Synthesis and antitumor activity evaluation of some thienopyrimidine derivatives

Article abstract of DOI:10.1080/00397911.2019.1697822

Some novel thienopyrimidine derivatives were synthesized via the reaction of 5- methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-carbohydrazide with different carbonyl compounds such as anhydrides, acid chlorides, carbon disulfide, phenyl isothiocyanate, triethyl orthoformate, diethyl acetylene dicarboxylate, acetylacetone, pyrazole-4-carboxaldehyde, and isatin. Also, the reaction of this carbohydrazide derivative with sodium nitrite in the presence of hydrochloric acid to give the corresponding azide derivative was discussed. The latter azide derivative was reacted with different amines to give the corresponding diheteryl urea derivatives. The antitumor activity evaluation of some representative examples of the synthesized compounds was examined against HePG2 and MCF-7 cell lines. Some of the newly synthesized compounds showed significant activity.

Full text of DOI:10.1080/00397911.2019.1697822

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and antitumor activity evaluation of
some thienopyrimidine derivatives
Amira T. A. Mohamed, Mohsen K. Abou-Elregal, Ahmed S. A. Youssef, Magdy
M. Hemdan, Sandy S. Samir & Wael S. I. Abou-Elmagd
To cite this article: Amira T. A. Mohamed, Mohsen K. Abou-Elregal, Ahmed S. A. Youssef,
Magdy M. Hemdan, Sandy S. Samir & Wael S. I. Abou-Elmagd (2019): Synthesis and antitumor
activity evaluation of some thienopyrimidine derivatives, Synthetic Communications, DOI:
10.1080/00397911.2019.1697822
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https://doi.org/10.1080/00397911.2019.1697822
Synthesis and antitumor activity evaluation of some
thienopyrimidine derivatives
Amira T. A. Mohamed, Mohsen K. Abou-Elregal, Ahmed S. A. Youssef, Magdy M.
Hemdan, Sandy S. Samir , and Wael S. I. Abou-Elmagd
Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Some novel thienopyrimidine derivatives were synthesized via the
reaction of 5- methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-5-car-
bohydrazide with different carbonyl compounds such as anhydrides,
acid chlorides, carbon disulfide, phenyl isothiocyanate, triethyl ortho-
formate, diethyl acetylene dicarboxylate, acetylacetone, pyrazole-4-
carboxaldehyde, and isatin. Also, the reaction of this carbohydrazide
derivative with sodium nitrite in the presence of hydrochloric acid to
give the corresponding azide derivative was discussed. The latter
azide derivative was reacted with different amines to give the corre-
sponding diheteryl urea derivatives. The antitumor activity evaluation
of some representative examples of the synthesized compounds was
examined against HePG2 and MCF-7 cell lines. Some of the newly
synthesized compounds showed significant activity.
Received 28 September 2019
KEYWORDS
1
,3,4-Oxadiazol-2-yl-thieno-
pyrimidines; thieno[2,3-
d]pyrimidines; 1,2,4-triazol-
3
-yl-thienopyrimidines
GRAPHICAL ABSTRACT
Introduction
Heterocyclic compounds containing thienopyrimidine moiety have attracted a great deal
[
1,2]
of interest because of their pharmacological and biological activities as antimicrobial,
[
3,4]
[5,6]
[7]
[8]
[9]
analgesic,
anti-inflammatory,
antiviral,
antioxidant,
antidepressant,
and
CONTACT Amira T. A. Mohamed
amirataher_82@yahoo.com
Chemistry Department, Faculty of Science, Ain
Shams University, Abassia, Cairo, Egypt.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A. T. A. MOHAMED ET AL.
Scheme 1. Reaction steps for formation of the acid hydrazide derivative 4.
[
10–15]
antitumor.
Thienopyrimidines are structural analogs of biogenic purines and can
be considered as potential nucleic acid antimetabolites so that large number of thieno
[
2,3-d]pyrimidine derivatives were found to be against different cancer types exerting
[
16–18]
their anticancer activities via various mechanisms.
In continuation of our efforts
to develop synthetic methods as well as our interest establishing biologically active het-
[
19–31]
erocyclic compounds,
prompted us to design some novel thienopyrimdine deriva-
tives with anticipated antitumor activity.
Results and discussion
[
30]
Our interest in the synthesis and use of acid hydrazide derivatives,
prompted us to
study the synthesis and the reactivity of 5-methyl-4-oxo-3, 4-dihydrothieno[2,3-d]pyr-
imidine-6-carbohydrazide 4 toward different carbon electrophiles.
At the first point of view, ethyl 2-amino-3-cyano-4-methyl thiophene-5-carboxylate 1
was prepared by Gewald reaction of ethyl acetoacetate with malononitrile and sulfur in
[
32]
the presence of triethylamine as a base catalyst under reflux conditions.
Attempts to convert the thiophene ester 1 to the hydrazide derivative 2 by heating
with hydrazine hydrate in dioxane was unsuccessful probably due to weak electrophilic-
ity of the C¼O ester by the free amino group. In order to increase the electrophilicity
of the C¼O of the ester group, the thiophene derivative 1 was treated with boiling for-
mic acid to afford the corresponding theinopyrimidone derivative 3, via condensation
followed by molecular cyclization reaction (Scheme 1). The structure of theinopyrimi-
done derivative 3 was proved by the disappearance of cyano group band in its IR spec-
ꢀ
1
trum, but it showed two absorption bands at 1704 and 1687 cm corresponding to
ꢀ
1
(
C¼O) of ester and cyclic amide, respectively, in addition to N–H at 3172 cm . The
1
HNMR displayed signals at d 12.60, 8.20 ppm for protons of NH and CH¼N groups as
well as the triplet and quartet signals for protons of ethyl ester group. Heating of ethyl

