacetic acid (5 mL) was heated for 24 h on a steam bath. The

Synthesis and Biological Activity of Some Derivatives
291
mixture was cooled and then poured into excess of ice and water. The
solid obtained was recrystallized from acetic acid to give 9.
8,8-Dimethyl-4-(4-fluorophenyl)-3-phenyl-2,4,7,8,9,10,11-
heptahydro-2-thioxo-4-imino-10-oxo-quinolino[3ꢀ,2ꢀ:
4,5]thieno[3,2-d]pyrimidine (11)
A mixture of compound 5 (0.01 mole) and phenyl isothiocyanate (0.01
mole) in pyridine (15 mL) was refluxed for 6 h. The reaction mixture was
cooled and diluted with water and the resulting solid was recrystallized
from DMF-ethanol to give 11.
N-[2-Cyano-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-
hexahydro-thieno[2,3-b]quinolin-3-yl]-formimidic Acid Ethyl
Ester (12)
A mixture of compound 5 (0.01 mole), triethyl orthoformate (3 mL), and
acetic anhydrid (10 mL) was heated under reflux for 4 h and then al-
lowed to cool. The product was collected and recrystallized from ethanol
to give 12.
N-[2-Cyano-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo- 4,5,6,7,8,9-
hexahydro-thieno[2,3-b]quinolin-3-yl]-acetamide (16)
A solution of compound 5 (0.01 mole) in acetic anhydride (10 mL) was
heated for 5 min. After cooling the solid that was separated was recrys-
tallized from ethanol to give 16.
N-Acetyl-N- [2-cyano-4-(fluorophenyl)-7,7-dimethyl-5-oxo-4,5,
6,7,8,9-hexahydro-thieno[2,3-b]quinolin-3-yl]-acetamide (17)
A solution of compound 5 (0.01 mole) in acetic anhydride (15 mL) was
refluxed for 3 h. After cooling the solid product thus formed was collected
and recrystallized from ethanol to give 17.
[2-Cyano-4-fluorophenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-
hexahydro-thieno[2,3-b]quinolin-3-yl]-urea (18)
To a solution of sodium ethoxide (prepared from 0.5 g of sodium and
50 mL of absolute ethanol), compound 5 (0.01 mole), and urea (0.01
mole) were added. The reaction mixture was refluxed for 6 h and then
concentrated in vacuo. On cooling and neutralizing with HCl, a solid

292
M. S. A. El-Gaby et al.
formed, which was collected by filtration, washed with water, and re-
crystallized from ethanol to give 18.
4-Amino-2,8,8-trimethyl-11-(4-fluorophenyl)-2,7,8,9,10,11-
hexahydro-2,10-dioxo-quinolino[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-
pyrimidine (19) and 4-amino-8,8-dimethyl-11-
(4-fluorophenyl)-2,7,8,9,10,11-hexahydro-2-thioxo-
10-oxo-quinolino-[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidine (20)
Method A
General procedure. A mixture of compound 5 (0.01 mole) and urea
or thiourea (0.01 mole) was heated on an oil bath at 180◦C for 2 h.
On cooling the product solidified, which was recrystallized from DMF-
ethanol to give 19 or 20, respectively.
Method B
A sample of compound 18 was heated on an oil bath at 180◦C for 2 h,
and then allowed to cool; the resulting solid was recrystallized from
DMF-ethanol to give 19.
3-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-4,5,6,7,8,9-
hexahydro-thieno[2,3-b]quinoline-2-carboxylic Acid (21)
A solution of compound 5 in conc. sulfuric acid (10 mL) was heated under
reflux for 20 min. The obtained solid was recrystallized from dioxane to
give 21.
3-Amino-7,7-dimethyl-10-(4-fluorophenyl)-6,7,8,9,10-penta-
hydro-9-oxo -pyrazolo[3ꢀ,4ꢀ: 4,5]thieno[2,3-b]quinoline (22)
A mixture of compound 5 (0.01 mole), hydroxylamine hydrochloride
(0.012 mole), and sodium ethoxide (0.01 mole) in ethanol (50 mL) was
heated under reflux for 3 h, was allowed to cool, and poured into cold
water (60 mL). The solid product was collected and recrystallized from
dioxane to give 22.
4-Amino-8,8-dimethyl-11-(4-fluorophenyl)-2,7,8,9,10,11-
hexahydro-2,10-dioxo- pyrido[2‘,3‘:4,5] thieno [2,3-b]-
quinolin-3-carbonitrile (23)
A mixture of compound 5 (0.01 mole), ethyl cyanoacetate (0.01 mole) and
piperidine (0.5 mL) in dimethylformamide (10 mL) was heated under

