Synthesis and antimicrobial activity of some new pyrido[3′,2′: 4,5]thieno[3,2-d]-pyrimidine derivatives

Article abstract of DOI:10.1080/10426500490422155

5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides (la,b) were reacted with aromatic aldehydes or with some cycloalkanones to give the corresponding tetrahydropyridothienopyrimidinone derivatives 2a-f and 4a-d. The reaction of compound 1b with urea and/or carbon disulfide has been carried out and their products were identified. Some representative compounds were screened in vitro for their antimicrobial activities.

Full text of DOI:10.1080/10426500490422155

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME
NEW PYRIDO[3′,2′:4,5]THIENO[3,2-d]- PYRIMIDINE
DERIVATIVES
Etify A. Bakhite a , Abdu E. Abdel-Rahman a & Elham A. Al-Taifi a
a Chemistry Department, Assiut University , Assiut, Egypt
Published online: 12 Aug 2010.
To cite this article: Etify A. Bakhite , Abdu E. Abdel-Rahman & Elham A. Al-Taifi (2004) SYNTHESIS AND ANTIMICROBIAL
ACTIVITY OF SOME NEW PYRIDO[3′,2′:4,5]THIENO[3,2-d]- PYRIMIDINE DERIVATIVES, Phosphorus, Sulfur, and Silicon and the
Related Elements, 179:3, 513-520, DOI: 10.1080/10426500490422155
To link to this article: http://dx.doi.org/10.1080/10426500490422155
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Phosphorus, Sulfur, and Silicon, 179:513–520, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490422155
SYNTHESIS AND ANTIMICROBIAL ACTIVITY
OF SOME NEW PYRIDO[3ꢀ,2ꢀ:4,5]THIENO[3,2-d]-
PYRIMIDINE DERIVATIVES
Etify A. Bakhite, Abdu E. Abdel-Rahman, and Elham A. Al-Taifi
Chemistry Department, Assiut University, Assiut, Egypt
(Received May 15, 2003; accepted September 17, 2003)
5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides
(1a,b) were reacted with aromatic aldehydes or with some cycloalka-
nones to give the corresponding tetrahydropyridothienopyrimidinone
derivatives 2a–f and 4a–d. The reaction of compound 1b with urea
and/or carbon disulfide has been carried out and their products were
identified. Some representative compounds were screened in vitro for
their antimicrobial activities.
Keywords: Antimicrobial activity; pyridothienopyrimidines; spiro com-
pounds; thieno[2,3-b]pyridines
In view of the wide spectrum of biological activity associated
with many condensed pyrimidines.1,2 thienopyridines,3−7 and pyrido-
thienopyrimidines,8,9 and as a continuation of our work on pyri-
dothienopyrimidines with anticipated biological activities,10−12 we
undertook the synthesis of the title compounds and their evaluation
regarding antimicrobial properties.
RESULTS AND DISCUSSION
5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides
(1a,b) were prepared following our previous method12 and used as
a starting materials in this investigation. Thus, when compounds
1a,b were heated with aromatic aldehydes in acetic acid or in
ethanol containing few drops of conc. HCl, a cyclocondensation reaction
Address correspondence to Etify A. Bakhite, Chemistry Department, Faculty of
Science, Assiut University, Assiut 71516, Egypt. E-mail: atiafy@acc.aun.edu.eg
513

514
E. A. Bakhite et al.
occurred and tetrahydropyridothienopyrimidines 2a–f were obtained
(Scheme 1).
SCHEME 1
The o-aminoamides 1a,b also were reacted with cyclopentanone or
cyclohexanone upon refluxing in glacial acetic acid or ethanol contain-
ing few drops of HCl. In view of the earlier reports,13 the products
of this reaction were identified as spiro compounds 4a–d rather than
Schiff’s bases 3a–d. The proposed pathway of this reaction is depicted
in Scheme 2. Thus, this reaction involves the formation of addition prod-
uct A which underwent spontaneous dehydration to give the expected
products 3a–d or 4a–d via two probable routes (a and b). If compounds
3a–d formed they may be underwent cycloaddition reaction to give 4a–
d.The reaction of compound 1b with urea by refluxing in decalin led to
the formation of pyridothieno-pyrimidindione 5. The thioxo analogue
6 was prepared by heating 1b with carbon disulfide in pyridine. Com-
pound 6 was reacted with an equimolar quantity of 4-bromophenacyl
bromide to give the S-alkylated product 7 which upon. with conc.H2SO4
furnished thiazolopyridothienopyrimidine 814 (Scheme 3). The struc-
tures of all newly synthesized compounds were confirmed by elemental
analyses (Table I) as well as spectroscopic data (Table II).
Finally, eight compounds were screened in vitro for their an-
timicrobial activity against three strains of bacteria (Serratia rho-
denii, Echerichia coli, and Micrococcus roseus) and two fungal species
(Aspergillus fumigatus and Fusarium oxysporum) using filter paper