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Scheme 2. Mechanistic pathway for the formation of compound 3.
thienoprimidine-6-carboxylate 3 with hydrazine hydrate in dioxane afforded the corre-
sponding acid hydrazide 4. The structure of compound 4 is evidenced from its IR,
1
HNMR and mass spectral data (Cf. Experimental part).
The suggested mechanism for intramolecular cyclization of compound 1 with formic
acid has been shown in (Scheme 2).
The free amino group of the acid hydrazide 4 underwent condensation reaction with
different acid anhydrides such as succinic, phthalic and 3,4,5,6-tetrachlorophthalic anhy-
drides in boiling acetic acid to gives the corresponding pyrrolidine, isoindoline, and tet-
rachloro isoindoline derivatives 5–7, respectively (Scheme 3).
The structures of the products 5–7 were proved by IR spectra, which showed two absorp-
tion bands of symmetrical and asymmetrical stretching viberation of C¼O in the

4
A. T. A. MOHAMED ET AL.
Scheme 3. Reaction of acid hydrazide 4 with different acid anhydrides and acid chlorides.
dioxopyrrolidine ring in addition to absorption of C¼O of pyrimidone nucleus. Further evi-
1
dence for the proposed structures that were gained from their HNMR spectra that were in
accordance with the suggested structures and EIMS spectra that revealed their correct
molecular ion peak, as well as some of abundant peaks (Cf. Experimental part).
Benzoylation of the acid hydrazide 4 with benzoyl chloride afforded the 1, 3, 4-oxadiazole
derivative 8. However, its reaction with chloroacetyl chloride gave the acetylation product

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Scheme 4. The reaction of acid hydrazide 4 with CS and phenyl isothiocyanate.
2
9. Attempt to cyclize 9 by boiling with alcoholic NaOH (10%) led to the acid derivative 10,
which was proved authentically by alkaline hydrolysis of the ester derivative 3 with alcoholic
NaOH (10%) (cf. Scheme 3).
The structures of compounds 8–10 were evidenced by studying their spectral as well
as analytical data. Their IR spectra exhibited absorption bands correlated with C¼O
and NH groups as well as a band for OH group in case of compound 10. Their
1
HNMR spectra were in accordance with their proposed structures. Further support is
gained from their EIMS spectra that revealed their correct molecular ion peaks beside
some of important peaks (Cf. Experimental part).
Moreover, the reaction of acid hydrazide 4 with carbon disulfide in the presence of
alcoholic KOH (10%) afforded the cyclization product 1,3,4-oxadiazol-2-thione deriva-
tive 11, via nucleophilic addition of the free amino group followed by intramolecular
cyclization. Similar reaction was carried out by treatment of acid hydrazide 4 with phe-
nyl isothiocyanate in boiling n-butanol, it gave the addition product 12, which under-
went cyclization by heating with alcoholic NaOH (10%) to give the triazolyl
thienopyrimidine derivative 13 (Scheme 4).
The structures of compounds 11–13 were evidenced from their analytical as well as
spectral data. Their IR spectra revealed absorption bands for NH, C¼O and C¼S
1
groups. Further support for their proposed structures was gained from their HNMR as