Synthesis and Biological Activity of Some Derivatives
293
reflux for 3 h.The solid product was collected and recrystallized from
ethanol to give 23.
4-Amino-8,8-dimethyl-11-(4-fluorophenyl)-2-phenyl-7,8,9,10,
11-pentahy-dro-10-oxo-pyrido[2ꢀ,3ꢀ:4,5] thieno[2,3-b]quinolin-
3-carbonitrile (24)
A mixture of compound 5 (0.01 mole), benzylidenemalononitrile (0.01
mole) and piperidine (0.01 mole) in ethanol (50 mL) was heated under
reflux for 2 h, allowed to cool, and poured into ice/H2O and acidified with
HCl. The solid product was collected and recrystallized from dioxane to
give 24.
4-Amino-2,8,8-trimethyl-11-(4-fluorophenyl)-6,7,8,9,10,11-
hexahydro-10-oxo-pyrido[2ꢀ,3ꢀ:4,5]thieno[2,3-b]quinolin-3-
carbonitrile (25)
A solution of equimolar amounts of acetaldehyde and malononitrile
(0.01 mole) in absolute ethanol (50 mL) was added to a suspension of
appropriate enaminonitrile 5 (0.01 mole) in absolute ethanol (20 mL)
and pyridine (0.5 mL). The reaction mixture was heated under reflux
for 4 h. The solvent was then evaporated under reduced pressure and
the solid product was recrystallized from dioxane to give 25.
ANTIMICROBIAL ACTIVITY
Seventeen compounds were screened in vitro for their antimicrobial ac-
tivities against Gram positive bacteria staphylococcus aureus (29213),
Gram negative bacteria Escherichia coli (ATCC 25922), and one yeast
fungus Saccharomyces cerevisiae by the agar diffusion technique.31
A
1 mg/mL-solution 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 microorganism’s culture tested after 24 h of
incubation at 30◦C for bacteria and 48 h of incubation at 28◦C for fungi.
The diameter of inhibition zone (mm) was measured (Table II).
Ofloxacin and SXT in a concentration (30 µg mL)−1and Mycostatine
(30 µg mL)−1 were used as a reference for antibacterial and antifungal
activities, respectively. The Minimal Inhibitory Concentration (MIC) of
the biologically active compounds was measured by a two-fold serial
dilution method.
The data obtained are summarized in (Table II). The
pyrazolothieno-quinoline having fluorophenyl, free amino group

294
M. S. A. El-Gaby et al.
TABLE I Physical and Analytical Data of the Synthesized
Compounds
Analysis %
required/(found)
Compound
no.
Yield
%
M.P.
◦C
Mol. formula (mol-wt)
C
H
N
3a
3b
5
86
81
78
57
75
76
81
64
71
68
61
76
59
63
59
76
64
66
71
157–158
226–228
263–264
231–233
219–221
> 350
C18H17N2OSF
(328)
C19H18N2O3S
(354)
65.85
65.60
64.41
64.70
65.40
65.10
62.33
62.60
63.80
63.60
63.96
63.70
62.12
62.30
64.54
64.20
65.25
65.50
64.55
64.80
63.86
63.70
61.46
61.20
61.46
61.30
59.15
59.50
62.18
62.50
62.83
63.10
63.59
63.90
70.45
70.10
66.67
66.40
5.18
4.80
5.08
5.20
4.90
4.70
5.19
5.50
4.56
4.80
4.82
4.60
4.71
4.40
4.58
4.20
5.20
5.40
4.89
4.60
4.88
4.60
4.63
4.90
4.63
4.80
4.46
4.70
4.92
4.70
4.97
4.60
4.38
4.10
4.66
4.40
4.86
4.50
8.54
8.70
7.91
8.20
C
20H18N3OSF
(367)
11.44
11.20
7.27
6
C20H20N3O2SF
(385)
C21H18N3O2SF
(395)
7.50
7
10.63
10.90
14.21
14.50
9.88
8
C
21H19N4OSF
(394)
9
242–244
146–147
208–210
314–316
123–125
293–295
> 350
C22H20N3OS2F
(425)
C27H23N4OS2F
(502)
9.60
11
12
16
17
18
19
20
21
22
23
24
25
11.16
11.50
9.93
C23H22N3O2SF
(423)
C22H20N3O2SF
(409)
C24H22N3O3SF
(451)
C21H19N4O2SF
(410)
9.60
10.27
10.50
9.31
9.50
13.66
13.80
13.66
13.40
13.15
13.50
7.25
C
C
C
21H19N4O2SF
(410)
21H19N4OS2F
(426)
20H19N2O3SF
(386)
> 350
> 350
7.10
199–201
> 350
C
20H19N4OSF
(382)
14.66
14.50
12.90
12.60
11.34
11.10
12.96
13.30
C
23H19N4O2SF
(434)
138–140
311–313
C
29H23N4OSF
(494)
C24H21N4OSF
(432)
22 and pyridothienoquinoline containing fluorophenyl, cyano and
free amino moieties 25 were found to be the most active compounds
against Saccharomyces cerrevisiae, whereas compounds 11, 17, and 23
exhibited a moderate activity against Staphylococcus aurous(29213).