Pyrimidine Derivatives
515
SCHEME 2
disc method.15 The results revealed that: (1) all tested compounds
showed high activity against Serratia rhodenii and no activity against
Echerichia coli; (2) most of the tested compounds exihibited con-
siderable activity against Micrococcus roseus; (3) only compound 4b
inhibited the growth of Aspergillus fumigatus; and (4) Compounds
4b, 4c, 4d showed moderate activity against Fusarium oxysporum
(Table III).
EXPERIMENTAL
All melting points are uncorrected and measured on a Gallan-
Kamp apparatus. IR spectra were recorded on a Shmiadzu 470 IR-
spectrophotometer (KBr; υmax in cm−1). 1H-NMR spectra on a Var-
ian EM-390, 90 MHz spectrometer with TMS as internal standard
or on a Jeol LA 400 MHz FT-NMR spectrometer (δ in ppm); MS on a

516
E. A. Bakhite et al.
SCHEME 3
Jeol JMS-600 mass spectrometer. Elemental analyses on an Elementar
Analyses system GmbH VARIOEL V2.3 July 1998 CHNS Mode.
8-Acetyl-2,9-diaryl-7-methyl-4-oxo-1,2,3,4-
tetrahydropyrido[3ꢀ ,2ꢀ :4,5]thieno[3,2-d]pyrimidines
(2a--f)
A mixture of 1a,b (0.002 mmol) and the respective aldehyde
(0.002 mmol) in glacial acetic acid (15 mL) or in ethanol (20 mL) con-
taining few drops of HCl was heated under reflux for 3 h. The product
was collected and recrystallized from acetic acid to give 2a–f in the form
of yellow needles.
Reaction of 1a,b with Cycloalkanones; Formation
of Spiro Compounds 4a--d
A mixture of 1a,b (0.002 mmol) and cyclopentanone or cyclohexanone
(0.002 mmol) in glacial acetic acid (15 mL) or in ethanol (20 mL) contain-
ing a few drops of HCl was heated under reflux for 3 h. The precipitate
that formed on cooling was collected and recrystallized from ethanol to
give yellow crystals of 4a–d.

Pyrimidine Derivatives
517
TABLE I Melting Points, Yields, and Analytical Data of All Newly
Synthesized Compounds
Analysis; calculated/found (%)
Comp.
no.
m.p. (◦C)
(yield%)
Mol. formula
(M.wt)
C
H
N
S
Cl
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
5
>360
(89)
>360
(82)
225–226
(80)
322–323
(85)
>360
(87)
317
(83)
268–270
(90)
323–224
(94)
278–279
(92)
338–339
(91)
>360
(73)
>360
(78)
298–299
(69)
285–286
(66)
C25H21N3O3S
(443.52)
C26H23N3O4S
(473.55)
67.70
67.89
65.95
65.87
62.82
62.71
64.35
64.44
62.82
63.18
59.76
59.91
65.54
65.73
66.19
66.37
62.04
62.38
62.79
63.03
56.04
56.21
53.80
53.70
52.14
52.28
53.76
53.41
4.77
4.58
4.90
5.14
4.22
4.32
4.05
4.11
4.22
4.18
3.55
3.47
5.50
5.48
5.79
5.74
4.73
4.79
5.04
5.13
3.13
3.17
3.01
3.07
2.86
2.91
2.60
2.73
9.47
9.41
8.87
8.92
8.79
8.77
9.38
9.39
8.79
8.36
8.71
8.58
9.97
9.82
9.65
9.87
9.87
9.77
9.55
9.44
10.89
10.70
10.46
10.31
7.02
7.30
7.23
7.15
7.23
7.00
6.77
6.53
6.71
7.00
7.16
7.35
6.71
6.91
6.65
6.42
7.61
7.44
7.36
7.52
7.53
7.60
7.29
7.36
8.31
8.00
15.95
16.19
10.71
10.50
11.04
11.32
—
—
—
—
C25H20ClN3O3S
7.42
7.71
7.91
7.72
7.42
7.25
14.70
14.51
—
(477.97)
C24H18ClN3O2S
(447.94)
C25H20ClN3O3S
(477.97)
C24H17Cl2N3O2S
(482.38)
C23H23N3O3S
(421.51)
C24H25N3O3S
(435.54)
—
—
—
C22H20ClN3O2S
8.32
8.21
8.06
8.28
9.19
9.43
8.82
8.72
—
(425.93)
C23H22ClN3O2S
(439.96)
C18H12ClN3O3S
(385.82)
18H12ClN3O2S2
(401.89)
C26H17BrClN3O3S2
598.92
6
C
7
—
—
—
8
C
26H15BrClN3O2S2
580.90
8-Acetyl-9-(4-chlorophenyl)-7-methylpyrido[3ꢀ ,2ꢀ :4,5]-
thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (5)
A mixture of 1b (1.43 g, 0.004 mmol) and urea (0.3 g, 0.005 mmol) in
decalin (30 mL) was refluxed for 4 h. The white product was collected
and crystallized from chloroform to give 5.
8-Acetyl-9-(4-chlorophenyl)-7-methyl-4-oxo-1,2,3,4-
tetrahydro-2-thioxopyrido[3ꢀ ,2ꢀ :4,5]-
thieno[3,2-d]pyrimidine (6)
A mixture of 1b (1.79 g, 0.005 mmol) and carbon disulfide (6 mL) in
dry pyridine (30 mL) was heated under reflux on a water bath for 48 h.