6
A. T. A. MOHAMED ET AL.
Scheme 5. Reaction of acid hydrazide 4 with different carbon electrophiles.
well as mass spectral data. The EIMS spectra exhibited the correct molecular ion peaks
of compounds 11 and 13; however, it was missed in case of compound 12 probably due
to its ease decomposition in the ionization chamber (cf. Experimental part).
[
33,34]
The pronounced biological activity of pyrazoles and oxadizoles,
promoted us to
utilize the amino function of the hydrazide derivative 4 in the design synthesis of new het-
erocyclic systems incorporating pyrazole or oxadiazole nucleus. Thus, hydrazide 4 has
been allowed to react with triethyl orthoformate, diethyl acetylene dicarboxylate and/or
acetyl acetone to afford the oxadiazole and pyrazole derivatives 14–16 (Scheme 5).
The structures of compounds 14–16 were evidenced from their IR spectra that exhibited
bands corresponding to NH and C¼O groups. Their structures were supported by their
1
HNMR spectra that revealed signals for protons of NH, CH, and CH groups as well as
3
multiplet signals for protons of two ethyl groups in the case of compound 15. Evidence was
gained from their mass spectra that showed their correct molecular ion peaks (cf.
Experimental part).
On the other hand, reactions of acid hydrazide 4 with a series of carbon electrophiles
such as 1,3-diphenyl pyrazole 4-carboxaldehyde, dibenzylidine hydrazine and/or isatin,
yielded the Schiff bases 17a, 17b, and18 as shown in (Scheme 6). The IR spectra of
compounds 17a, 17 b, 18 showed band characteristic for NH and C¼O groups. Their
1
HNMR spectra were in accordance with the suggested structures (cf. Experimental
1
part). Inspection of the HNMR spectrum of compound 18 revealed the existence of a

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Scheme 6. Reaction of acid hydrazide 4 with different carbonyl compounds.
singlet signal in the upfield region at d 2.73 ppm for methine proton CH, as well as a
broad singlet for NH proton. This suggests the existence of compound 18 as an equi-
c
librium mixture of tautomers 18a and b in the ratio of 3:7, respectively. The higher d
value for the broad singlet of NH proton suggests its existence as its chelated form
c
shown (Scheme 6). Also, the higher percentage of the tautomer 18a may be due to the
extended conjugation. Further support for the assigned structures of compounds 17a,
1
7b, 18 is found in their mass spectra that revealed their molecular ion peaks and other
abundant peaks.
A chemical proof for the structure of compound 17b was gained by heating the
hydrazide derivative 4 with benzaldehyde in dioxane that gave a substance which was
identical in all respects m.p., m.m.p., and TLC with compound 17b.
A further aspect of the behavior of acid hydrazide compound 4 was exemplified by
ꢁ
reaction with nitrous acid at a temperature between 0 and 5 C, which afforded the cor-
responding 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbonylazide 19. The
aroyl azide 19 reacted with different nucleophilic reagents such as p-anisidine, 4-amino-

