Synthesis of Some New Substituted Thieno[2,3-d]pyrimidine Derivatives as Antimicrobial Agents

Article abstract of DOI:10.1134/S1070363219070247

A series of thieno-pyrimidine derivatives are synthesized from 5′-amino-2,3′-bithiophene-4′-carboxylate via the corresponding intermediate N-benzoylated carboxamide derivatives. The target compounds are tested for antibacterial and antifungal activity. Some of the synthesized compounds demonstrate potent antibacterial activity with LD₅₀ comparable with the reference drug indomethacin.

Full text of DOI:10.1134/S1070363219070247

ISSN 1070-3632, Russian Journal of General Chemistry, 2019, Vol. 89, No. 7, pp. 1528–1534. © Pleiades Publishing, Ltd., 2019.
Synthesis of Some New Substituted Thieno[2,3-d]pyrimidine
Derivatives as Antimicrobial Agents
M. F. El-Shehrya,b, H. M. Hosnia, A. E. Amrc,d*, A. A. Ibrahimd,
Ahmed A. Fayede,f, and D. H. Elnaggard
a Pesticide Chemistry Department, National Research Center, Dokki, Cairo, 12622 Egypt
b Al-Zahrawy University College, Karbala, Iraq
c Pharmaceutical Chemistry Department, College of Pharmacy, Drug Exploration and Development Chair (DEDC),
King Saud University, Riyadh, 11451 Saudi Arabia
*e-mail: aamr@ksu.edu.sa
d Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, 12622 Egypt
e Respiratory Therapy Department, College of Medical Rehabilitation Sciences, Taibah University,
Madinah Munawara, 22624 Saudi Arabia
f National Research Center, Cairo, Dokki 12622, Egypt
Received May 9, 2019; revised July 11, 2019; accepted July 15, 2019
Abstract—Aseries of thieno-pyrimidine derivatives are synthesized from 5'-amino-2,3'-bithiophene-4'-carboxylate via the
corresponding intermediate N-benzoylated carboxamide derivatives. The target compounds are tested for antibacterial
and antifungal activity. Some of the synthesized compounds demonstrate potent antibacterial activity with LD50
comparable with the reference drug indomethacin.
Keywords: thiophene moiety, thieno[2,3-d]pyrimidines derivatives, antimicrobial activity
DOI: 10.1134/S1070363219070247
Thiophene and its derivatives are distinguished
as important structural components of some drugs
[1–6] and active antitumor [7], antiviral [8], anti-
microbial [9–14], and anti-inflammatory [15, 16]
compounds. Based on these facts and in continua-
tion of our recent studies in heterocyclic chemistry
[17–21], we have synthesized novel thieno[2,3-d]-
pyrimidin-4(3H)-ones, 3-(4-substituted benzylidene-
amino) and benzoylhydrazinecarbonyl derivatives for
testing their antibacterial and cytotoxic activities.
ing to formation of 4-chlorothienopyrimidine derivative
7, which upon reaction with secondary amines, gave the
corresponding 4-substituted morpholine 8 and 4-hydra-
zine 9 derivatives. The compound 9 was treated with
phenyl isothiocyanate with formation of phenylhyd-
razine carbothioamide derivative 10 in poor yield
(Scheme 2).
Thieno[2,3-d]pyrimidin-4(3H)-one derivative (11)
was obtained either by refluxing compound 2a with
hydrazine hydrate in butanol, or refluxing 4'-hydrazine-
carbonyl derivative 4 in butanol. The Schiff bases 12a,
12b were produced by condensation of 11 with an al-
dehyde, 4-chlorobenzaldehyde or 4-nitrobenzaldehyde
under refluxing in isopropanol containing a catalytic
amount of glacial acetic acid (Scheme 3).
RESULTS AND DISCUSSION
Ethyl 5'-amino-2,3'-bithiophene-4'-carboxylate (1),
synthesized from the corresponding 2-acetylthiophene
[14], reactedwithabenzoylchloridetogivethecorrespond-
ing N-benzoylated derivatives 2a–2c (Scheme 1). Presence
of the 4'-ethylcarboxylate group in compounds 2a–2c
made these to act as versatile precursors for the synthe-
sis of 4'-carboxamide (3) and 4'-hydrazinecarbonyl 4
derivatives.