518
E. A. Bakhite et al.
TABLE II Spectral Data of All Newly Synthesized Compounds
Comp. no.
Spectral data
2a
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (CDCl3): 7.73 (d, J =
4.0 Hz, 1H, CONH); 6.98–7.53 (m, 9H, ArH’s); 5.89 (d, J = 4.0 Hz,
1H, NH); 5.79 (t, J = 4.0 Hz, 1H, CH at C-2); 3.91 (s, 3H, OCH3);
2.74 (3H, COCH3); 2.07 (s, 3H, CH3 at C-7).
2b
2c
IR: 3400, 3200(2NH); 1690, 1640(2C O).
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (DMSO-d6)): 8.43 (d,
J = 4.0 Hz, 1H, CONH); 7.09–7.41 (m, 8H, ArH’s); 5.74 (t, J = 4.0
Hz, 1H, CH at C-2); 5.18(d, J = 4.0 Hz, 1H, NH); 3.82(s, 3H, OCH3);
2.49 (3H, COCH3); 1.96 (s, 3H, CH3 at C-7). MS: 479.7 (M+ + 2,
11%); 478.7 (M+ + 1, 38%); 477.6 (M+, 41%); 476.6 (M+ − 1, 37%);
475.6 (M+ − 2, 100%); 364.9 (M+ − 2-C6H4Cl, 91%).
2d
2e
IR: 3400, 3200(2NH); 1690, 1640(2C O).
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (CDCl3)): 7.85 (d,
J = 4.0 Hz, 1H, CONH); 6.87–7.44 (m, 8H, ArH’s); 6.08 (d, J = 4.0
Hz, 1H, NH); 5.70 (t, J = 4.0 Hz, 1H, CH at C-2); 3.86 (s, 3H, OCH3);
2.64 (3H, COCH3); 2.05 (s, 3H, CH3 at C-7).
2f
IR: 3400, 3200(2NH); 1690, 1640(2C O).
4a
4b
IR: 3400, 3200(2NH); 1690, 1640(2C O).
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (CDCl3)): 7.31–7.33
(d, J = 8.5 Hz, 2H, ArH’s); 7.06–7.08 (d, J = 8.5 Hz, 2H, ArH’s);
6.18 (s, 1H, CONH); 4.09 (s, 1H, NH); 3.88 (s, 3H, OCH3); 2.62 (3H,
COCH3); 2.06 (s, 3H, CH3 at C-7); 1.90–1.96 (m, 2H, CH2 of
cyclohexylidene ring; 1.13–1.49 (m, 6H, 3 CH2 of cyclohexylidene
ring); 0.81–0.83 (m, 2H, CH2 of cyclohexylidene ring).
4c
4d
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (CDCl3)): 7.52–7.54
(d, J = 8.3 Hz, 2H, ArH’s); 7.32–7.34 (d, J = 8.3 Hz, 2H, ArH’s); 6.17
(s, 1H, CONH); 3.64 (s, 1H, NH); 2.62 (3H, COCH3); 2.10 (s, 3H, CH3
at C-7) 1.29–1.77 (m, 8H, 4CH2 of cyclopentylidene ring).
IR: 3400, 3200(2NH); 1690, 1640(2C O). 1H-NMR (CDCl3)): 7.56–7.58
(d, J = 8.0 Hz, 2H, ArH’s); 7.41–7.43 (d, J = 8.0 Hz, 2H, ArH’s);
6.42(s, 1H, CONH); 3.85 (s, 1H, NH); 2.66 (3H, COCH3); 2.15 (s, 3H,
CH3 at C-7); 1.92–1.95 (m, 2H, CH2 of cyclohexylidene ring;
1.17–1.54 (m, 6H, 3 CH2 of cyclohexylidene ring); 0.78–0.80 (m, 2H,
CH2 of cyclohexylidene ring). MS: 441 (M+ + 2, 1%); 440 (M+ + 1,
5%); 439 (M+, 18%); 438 (M+ − 1, 13%); 437 (M+ − 2, 42%); 396
(M+-COCH3, 41%); 394 (M+ − 2-COCH3, 100%).
5
IR: 3500–3200 (2NH); 1750-1650 (3C O). MS: 387 (M+ + 2, 9%);
386 (M+ + 1, 3%); 385 (M+, 26%); 370 (M+ -CH3, 38%);
369 (M+ − 1-CH3, 63%); 354.9 (M+ − 1-2CH3, 100%).
6
7
IR: 3400, 3100(2NH); 1690, 1650(2C O).
IR: 3250 (NH); 1690, 1650 (2C O).). 1H-NMR (CD3CO2D): 7.1–7.6 (m,
8H, ArH’s); 5.0 (s, 2H, SCH2); 2.8 (s, 3H, CH3); 2.2 (s, 3H, CH3 at
C-7).). MS: 598 (M+, 28%); 594 (M+ − 4, 100%); 592 (M+-6, 70%);
570 (M+ -CO, 30%).
8
IR: 1690 (2C O). 1H-NMR (CDCl3)): 7.46–7.56 (dd, J = 8.0 Hz, 4H,
ArH’s); 7.28–7.36 (dd, J = 8.0 Hz, 4H, ArH’s); 6.76 (s, 1H,
CH-thiazole); 2.68 (3H, COCH3); 2.03 (s, 3H, CH3 at C-8).