8
A. T. A. MOHAMED ET AL.
Scheme 7. Formation of acid azide 19 and reactions with different nucleophiles.
1
,5-dimethyl-2-phenyl-1,2- dihydro-3H-pyrazol-3-one and ethanol to afford the urea
derivatives 20a, 20b, and the ethyl carbamate derivative 21. It is rationalized that the
reaction proceeded through the conversion of the aroyl azide 19 to the isocyanate inter-
mediate (not isolated) through Curtius rearrangement, followed by the concurrent
attack of the nucleophilic reagents to afford the adduct 20a, 20b, 21 (Scheme 7). The
IR spectra of compounds 20a, 20b, 21 exhibited bands correlated with NH and C¼O
1
groups as well as a band for azido group for compound 19. The HNMR spectra sup-
ported the structures of compounds 20a, 20b, 21 as they showed signals for protons of
NH, alkyl, and multiplet signals for aromatic protons of compounds 20a and 20b.
Further proof for the structures of compounds 20a, 20b is gained from their EIMS
spectra that showed their molecular ion peaks as well as some important peaks (cf.
Experimental part).
The proposed mechanism for the formation of compounds 20a, 20b, 21 can be
explained as depicted in (Schemes 8).
Antitumor activity evaluation
The anti-tumor efficacy of the compounds against HePG2 and MCF-7 cell lines was
[
35,36]
established compared with doxorubicin by using the MTT assay.
The results
revealed that compounds 4, 14, 19, and 21 were the most active derivatives among the
series of tested compounds whereas other compounds exhibited little or no activity. The
effective dose calculated as IC , which corresponds to the compound concentration
5
0
resulted in 50% mortality in the total cells count and presented in (Table 1).

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9
Scheme 8. Mechanistic pathway for the formation of compounds 20a, 20b, 21.
Table 1. Cytotoxic activity of some compounds against human tumor cells.
In vitro cytotoxicity IC50 (mM)
Compounds
HePG2
MCF-7
DOX
3
4
4.50 ± 0.3
62.75 ± 3.0
6.65 ± 0.5
4.17 ± 0.2
70.61 ± 3.9
7.08 ± 0.8
5
6
7
8
1
1
1
1
1
1
1
1
2
2
29.51 ± 2.1
23.67 ± 1.7
74.13 ± 3.3
86.40 ± 3.9
36.01 ± 2.5
41.68 ± 2.8
13.81 ± 1.2
65.28 ± 3.1
47.22 ± 2.9
33.84 ± 2.3
18.93 ± 1.4
88.49 ± 4.2
9.49 ± 0.8
25.81 ± 1.9
14.50 ± 1.3
61.17 ± 3.4
81.23 ± 4.5
42.35 ± 2.9
32.56 ± 2.3
17.23 ± 1.5
38.42 ± 2.6
53.48 ± 3.1
45.05 ± 3.0
21.39 ± 1.8
92.48 ± 5.1
10.67 ± 1.1
8.79 ± 0.9
1
2
4
5
6
7a
7b
8
0a
1
12.05 ± 1.0
IC50 (mM): 1–10 (very strong); 11–20 (strong); 21–50 (moderate); 51–100 (weak and above 100 non-cytotoxic). DOX:
doxorubicin.
Experimental
Melting points were determined using an electrothermal Gallenkamp Scientific melting
point apparatus and are uncorrected. The infrared (IR) spectra were recorded on
Nicolet 7600 (USA)FT-IR infrared spectrophotometer using the KBr pellet technique at