Antimicrobial activity. The compounds 3–12 were
tested for their in-vitro antimicrobial activity against
gram-positive Staphylococcus aureus and Bacillus sub-
tilis, and gram-negative Escherichia coli bacteria using
antibiotic Ciprofloxacin (50 μg /mL) as a reference drug,
and fungi (Aspergillus flavus and Candida albicans) us-
ing antibiotic Fusidic acid (50 μg /mL). The compounds
were tested in concentration of 50 μg/mL using inhibi-
Refluxing of compound 3 under basic conditions led to
the product of cyclization 6 in good yield. Generally, com-
pound 6 can be regarded as an active intermediate lead-
1528

SYNTHESIS OF SOME NEW SUBSTITUTED THIENO[2,3-d]PYRIMIDINE DERIVATIVES
Scheme 1. Synthetic roots to compounds 2–5.
1529
CONH2
O
CONHNH2
O
S
S
S
N
H
S
N
H
Cl
4
Cl
3
NH2NH2, EtOH, reflux
NH4OH, EtOH, 70C
2a
O
Ar-COCl
COOEt
O
S
OEt
NH2
S
Benzene, room temperature
S
S
N
Ar
H
1
2a2c
LiOH,
EtOH, reflux
O
S
OH
NH2
S
5
(b),
Cl
(a),
(c).
Cl
Ar' =
Cl
O
O
Me
Cl
tion zone diameter (mm) as a criterion of antimicrobial
activity (see the table).
equimolar amounts of compound 1 (0.01 mol) and an ap-
propriate acid chloride (0.01 mol) in dry benzene (10 mL)
was stirred for 3 h. The separated solid was filtered off,
washed with petroleum ether 60–80 and crystallized
from ethanol to give the corresponding compounds
2a–2c.
EXPERIMENTAL
Melting points were determined in open glass capil-
lary tubes on an Electro Thermal Digital melting point
apparatus (model: IA9100), and are uncorrected. CHN
microanalysis was carried out on a Microanalytical Unit,
NRC. FTIR spectra were recorded on a Nexus 670 FTIR
Ethyl 5'-(4-chlorobenzamido)-2,3'-bithiophene-4'-
carboxylate (2a). Yield 77%, mp 195–197°C. IR spec-
trum, ν, cm–1: 3250 (NH), 1725, 1655 (2C=O). 1H NMR
spectrum, δ, ppm: 1.10 t (3H, CH3 ethyl), 4.22 q (2H,
CH2 ethyl), 7.08–7.98 m (8H, Ar-H and thiophene-H),
11.95 br.s (1H, NH, exchangeable with D2O). 13C NMR
spectrum, δC, ppm: 14.30 (CH3), 61.23 (CH2), 113.35,
118.39, 126.19, 127.25, 127.69, 129.70, 129.83, 131.18,
131.65, 137.56, 138.32, 145.94, 162.99, 165.32. MS:
m/z: 391 [M]+. Found, %: C 55.11; H 3.49; N 3.49.
C18H14ClNO3S2. Calculated, %: C 55.17; H 3.60; N 3.57.
1
Nicolet spectrophotometer. H and 13C NMR spectra
were measured on a Jeol 500 MHz (1H) and 125 MHz
(13C) spectrometer using DMSO-d6 as a solvent. Mass
spectra were measured on a MAT Finnigan SSQ 7000
spectrometer, using the electron impact technique (EI).
TLC was performed on silica gel aluminum sheets,
60 F254 (E. Merck).
Synthesis of ethyl 5'-(substituted phenyl)-2,3'-
bithiophene-4'-carboxylate (2a–2c). A mixture of
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1530
EL-SHEHRY et al.
Scheme 2. Synthetic roots to compounds 6–10.
