Synthesis of Pyrano[2,3-d]pyrimidine-2,4-diones and Pyridino[2,3-d]pyrimidine-2,4,6,8-tetraones: Evaluation Antitumor Activity

Article abstract of DOI:10.1002/jhet.3830

A series of some novel pyrano[2,3-d]pyrimidine 4–10 with 75–95% yields and pyridino[2,3-d]pyrimidine derivatives 11–16 with 75–92% yields is reported. The building structures have been achieved by reaction of 5-arylidene barbituric acid 2 and active nucle

Full text of DOI:10.1002/jhet.3830

Received: 24 August 2019
DOI: 10.1002/jhet.3830
Revised: 2 November 2019
Accepted: 5 November 2019
A R T I C L E
Synthesis of Pyrano[2,3‐d]pyrimidine‐2,4‐diones and
Pyridino[2,3‐d]pyrimidine‐2,4,6,8‐tetraones: Evaluation
Antitumor Activity
Reda A. Haggam1,2
| Mohamed G. Assy2 | Enaiat K. Mohamed2 |
Abdussattar S. Mohamed2
1 Department of Chemistry, Faculty of
Science, Islamic University in Almadinah
Almonawara, Almadinah Almonawara,
Saudi Arabia
2 Department of Chemistry, Faculty of
Science, Zagazig University, Zagazig
44511, Egypt
Abstract
A series of some novel pyrano[2,3‐d]pyrimidine 4–10 with 75–95% yields and
pyridino[2,3‐d]pyrimidine derivatives 11–16 with 75–92% yields is reported.
The building structures have been achieved by reaction of 5‐arylidene
barbituric acid 2 and active nucleophile carbon or nitrogen as examples
barbituric acid and acetyl acetone or refluxing of bispyrimidine‐2,4,6‐trione
derivative 3 with cyclizing reagents such as phosphorous pentoxide, hydrazine
hydrate and aminothiazole. The newly synthesized structures have been eluci-
dated on the basis of their spectral analysis. Some selected members were
screened for antitumor activity. Among the screened compounds 9, 16, 7, 10
and 8 exhibited high antitumor activity.
Correspondence
Reda A. Haggam, Department of
Chemistry, Faculty of Science, Islamic
University in Almadinah Almonawara,
Almadinah Almonawara. Saudi Arabia.
Email: rhaggan99@hotmail.com
1 | INTRODUCTION
under the trade name of luminal is still a popular anti-
convulsant both in the oral and injectable forms.[18]
Barbituric acid is a pyrimidine heterocyclic ring with an
active methylene group that can be involved in condensa-
tion reactions with aldehydes, ketones and δ,
β‐unsaturated carbonyl compounds forming other hetero-
cycles compounds with an outstanding biological activity.
Barbituric acid and its derivatives have been attracting
considerable attention due to their wide range of pharma-
cological activities such as in‐vitro antitubercular and in‐
vivo anticonvulsant,[1–5] antibacterial, antiurease and
antioxidant properties.[6,7] On the other hand, the barbi-
turates possess several pharmacological applications, like
anticancer,[8] antituberculosis,[9] antiviral,[10] sedative,
anxiolytic and urease inhibition[11] and anti‐proliferative
activities.[12] Also, 5‐alkyl‐ and 5,5‐dialkylbarbituric acids
are widely used as medical agents for the treatment of
neurological diseases, depressions, and memory impair-
ment.[13] Pyrimido[4,5‐d]pyrimidines barbituric acid
derivatives are generally used as antitumors.[14–17] Barbi-
tone (I) is a barbituric acid derivative acts as a popular
hypnotic while phenobarbitone (II) that is marketed
hexobarbitone is the first rapidly acting intravenous
anaesthetic agent (III) (Figure 1).[18]
Recently, some new procedures for preparation and
reactions of barbituric acid derivatives are presented. As
examples, synthesis and dynamics studies of barbituric
acid derivatives as urease inhibitors are reported.[19] The
synthesis, tautomerism and antibacterial activity with
SAR study of novel barbiturates is presented.[6] Novel Y‐
shaped barbituric acid derivatives including molecular
docking have been designed.[20] A reproducible synthesis
of several new disubstitutedarylazo‐barbituric and thio-
barbituric acids is described.[21]
A review about
enantioselective catalytic transformations of barbituric
acid derivatives is achieved.[22] As continuing our project
towards chemistry of pyrimidines, a series of condensed
heterocycles was built utilizing barbituric acid as starting
materials.[23] In view of these interesting studies it has
been planned to synthesize more heterocycles involving
barbituric acid skeleton with evaluation their anticancer
activities.