1
0
A. T. A. MOHAMED ET AL.
1
the Central Laboratory of Faculty of Science, Ain Shams University. HNMR spectra
were recorded on a GEMINI 300 BB-400 MHz spectrometer using tetramethylsilane
(
TMS) as internal standard in dimethyl sulfoxide (DMSO-d6) as a solvent with chemical
13
shift d expressed in ppm at the main defense chemical laboratory and C-NMR spectra
were recorded on a Mercury 300 BB-75 MHZ spectrometer and referenced to solvent
signal d ¼ 39.50 ppm for DMSO-d6 at Cairo University. Mass spectra were measured on
a GC-MSQP 1000-Ex spectrometer at the Regional Center for Mycology and
Biotechnology of Al-Azhar university and on Agilent technologies 5977 AMSD 7890B
CTC system at the Central Laboratory of Faculty of Science, Ain Shams University.
Elemental analyses were carried out at the Microanalytical Center of Faculty of Science,
Cairo University. Followup of the reactions and checking the homogeneity of the com-
pounds were made by TLC on silica gel-protected aluminum sheets (F254, Merck) and
the spots were detected by exposure to UV-lamp. The anticancer activity was done at
the Micro Analytical Center at Mansoura University.
Reaction of the cyano amino derivative 1 with formic acid
A solution of compound 1 (1 g, 0.005 mol) in formic acid (20 mL), was refluxed on a hot
plate for 15 h, then left to cool at room temperature. The precipitated solid obtained was
filtered off, washed with water several times and recrystallized from benzene-ethanol to
give compound 3.
Ethyl-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (3)
o
ꢀ1
Off white crystals (60%), m.p. 288–290 C, (benzene/ethanol); FTIR (KBr) cm : 3172
(
1
2
NH), 3063 (Aryl-H), 2924, 2874 (Alkyl-H), 1704 (C¼O) of conjugated ester,
1
687(C¼O) of amide. HNMR (DMSO-d6): d 1.31 (t, 3H, CH CH , J ¼ 7.2, 6.9 Hz),
2
3
.82 (s, 3H, CH of thiophene), 4.29 (q, 2H, CH CH J ¼ 7.2, 6.9 Hz), 8.20 (s,1H,
3
2
3
CH¼N), 12.60 (br.s, 1H, NH of pyrimidinone, exchangeable). M/Z (70 ev) m/z (%): 238
þ
(M , 74), 228(23), 203(48), 202(89), 193(40), 188(26), 150(36), 139(40), 105(38), 95(75),
9
0(100). Anal.calcd for C H N O S (238.26): C, 50.41; H, 4.23; N, 11.76; S, 13.46.
10 10 2 3
Found: C, 50.19; H, 4.52; N, 11.31; S, 13.63%.
Reaction of the thieno pyrimidine derivative 3 with hydrazine hydrate
To a solution of compound 3 (1 g, 0.002 mol) in dioxane (20 mL), hydrazine hydrate
(1 mL, 0.02 mol) was added. The reaction mixture was heated under reflux for 7 h. A
solid product was precipitated while hot, filtered off, washed with water for several
times and recrystallized from dioxane.
5
-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbohydrazide (4)
o
ꢀ1
Off white crystals (64%), m.p. >300 C, (dioxane); FTIR (KBr) cm : 3429, 3263, 3122
(
1
NH), 3058 (Aryl-H), 2925, 2855 (Alkyl-H), 1690 (C¼O). HNMR (DMSO-d6): d 2.67
s, 3H, CH ), 4.57 (br.s, 2H, NH exchangeable), 8.13 (s,1H, CH¼N), 9.49 (br.s,
(
3
2,

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11
1
H,NH, exchangeable), 12.50 (br.s, 1H,NH of pyrimidinone, exchangeable). M/Z (70 ev)
þ
þ
m/z (%): 225(M þ1, 48), 224(M , missed), 193(100), 165(51), 91(38), 89(59), 83(47),
8
2
1(60), 63(31), 52(28), 45(26). Anal.calcd for C H N O S (224.24): C, 42.85; H, 3.60; N,
8 8 4 2
4.99; S, 14.30. Found: C, 42.53; H, 3.76; N, 24.68; S, 14.01%.
Reaction of the carbohydrazide derivative 4 with sodium nitrite. Formation
of azide derivative 20
To a stirred solution of compound 4 (1 g, 0.004 mol) in cold diluted hydrochloric acid
(20 mL), solution of sodium nitrite (1.1 g, 10 mL, 0.03 mol) was added dropwise. The
reaction mixture was stirred for 1 h. A solid product was precipitated while stirring, fil-
tered off, and washed with water several times to give compound 20.
5
-Methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carbonyl azide (20)
o
ꢀ1
Beige powder (94%), m.p. 130 C (dec); FTIR (KBr) cm : 3173 (NH), 3068 (Aryl-H),
1
2
941, (Alkyl-H), 2161(N ), 1692, 1667(C ¼ O). HNMR (DMSO-d6): d 2.83 (s, 3H,
3
CH ), 8.26 (s,1H, CH ¼ N), 12.74 (br.s, 1H,NH of pyrimidinone, exchangeable).
3
ORCID
Sandy S. Samir
http://orcid.org/0000-0002-5637-8200
Wael S. I. Abou-Elmagd
http://orcid.org/0000-0002-8317-3972
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