O
N
NaOH, i-PrOH,
CONH2
S
NH
reflux
S
O
S
S
N
H
Cl
Cl
6
3
POCl3PCl5,
80C
O
Morpholine, THF,
N
N
Cl
N
Et3N, 30C
S
N
S
S
S
N
Cl
Cl
8
7
NH2NH2,
EtOH, reflux
H
N
H
N
HN
N
NHNH2
S
PhNCS
S
N
S
N
N
DMF, reflux
S
S
Cl
Cl
10
9
Ethyl 5'-[2-(2,4-dichlorophenoxy)acetamido]-
2,3'-bithiophene-4'-carboxylate (2b). Yield 85%, mp:
218–220°C. IR spectrum, ν, cm–1: 3245 (NH), 1730,
O). 13C NMR spectrum, δ, ppm: 13.76, 62.71, 75.52,
D2
115.51, 117.32, 120.65, 124.22, 125.58, 127.43, 127.85,
129.31, 131.65, 131.99, 132.92, 135.83, 137.44, 143.81,
164.80, 169.72, 173.21. MS: m/z: 435 [M]+. Found, %:
C 55.00; H 4.06; N 3.15. C20H18ClNO4S2. Calculated,
%: C 55.10; H 4.16; N 3.21.
1
1659 (2C=O). H NMR spectrum, δ, ppm: 1.04 t (3H,
CH3 ethyl), 4.14 q (2H, CH2 ethyl), 5.06 s (2H, CH2),
7.10–7.68 m (7H, Ar-H and thiophene-H), 11.66 br.s
(1H, NH, exchangeable with D2O). 13C NMR spectrum,
δC, ppm: 14.30, 61.23, 112.05, 116.32, 121.31, 126.05,
127.21, 128.05, 128.11, 129.14, 130.54, 131.52, 132.93,
136.26, 139.37, 144.08, 163.72, 166.10, 178.32. MS:
m/z: 456 [M]+. Found, %: C 49.88; H 3.25; N 3.00.
C19H15Cl2NO4S2. Calculated, %: C 50.01; H 3.31; N 3.07.
Synthesis of 5'-(4-chlorobenzamido)-2,3'-bithio-
phene-4'-carboxamide (3). To a solution of compound
2a (0.01 mol) in ethanol (30 mL), ammonia solution
(20 mL, 50%) was added. The reaction mixture was
heated to 70ºC upon stirring for 8 h. The formed pre-
cipitate was filtered off, washed with water, and crys-
tallized from ethanol to give compound 3. Yield 75%,
mp: 186–188°C. IR spectrum, ν, cm–1: 3450–3190 (NH,
NH2), 1680, 1667 (2C=O). 1H NMR spectrum, δ, ppm:
4.12 br.s (2H, NH2, exchangeable with D2O), 6.34–7.98
m (8H, Ar-H and thiophene-H), 11.95 br.s (1H, NH,
exchangeable with D2O). 13C NMR spectrum, δC, ppm:
115.71, 124.93, 126.42, 127.74, 128.80, 129.33, 131.12,
Ethyl 5'-[2-(4-chloro-2-methylphenoxy]acet-
amido)-2,3'-bithiophene-4'-carboxylate (2c). Yield
65%, mp: 204-206°C. IR spectrum, ν, cm–1: 3255 (NH),
1
1727, 1658 (2C=O). H NMR spectrum, δ, ppm: 1.03
t (3H, CH3 ethyl), 2.11 t (3H, CH3), 4.15 q (2H, CH2
ethyl), 4.94 q (2H, CH2), 6.68–7.55 m (7H, Ar-H and
thiophene-H), 11.81 br.s (1H, NH, exchangeable with
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SYNTHESIS OF SOME NEW SUBSTITUTED THIENO[2,3-d]PYRIMIDINE DERIVATIVES
1531
Scheme 3. Synthetic roots to compounds 11 and 12.
O
CONHNH2
O
NH2
S
S
N
n-butanol, reflux
S
N
H
S
N
Cl
Cl
4
11
NH4OH,
EtOH, 70C
OHC
X
AcOH, i-PrOH,
reflux
X
O
COOEt
O
N
S
S
N
S
N
H
S
N
Cl
Cl
2a
12a, 12b
X = Cl (a), NO2 (b).
131.96, 135.52, 139.14, 140.37, 144.18, 163.27, 169.39.
MS: m/z: 362 [M]+. Found, %: C 52.87; H 3.00; N 7.64.