J Heterocyclic Chem. 2019;1–9.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
HAGGAM ET AL.
and nitrogen nucleophiles. Upon heating compound 2a
with
active
methylene
compounds
such
as
cyanoacetamide, malononitrile and ethylcyanoacetate in
ethanol and few drops of trimethylamine for 1–3 h,
pyrano[2,3‐d]pyrimidine derivatives 4–10 are formed
with yields in the range in between 75 and 95%
(Scheme 2). The symmetrical structure of pyrano[2,3‐d]
pyrimidine‐2,4,6,8‐tetraone 4 was established through its
spectral data. Its IR spectrum exhibited absorption bands
at 3204, 3182 cm−1 for 2NH and 1716, 1680 cm−1 for
FIGURE 1 Structure of barbitone (I), phenobarbitone (II) and
hexobarbitone (III)
1
2C=O groups. The H NMR spectrum of 4 displayed a
2 | RESULTS AND DISCUSSION
singlet signal at δ = 4.41 ppm for CH pyran and two
broad singlets at δ = 11.14, 11.22 ppm for 4NH protons
which are D2O exchangeable. This indicates that it is a
symmetrical compound. Its 13C NMR spectrum showed
that two signals at δ = 150.6 and 165.4 ppm for the
4C=O groups (Scheme 2). The 1H NMR spectrum of
pyrano[2,3‐d]pyrimidine‐2,4‐dione 5 showed three sin-
glets at δ = 2.23, 2.61 and 4.37 ppm for the two methyl
groups and the CH pyran. Also, the two broad singlets
at δ = 10.30, 11.33 ppm for 2NH protons are D2O
exchangeable. Moreover, its 13C NMR spectrum displayed
characteristic signals at δ = 15.8 ppm for (CH3), 28.6 ppm
for (COCH3) and 36.1 ppm for (CH pyran) as shown in
(Scheme 2). Elucidation the structure of compound 6
was explained in details (see the experimental section).
The IR spectrum of pyrano[2,3‐d]pyrimidine‐6‐
carboxamide 7 showed str. Absorption bands at 3385,
3381 and 1671 cm−1 for NH2 and amide carbonyl. The
1H NMR spectrum revealed two singlet signals at
δ = 7.61, 8.12 ppm for 2NH2 and two broad signals at
δ = 10.98, 11.12 ppm 2NH protons which are D2O
In this publication,we report on synthesis of several
derivatives of pyrano[2,3‐d]pyrimidine derivatives,
pyridino[2,3‐d]pyrimidines and studying their anticancer
activity. The starting materials 5‐arylidene barbituric acid
2a,b and bispyrimidine‐2,4,6‐trione derivative 3a,b were
synthesized via 3‐ substituted benzaldhyde as a substrate.
Knoevenagel type condensation reaction of barbituric
acid (1) with 3‐nitrobenzaldhyde or 3‐trifluoro-
methylbenzaldhyde in aqueous medium without catalyst
and at room temperature took place according to the
method described in the literature[24–26] (Scheme 1). The
condensation occurred easily and completed through just
an hour, affording compound 2a and 2b in 98% and 28%
yields, respectively. On the other hand, we have found
that condensation of two equiv. of barbituric acid (1) with
3‐nitrobenzaldhyde or 3‐trifluoromethylbenzaldhyde in
acetic acid under stirring for 30 min gave 3a with high
yield (71%) and 3b with low yield (43%)[27] (Scheme 1).