Synthesis and Biological Activity of Some Derivatives
295
TABLE II Antimicrobial Activity of the Newly Synthesized
Compounds
Staphylococcus
Escherichia coli Saccharomyces
Compound no.
aureus (29213)
(ATCC 25922)
cerevisiae
3a
5b
+
+
0
0
0
0
6
8
+
+
0
0
0
0
9
11
12
16
17
18
19
20
21
22
23
24
+
0
0
0
0
0
++
0
++
+
+
0
++
0
0
0
0
0
+
+
+
0
+
+
+
+
0
0
+
+ + ++
+
+
0
0
++
+
+
25
0
+ + +
Ofloxacin (Tarivid)a
SXTa
+ + ++
+ + +
+ + +
0
0
+ + ++
0
+ + +
0
Mycostatineb
DMF
0
0
0
aOfloxacin and SXT were supplied from Oxoid lab., England.
bManufactured 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.
From these results it can be concluded that the biologically active
compounds 22 and 25 (MIC values were <50 µg/mL) are nearly as
active as the standard fungicide Mycostatine.
RADIOSTABILITY OF THE BIOLOGICALLY
ACTIVE COMPOUNDS
The aim of the present work is to investigate the stability of the chem-
ical structure of the biologically active compounds 22 and 25 after
irradiation. These compounds in a dry state were exposed to doses of
gamma irradiation ranging from 5–40 KGy. Ultraviolet measurements
(UV spectra) and Thin Layer Chromatography (TLC) were run before

296
M. S. A. El-Gaby et al.
TABLE III UV and Visible Data of the Biologically Active
Compounds Before and After Gamma Irradiation
Dose
Compound
no.
(KGy)
control
Conc.
(mol)
Abs.
(O.D.)
Abs.
(O.D.)
λ
max(1)
λ
max(2)
299
299
299
299
299
299
299
299
268
268
268
268
268
268
268
268
1.120
1.126
1.128
1.127
1.130
1.134
1.132
1.136
0.843
0.880
0.889
0.891
0.895
0.899
0.890
0.896
370
370
370
370
370
370
370
370
369
369
369
369
369
369
369
369
0.740
0.752
0.751
0.763
0.801
0.769
0.764
0.770
1.942
1.950
1.956
1.963
1.968
1.980
1.974
1.979
22
25
5
10
15
20
25
30
40
5 × 10−5
5
10
15
20
25
30
40
5 × 10−5
and after irradiation to probe any change after irradiation. The UV
spectra of unirradiated (Control) and irradiated compounds in DMF as
solvent are listed in (Table III).
The results showed that the biologically active compounds 22 and 25
remain radioresistant, retaining their structures unchanged up to 40
KGy (Table III).
Further, TLC analyses (Rf) were made on precoated silica gel G
sheets IB-F and were detected by the use of a UV lamp at 254 nm. The
Rf values of the unirradiated compounds 22 and 25 were 0.31 and 0.22,
respectively [eluent benzene/ethylacetate 8.5/1.5] after irradiation; the
irradiated compounds gave identical Rf values as before irradiation.
This means that the structures of these compounds remain radioresis-
tant, and radiosterilization of these compounds in dry form by gamma
irradiation may prove to be applicable.
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