C16H11ClN2O2S2. Calculated, %: C 52.96; H 3.06; N 7.72.
mixture was poured into 50 mL of cold water and treated
with 1N HCl to pH 4–5. The solid formed was filtered
off and recrystallized from ethanol to give compound 5.
Yield 60%, mp 112–114°C. IR spectrum, ν, cm–1: 3450
(OH), 3250 (NH2), 1710 (C=O). 1H NMR spectrum, δ,
ppm: 7.07–7.85 m (8H, Ar-H, NH2 and thiophene-H),
12.36 br.s,(1H, OH). 13C NMR spectrum, δC, ppm:
102.13, 111.87, 124.27, 125.00, 128.07, 130.37, 132.23,
164.72, 167.78. MS: m/z: 225 [M]+. Found, %: C 47.87;
H 3.05; N 6.16. C9H7NO2S2. Calculated, %: C 47.98; H
3.13; N 6.22.
Synthesis of 4-chloro-N-(4'-(hydrazinecarbonyl)-
2,3'-bithiophen-5'-yl)benzamide (4). A mixture of
compound 2a (0.01 mol) with hydrazine hydrate (15 mL;
0.03 mol) in ethanol (20 mL) was refluxed for 6 h, then
concentrated to half of its volume and cooled down to
room temperature. A white crystalline product was crys-
tallized from ethanol to give compound 4. Yield 60%,
mp: 165–167°C. IR spectrum, ν, cm–1: 3438–3250 (2NH,
NH2), 1680, 1665 (2C=O). 1H NMR spectrum, δ, ppm:
4.37 br.s (2H, NH2, exchangeable with D2O), 6.67 br.s
(1H, NH, exchangeable with D2O), 7.08–7.98 m (8H,
Ar-H and thiophene-H), 12.01 br.s (2H, 2NH, exchange-
able with D2O). 13C NMR spectrum, δC, ppm: 116.75,
127.65, 128.34, 129.73, 130.06, 130.06, 130.59, 132.12,
135.82, 136.19, 139.10, 141.06, 162.69, 165.71. MS:
m/z: 377 [M]+. Found, %: C 50.72; H 3.12; N 11.08.
C16H12ClN3O2S2. Calculated, %: C 50.86; H 3.20; N 11.12.
Synthesis of 2-(4-chlorophenyl)-5-(thiophen-2-yl)-
thieno[2,3-d]pyrimidin-4(3H)-one (6). To a solution
of compound 3 (0.01 mol) in isopropanol (50 mL) was
added 5% solution of NaOH (0.1 mol), and the mixture
was refluxed for 3 h. After cooling down, the reaction
mixture was poured into ice cold water upon stirring, and
acidified with HCl to pH 5–6. The residue was filtered off,
dried and crystallized from butanol to give compound 6.
Yield 59%, mp 208–210°C. IR spectrum, ν, cm–1: 3460
(NH), 1670 (CO). 1H NMR spectrum, δ, ppm: 7.01–7.23
m (8H, Ar-H and thiophene-H), 11.21 br.s (1H, NH,
exchangeable with D2O). 13C NMR spectrum, δC, ppm:
114.67, 117.20, 124.79, 126.27, 128.20, 128.60, 130.55,
Synthesis of 5'-amino-2,3'-bithiophene-4'-carbox-
ylic acid (5). Compound 1 (0.01 mol) was added to a solu-
tion of LiOH (0.01 mol) in EtOH–H2O (1 : 1.5, 50 mL)
and refluxed for 1 h. Upon cooling down the reaction
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1532
EL-SHEHRY et al.
Anti-microbial activity of the synthesized compounds
Diameter of inhibition zone, mma
Compound
+ve bacteria
–ve bacteria
fungi
S. aureus
B. subtitls
E. coli
14
15
9
A. flavus
12
C. albicans
4
5
6
7
8
9
17
19
15
14
22
20
21
14
13
20
14
14
20
13
17
19
21
20
9
15
20
14
16
17
21
19
12
22
23
18
15
21
20
16
21
20
6
13
18
22
10
19
11
13
12
7
22
21
11
9
Ciprofloxacinb
Fusidic acid
21
19
23
16
a
(≥15 mm) no inhibition, (16–20 mm) moderate inhibition, (≥20 mm) maximum inhibition.