From the obtained results, we decided to deal with the
nitro derivative 2a not only owing to its high yield, but
also this is in agree with the published data.[28,29] Here
we present the behaviour of activated exocyclic double
bond of 5‐aylidene barbituric acid 2a towards the carbon
1
exchangeable. The H NMR spectrum of pyrano[2,3‐d]
pyrimidine carboxylate 9 gave triplet at δ = 1.32 ppm
and quartet at δ = 4.85 ppm with coupling costant
SCHEME 1 Synthesis of the starting materials 2a,b and 3a,b [Color figure can be viewed at wileyonlinelibrary.com]

HAGGAM ET AL.
3
SCHEME 2 Reaction of 5‐arylidene barbituric acid 2a with different active carbon and nitrogen nucleophiles reagents [Color figure can be
viewed at wileyonlinelibrary.com]
J = 6.3 Hz responsible for CH3 and CH2 groups, respec-
tively (Scheme 2). The structure confirmation of com-
pounds 8 and 10 are mentioned in the experimental
section.
compound 16 gave singlet at δ = 10.23 ppm for the NH
indole moiety. The broad singlets at δ = 10.23, 11.28
and 11.37 ppm for NH protons are D2O exchangeable as
well (Scheme 3).
Upon refluxing of bispyrimidine‐2,4,6‐trione derivative
3a[27] and heterocyclizing reagents such as P2O5, acet-
amide, hydrazine hydrate and aminothiazole in presence
of anhydrous sodium acetate in ethanol (30–50 mL) for
1–2 h produced pyridino[2,3‐d]pyrimidine derivatives
11–16 with 75–92% yields (Scheme 3). The IR spectrum
of acetyl‐pyridino[2,3‐d]pyrimidine 12 showed str.
Absorption bands at 1702, 1667, 1664 cm−1 for amide car-
3 | ANTITUMOR ACTIVITY
3.1 | Tumor cell growth assay
The effects of compounds 5, 7, 8, 9, 10, 11, 13 and 16 on
the in vitro growth of human tumor cell lines were evalu-
ated according to the procedure adopted by the National
Cancer Institute (NCI, USA) in the ‘In vitro Anticancer
Drug Discovery Screen’ that uses the protein‐binding dye
sulforhodamine B to assess cell growth. Briefly, exponen-
tially, cells growing in 96‐well plates were then exposed
for 48 h to five serial concentrations of each compound,
starting from a maximum concentration of 150 μM. Fol-
lowing this exposure period adherent cells were fixed,
washed, and stained. The bound stain was solubilized
1
bonyl groups. The H NMR spectrum of 12 revealed two
singlets at δ = 1.95 and 4.51 ppm for methyl protons
and and the CH pyran. Moreover, the broad singlets at
δ = 11.24, 11.38 ppm for 4NH protons are D2O exchange-
able (Scheme 3). The 1H NMR spectrum of compound 13
displayed two singlets at δ = 8.21 ppm characteristic for
amino group and at δ = 4.47 ppm for the CH pyran. To
prove the structure of compounds 14 and 15 see the
experimental section). The 1H NMR spectrum of

4
HAGGAM ET AL.
SCHEME 3 Reaction of bispyrimidine‐2,4,6‐trione derivative 3a and heterocyclizing reagents [Color figure can be viewed at
wileyonlinelibrary.com]
and the absorbance was measured at 492 nm in a plate
reader (Bio‐Tek Instruments Inc., Power wave XS,
Wincoski, USA). For each tested compound and cell line,
a dose–response curve was obtained and the minium
inhibitor concentration inhibition of 50% (IC50), corre-
sponding to the concentration of the compounds that
inhibited 50% of the cancer cell lines, was calculated as
described elsewhere. Doxorubicin was used as a positive
control and tested in the same manner.
investigated cell lines (HCT‐116, HepG‐2 and PC‐3,
which is higher than that of the standard drug (doxorubi-
cin) as shown in Table 1 and Figure 2. In addition to,
compounds 7, 10 and 8 displayed high cytotoxicity effect
for the three tumor cell lines as well. Moreover, com-
pounds 13, 5 and 11 gave moderate inhibitory effect on
the cancer cell lines.