Pyrimidine Derivatives
519
TABLE III The Antimicrobial Activities of Some Representative Compounds
Tioconazole
Compd. no.
2f
4b
4c
4d
5
6
7
8
tyrosyd
S. rhodenii
E. coli
M. roseus
A. fumigatus
F. oxysporum
++ +++ +++ +++ ++ +++ ++ +++
++
++
−
+
−
−
−
−
−
++
−
−
−
−
+
−
−
−
−
−
+++
−
−
+
−
−
−
++
−
+
++
+
+++
+++
+
−
−
−: No activity; +: moderate activity (inhibition zone 7–10 mm); ++: strong activity
(inhibition zone 11–15 mm); +++: very strong activity (inhibition zone 16–20 mm).
During reaction time H2S evolved. The solvent was removed by distil-
lation under reduced pressure and the residue was crystallized from
acetic acid as yellow crystals of 6.
8-Acetyl-2-(4-bromophenacylthio)-9-(4-chlorophenyl)-
7-methylpyrido[3ꢀ ,2ꢀ :4,5]thieno[3,2-d]pyrimidine-
4(3H)-one (7)
To a mixture of 6 (0.8 g, 0.002 mmol), 4-bromophenacyl bromide (0.55 g,
0.002 mmol) and sodium acetate trihydrate (0.27 g, 0.002 mmol) in
ethanol (30 mL) were then added. The mixture was refluxed for 3 h. The
precipitate which formed on cooling was filtered off and recrystallized
from ethanol to give pale yellow crystals of 7.
9-Acetyl-3-(4-bromophenyl)-10-(4-chlorophenyl)-
8-methylthiazolo[3ꢀꢀ ,2ꢀꢀ -a]pyrido[3ꢀ ,2ꢀ :4,5]thieno[3,2-d]-
pyrimidine-5-one (8)
To a sample of 7 (0.59 g, 0.001 mmol) in acetic acid (10 mL), conc. sulfuric
acid (3 mL) was added and the mixture was gently heated for 6 h. After
cooling, the reaction mixture was poured onto ice-water (30 mL) and
neutralized with NaHCO3 solution. The precipitate was collected and
crystallized from ethanol to give compound 8.
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