Standard drug concentration 50 μg/mL.
b
136.01, 138.45, 145.61, 153.63, 159.10, 164.59, 166.47.
MS: m/z: 344 [M]+. Found, %: C 55.65; H 2.56; N 8.05.
C16H9ClN2OS2. Calculated, %: C 55.73; H 2.63; N 8.12.
THF was removed under reduced pressure. The residual
mixture was poured into water (200 mL), the precipitate
was filtered off to give compound 8. Yield 65%, mp
1
132–134°C. H NMR spectrum, δ, ppm: 2.08 t (4H,
Synthesis of 4-chloro-2-(4-chlorophenyl)-5-(thio-
phen-2-yl)thieno[2,3-d]pyrimidine (7). To a solution
of compound 6 (5 mmol) in phosphorus oxychloride
(10 mL) was added a mixture of phosphoric anhydride
(5 mmol) with phosphorus oxychloride (5 mL). The reac-
tion mixture was refluxed for 4 h. After cooling down, it
was poured onto water with crushed ice and neutralized
by 5% NaOH solution. The precipitate was filtered off,
washed with water and crystallized from ethanol to give
compound 7. Yield 70%, mp 168–170°C. 1H NMR spec-
trum, δ, ppm: 7.06–8.17 m (8H, Ar-H and thiophene-H).
13C NMR spectrum, δC, ppm: 114.74, 117.98, 125.00,
126.40, 128.12, 128.65, 129.98, 136.60, 138.26, 146.53,
151.53, 158.65, 164.78, 166.93. MS: m/z: 363 [M]+.
Found, %: C 52.80; H 2.12; N 7.63. C16H8Cl2N2S2. Cal-
culated, %: C 52.90; H 2.22; N 7.71.
2CH2N), 3.18 t (4H, 2CH2O), 6.90–8.52 m (8H,Ar-H and
thiophene-H). 13C NMR spectrum, δC, ppm: 31.16, 39.63,
40.34, 115.68, 116.45, 119.58, 123.66, 124.81, 125.54,
126.22, 128.89, 129.04, 130.46, 132.16, 137.50, 138.57,
162.79, 164.67, 165.46, 179.82. MS: m/z: 413 [M]+.
Found, %: C 57.96; H 3.82; N 10.06. C20H16ClN3OS2.
Calculated, %: C 58.03; H 3.90; N 10.15.
Synthesis of 2-(4-chlorophenyl)-4-hydrazinyl-5-
(thiophen-2-yl)thieno[2,3-d]pyrimidine (9). A mix-
ture of compound 7 (0.01 mol) with hydrazine hydrate
(15 mL, 0.03 mol) in ethanol (20 mL) was refluxed for
6 h, then concentrated to half of its volume and cooled
down to room temperature. A white crystalline product
was crystallized from ethanol. Yield 60%, mp 162–164°C.
IR spectrum, ν, cm–1: 3430, 3250 (NH, NH2). 1H NMR
spectrum, δ, ppm: 3.73 br.s (2H, NH2, exchangeable with
D2O), 7.11–7.97 m (8H, Ar-H and thiophene-H), 11.10
br.s (1H, NH, exchangeable with D2O). 13C NMR spec-
trum, δ, ppm: 116.93, 116.96, 121.96, 125.56, 126.24,
128.19, 130.45, 137.20, 137.50, 138.52, 144.32, 145.06,
Synthesis of 4-{2-(4-chlorophenyl)-5-(thiophen-2-
yl)thieno[2,3-d]pyrimidin-4-yl}morpholine (8). Trieth-
ylamine (0.026 mol) and morpholine (0.019 mol) were
added to a solution of compound 7 (0.017 mol) in THF
(80 mL). After stirring for 2 h at 30°C, the excess of
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SYNTHESIS OF SOME NEW SUBSTITUTED THIENO[2,3-d]PYRIMIDINE DERIVATIVES
1533
163.68, 164.27. MS: m/z: 358 [M]+. Found, %: C 53.40;
H 3.00; N 15.55. C16H11ClN4S2. Calculated, %: C 53.55;
H 3.09; N 15.61.