It is clearly notable that, all the tested compounds
showed significant inhibitory activities against the three
human tumor cell lines, Liver Carcinoma (HepG‐2),
Colon Carcinoma (HCT‐116) and Prostate Cancer (PC‐
3). The obtained results showed that the compounds 9
and 16 exhibited an amazing cytotoxicity effect, to the
4 | CONCLUSION
In conclusion, we reported a series of some new deriva-
tives of pyrano[2,3‐d]pyrimidine and pyridino[2,3‐d]
pyrimidine that are synthesized with very good yields
starting with 5‐arylidene barbituric acid and

HAGGAM ET AL.
5
1H NMR spectra were recorded with Brucker AC‐
400 MHz spectrometer at nucleic acid unit, Zagazig Uni-
versity. Chemical shift are expressed as δ (ppm) scale rel-
ative to TMS as an internal standard and DMSO‐d6 as
solvent. Elemental analyses were determined on a
Parkin‐Elmer model 240 at Micro‐analytical Center Cairo
University.
TABLE 1 Cytotoxicity of the screened compounds 5, 7, 8, 9, 10,
11, 13 and 16 (IC50, μg/mL)
IC50 (μg/mL)
Cpd. Nu.
HCT‐116
Hep‐G2
PC‐3
5
7.65
1.40
3.4
5.21
0.90
2.80
0.25
1.50
9.9
4.80
1.70
3.14
0.53
3.30
9.7
7
8
9
0.34
2.3
5.1 | General synthetic procedure of
compounds 4–10
10
11
11.3
5.7
A mixture of compound 5‐aylidene barbituric acid 2a
(2.00 mmol) and compounds such as barbituric acid, acetyl
acetone, ethylacetoactate, cyanoacetamide, malononitrile,
ethylcyanoacetate and thiourea (2. 00 mmol) in ethanol
(50 mL) and few drops of triethylamine was refluxed for
1–3 h. The reaction mixture was cooled at room tempera-
ture and poured into ice cold water. The crude product
was filtered off and crystallized from a proper solvent to
deliver the compounds 4–10 with 75–95% yields.
13
8.5
6.5
16
0.28
0.471
0.39
0.467
0.64
0.73
Doxorubicin standard
bispyrimidine‐2,4,6‐trione derivative via easy approaches.
By studying the antitumor activity for some selected com-
pounds, we found that compounds 9 and 16 exhibited
antitumor activity, which is higher than the standard
drug (doxorubicin), against the human tumor cell lines,
(HCT‐116, HepG‐2 and PC‐3). The reason of the activity
may be owing to the presence of the polar amino group
that increases the ability of the chemotherapeutic agent
to pentrate the cell wall of the microorganism. These
wonderful results encourage us to do further research
on such heterocycles.
5.2 | 5‐(3‐Nitrophenyl)‐1,3,7,9‐tetrahydro‐
5H‐pyrimidino[5′,4′‐5,6]pyrano[2,3‐d]
pyrimidine‐2,4,6,8‐tetraone (4)
The crude product was crystallized from ethanol to give
compound 4 in 75% yield as white crystals, mp 260–
261°C, ir (KBr): NH 3204, 3182, 2C=O 1716, 1680, 1621,
1
1507 C=N and C=C cm−1. H nmr (400 MHz, DMSO‐
d6): δ 4.41 (s, 1H, CH pyran), 7.27–7.54 (m, 4H, ArH's),
11.14 (brs, 2H, 2NH), 11.22 (brs, 2H, 2NH). 1H nmr
(400 MHz, DMSO‐d6, D2O exchangeable): δ 4.41 (s, 1H,
CH pyran), 7.27–7.54 (m, 4H, ArH's). 13C nmr (75 MHz,
DMSO‐d6): δ 35.7 (CH pyran), 90.3 (2C=C alkene),
119.4, 124.3, 130.1, 135.2, 144.1, 147.7 (Ph‐carbons),
150.6 (2NC=ON), 157.2 (2C‐O), 165.4, (2C=O); Anal.
Calcd for C15H9N5O7 (371.26): C, 48.63; H, 2.57; N,
18.89. Found: C, 48.53; H, 2.44; N, 18.86.
5 | EXPERIMENTAL
All melting points were measured via electro thermal IA
9100 series digital melting point apparatus with open cap-
illary tube and are uncorrected. The experiments were
carried out using drying solvents. TLC was performed
on Merck Silica Gel 60F254 have been detection by UV
light. The IR spectra were recorded on a Parkin‐Elmer
model 1600 FTIR spectrometer as KBr discs (USA). The
FIGURE 2 Cytotoxicity chart of the
screened compounds 5, 7, 8, 9, 10, 11, 13
and 16 (IC50, μg/mL) [Color figure can be
viewed at wileyonlinelibrary.com]

6
HAGGAM ET AL.
(C=O), 155.1, 158.7, 164.1 (C=O); Anal. Calcd. for
C14H11N5O6 (345.27): C, 48.76; H, 3.29; N, 20.33. Found:
C, 48.70; H, 3.21; N, 20.28.
5.3 | 6‐Acetyl‐7‐methyl‐5‐(3‐nitrphenyl)‐
1H‐pyrano[2,3‐d]pyrimidine‐2,4(3H,5H)‐
dione (5)
The crude product was crystallized from ethanol to give
compound 5 in 82% yield as yellow crystals, mp 245–
246°C, ir (KBr): NH 3219, 3213, 3C=O 1710, 1703, 1686,
5.6 | 7‐Amino‐5‐(3‐nitrphenyl)‐2,4‐dioxo‐
2,3,4,5‐tetrahydro‐1H‐pyrano[2,3‐d]
pyrimidine‐6‐carbonitrile (8)
1
1568 C=C cm−1. H nmr (400 MHz, DMSO‐d6): δ 2.23
(s, 3H, CH3), 2.61 (s, 3H, CH3), 4.37 (s, 1H, CH pyran),
7.71–8.19 (m, 4H, ArH's), 10.30, 11.33 (brs, 2H, 2NH).
1H nmr (400 MHz, DMSO‐d6, D2O exchangeable): δ 2.23
(s, 3H, CH3), 2.61 (s, 3H, CH3), 4.37 (s, 1H, CH pyran),
7.71–8.19 (m, 4H, ArH's). 13C nmr (75 MHz, DMSO‐d6):
δ 15.8 (CH3), 28.6 (COCH3), 36.1 (CH pyran), 88.1, 92.5,
119.2, 120.1, 121.6, 129.4, 135.6, 143.2, 148.1, 151.2
(C=O), 155.2, 159.6, 164.6 (C=O), 195.2 (COCH3); Anal.
Calcd. for C16H13N3O6 (343.29): C, 56.20; H, 3.89; N,
12.29. Found: C, 55.98; H, 3.82; N, 12.24.
The crude product was crystallized from ethanol to give
compound 8 in 76% yield as yellow crystals, mp 286–
287°C, ir (KBr): NH2 3381, 3378, NH 3184, 3162, CN
2235, 2C=O 1708, 1681, 1518 C=C cm−1 1H nmr
.
(400 MHz, DMSO‐d6): δ 4.27 (s, 1H, CH pyran), 7.38–
7.45 (m, 4H, ArH's), 7.53, (s, 2H, NH2), 11.23, 11.40 (brs,
2H, 2NH). 13C nmr (75 MHz, DMSO‐d6): δ 35.5 (CH
pyran), 58.6, 88.5, 118.5, 119.6 (CN), 123.8, 130.2, 135.3,
145.3, 148.1, 150.4 (C=O), 153.7, 157.7, 163.8 (C=O);
Anal. Calcd. for C14H9N5O5 (327.25): C, 51.44; H, 2.80;
N, 21.43. Found: C, 51.38; H, 2.77; N, 21.40.