CH=N), 7.13–7.89 m (12H, Ar-H and thiophene-H). 13C
NMR spectrum, δC, ppm: 118.20, 118.56, 122.04, 126.87,
127.77, 128.09, 128.53, 129.08, 132.17, 135.23, 135.25,
136.51, 136.54, 138.10, 155.28, 155.30, 158.05, 158.07,
164.01. MS: m/z: 482 [M]+. Found, %: C 57.15; H 2.65;
N 8.60. C23H13Cl2N3OS2. Calculated, %: C 57.27; H
2.72; N 8.71.
Synthesis of 2-{2-(4-chlorophenyl)-5-(thiophen-2-
yl)thieno[2,3-d]pyrimidin-4-yl}-N-phenyl-hydrazine
carbothioamide(10). Amixtureofcompound9(0.01mol)
with phenyl isothiocyanate (0.01 mol) in DMF (20 mL)
was refluxed for 2 h. The obtained precipitate was filtered
off and crystallized from n-butanol to give compound
10. Yield 55%, mp 112–114°C. IR spectrum, ν, cm–1:
3420–3215 (3NH). 1H NMR spectrum, δ, ppm: 7.08–7.96
m (13H, Ar-H and thiophene-H), 10.41 s, 11.08 s, 11.92
2-(4-Chlorophenyl)-3-(4-nitrobenzylideneamino)-
5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one
(12b). Yield 60%, mp 261-263°C. IR spectrum, ν, cm–1:
1
1670 (C=O). H NMR spectrum, δ, ppm: 5.73 s (1H,
CH=N), 7.16–7.92 m (12H, Ar-H and thiophene-H). 13C
NMR spectrum, δC, ppm: 119.04, 119.82, 123.06, 124.95,
126.40, 128.57, 128.74, 129.17, 133.55, 134.96, 135.05,
136.86, 137.51, 150.45, 156.54, 156.30, 157.60, 159.57,
164.62. MS: m/z: 493 [M]+. Found, %: C 55.95; H 2.58;
N 11.29. C23H13ClN4O3S2. Calculated, %: C 56.04; H
2.66; N 11.37.
13
s (3H, 3NH, exchangeable with D2O). C NMR spec-
trum, δC, ppm: 123.66, 124.81, 125.54, 126.22, 127.85,
128.19, 128.78, 128.90, 129.04, 129.19, 130.46, 132.16,
137.19, 138.57, 162.79, 164.29, 164.67, 165.46, 179.82.
MS: m/z: 493 [M]+. Found, %: C 55.80; H 3.18; N 14.08.
C23H16ClN5S3. Calculated, %: C 55.92; H 3.26; N 14.18.
Synthesis of 3-amino-2-(4-chlorophenyl)-5-(thio-
phen-2-yl)thieno[2,3-d]pyrimidin-4(3H)-one (11). a.
A mixture of compound 2a (0.02 mol) with hydrazine
hydrate 95% (5.01 g, 0.1 mol) were refluxed in butanol
(10 mL) for 8 h. Addition of ethanol (2 mL) to the reac-
tion mixture gave the product as white precipitate, which
was filtered off and recrystallized from aqueous ethanol
to give compound 11.
Antimicrobial activity. Antimicrobial activity of the
synthesized compounds was determined by the agar dif-
fusion method [22, 23].
ACKNOWLEDGMENTS
The authors are grateful to the Deanship of Scientific
Research, king Saud University for funding through Vice
Deanship of Scientific Research Chairs.
b. Compound 4 (0.02 mol) was refluxed in butanol
(10 mL) for 24 h. The excess solvent was distilled off
and the solid residue was air dried and then recrystal-
lized from aqueous ethanol to give compound 11. Yield
60%, mp 253–255°C. IR spectrum, ν, cm–1: 3260 (NH2),
CONFLICT OF INTEREST
No conflict of interest was declared by the authors.
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Synthesis of compounds 12a, 12b. A mixture of
compound 5 (0.01 mol) with an appropriate aryl aldehyde
(0.01 mol) in isopropanol containing glacial acetic acid
(2 mL) was refluxed for 2 h. Upon cooling down, the
precipitate was filtered off and crystallized from methanol
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