5.4 | 6‐Acetyl‐7‐hydroxy‐5‐(3‐nitrphenyl)‐
1H‐pyrano[2,3‐d]pyrimidine‐2,4(3H,5H)‐
dione (6)
5.7 | Ethyl7‐amino‐5‐(3‐nitrphenyl)‐2,4‐
dioxo‐2,3,4,5‐tetrahydro‐1H‐pyrano[2,3‐d]
pyrimidine‐6‐carboxylate (9)
The crude product was crystallized from acetic acid to
give compound 6 in 95% yield as pale white crystals, mp
275–274°C, ir (KBr): OH 4415, NH 3222, 3214, 3C=O
The crude product was crystallized from ethanol to give
compound 9 in 92% yield as yellow crystals, mp 201–
202°C, ir (KBr): NH2 3396, 3388, NH 3181, 3176, 3C=O
1
1705, 1680, 1664, 1622 C=C cm−1. H nmr (400 MHz,
DMSO‐d6): δ 2.75 (s, 3H, CH3), 4.25 (s, 1H, CH pyran),
7.68–7.89 (m, 4H, ArH's), 11.10, 11.31 (brs, 2H, 2NH),
1
1738, 1716, 1684, C‐O 1150, 1527 C=C cm−1. H nmr
1
(400 MHz, DMSO‐d6): δ 1.32 (t, 3H, J = 6.3 Hz, CH3),
4.85 (q, 2H, J = 6.3 Hz, CH2), 4.23 (s, 1H, CH pyran),
7.42–7.48 (m, 4H, ArH's), 7.51, (s, 2H, NH2), 10.94,
11.85 (s, 1H, OH). H nmr (400 MHz, DMSO‐d6, D2O
exchangeable): δ 2.75 (s, 3H, CH3), 4.25 (s, 1H, CH
pyran), 7.68–7.89 (m, 4H, ArH's). 13C nmr (75 MHz,
DMSO‐d6): δ 27.5 (COCH3), 36.4 (CH pyran), 87.3, 93.5,
118.2, 119.6, 122.0, 130.1, 135.2, 143.7, 148.5, 151.6
(C=O), 158.3, 164.3 (C=O), 194.3 (COCH3), 198.2; Anal.
Calcd. for C15H11N3O7 (345.26): C, 52.26; H, 3.29; N,
12.25. Found: C, 52.18; H, 3.21; N, 12.17.
1
11.36 (brs, 2H, 2NH). H nmr (400 MHz, DMSO‐d6, D2O
exchangeable): δ 1.32 (t, 3H, J = 6.3 Hz, CH3), 4.23 (s,
1H, CH pyran), 4.85 (q, 2H, J = 6.3 Hz, CH2), 7.42–7.48
(m, 4H, ArH's). 13C nmr (75 MHz, DMSO‐d6): δ 15.4
(CH3), 35.4 (CH pyran), 65.8 (OCH2), 89.3, 98.5, 118.2,
120.4, 122.8, 130.6, 134.3, 144.7, 148.5, 150.8 (C=O),
154.3, 158.4, 163.9 (C=O); Anal. Calcd. for C14H9N5O5
(374.30): C, 51.40; H, 3.81; N, 15.03. Found: C, 51.34; H,
3.77; N, 14.97.
5.5 | 7‐Amino‐5‐(3‐nitrphenyl)‐2,4‐dioxo‐
2,3,4,5‐tetrahydro‐1H‐pyrano[2,3‐d]
pyrimidine‐6‐carboxamide (7)
The crude product was crystallized from ethanol to give
compound 7 in 78% yield as yellowish powder, mp 267–
268°C, ir (KBr): NH2 3385, 3381, NH 3184, 3162, 3C=O
5.8 | 7‐Amino‐4‐(3‐nitrphenyl)‐4H‐
pyrimido[5,4‐e][1,3]oxazine‐5,7‐(1H,8H)‐
dione (10)
1
1712, 1685, 1671, 1511 C=C cm−1. H nmr (400 MHz,
DMSO‐d6): δ 4.32 (s, 1H, CH pyran), 7.43–7.57 (m, 4H,
The crude product was crystallized from ethanol to give
compound 10 in 85% yield as yellow crystals, mp 240–
241°C, ir (KBr): NH2 3410, 3398, NH 3154, 3132, 2C=O
ArH's), 7.61, 8.12 (s, 4H, 2NH2), 10.98, 11.12 (brs, 2H,
1
2NH). H nmr (400 MHz, DMSO‐d6, D2O exchangeable):
δ 4.32 (s, 1H, CH pyran), 7.43–7.57 (m, 4H, ArH's). 13C
nmr (75 MHz, DMSO‐d6): δ 35.6 (CH pyran), 83.6, 88.9,
118.8, 119.2, 122.8, 130.3, 135.6, 144.6, 148.2, 150.8
1709, 1664, 1533 C=C cm−1. H nmr (400 MHz, DMSO‐
1
d6): δ 4.42 (s, 1H, CH pyran), 7.35–7.47 (m, 4H, ArH's),
7.49, (s, 2H, NH2), 11.39, 11.50 (brs, 2H, 2NH). 13C nmr

HAGGAM ET AL.
7
(75 MHz, DMSO‐d6): δ 35.7 (CH pyran), 89.7, 119.5,
121.1, 123.4, 130.4, 135.7, 143.2, 148.7, 152.0 (C=O),
155.3, 158.0, 165.1 (C=O); Anal. Calcd. for C12H9N5O5
(303.23): C, 47.55; H, 3.20; N, 23.14. Found: C, 47.53; H,
2.99; N, 23.10.
5.12 | 10‐Amino‐5‐(3‐nitrophenyl)‐
1,3,5,7,9,10‐hexahydropyrimidino[5′,4′‐5,6]
pyridino[2,3‐d]pyrimidine‐2,4,6,8‐tetraone
(13)
The crude product was crystallized from ethanol to give
compound 13 in 86% yield as pale white crystals;, mp
286–287°C, ir (KBr): NH2, NH 3429, 3223, 3174, 3156,
5.9 | General synthetic procedure of
compounds 11–16
1
4C=O 1695, 1668, 1645 C=C cm−1. H nmr (400 MHz,
DMSO‐d6): δ 4.47 (s, 1H, CH pyran), 7.11–7.35 (m, 4H,
ArH's), 8.21 (s, 2H, NH2), 11.17 (brs, 2H, 2NH), 11.35
(brs, 2H, 2NH). 1H nmr (400 MHz, DMSO‐d6, D2O
exchangeable): δ 4.47 (s, 1H, CH pyran), 7.11–7.35 (m,
4H, ArH's). 13C nmr (75 MHz, DMSO‐d6): δ 36.3 (CH
pyran), 88.3 (2C=C alkene), 119.6, 124.3, 129.8, 135.7,
143.2, 147.5 (Ph‐carbons), 151.1 (2NC=ON), 154.2 (2C‐
N), 165.7, (2C=O), 174.3(CH3C=O); Anal. Calcd. for
C15H11N7O6 (385.29): C, 46.78; H, 2.90; N, 25.55. Found:
C, 46.76; H, 2.88; N, 25.45.
A mixture of bispyrimidine‐2,4,6‐trione derivative 3a
(2.00 mmol)[27] and an reagents like P2S5, P2O5, acet-
amide, hydrazine hydrate, benzamide, aniline and
aminothiazole[30] (2. 00 mmol) ethanol and NaOAc (30–
50 mL) was refluxed for 1–2 h after TLC showed disap-
pearance of the starting materials. The reaction mixture
was cooled and poured into ice cold water. The crude
product was filtered off and crystallized from a proper sol-
vent to result in the compounds 11–16 with yields in
between 75 and 92%.
5.13 | 10‐Benzoyl‐5‐(3‐nitrophenyl)‐
1,3,5,7,9‐pentahydropyrimidino[5′,4′‐5,6]
pyridino[2,3‐d]pyrimidine‐2,4,6,8‐tetraone
(14)
5.10 | 5‐(3‐Nitrophenyl)‐1,3,7,9‐tetrahydro‐
5H‐hydropyrimidino[5′,4′‐5,6]thiino[2,3‐d]
pyrimidine‐2,4,6,8‐tetraone (11)
The crude product was crystallized from ethanol to give
compound 11 in 88% yield as pale white crystals, mp
255–256°C, ir (KBr): NH 3173, 3159, 4C=O 1717, 1665,
The crude product was crystallized from ethanol to give
compound 14 in 77% yield as pale white crystals, mp 278–
279°C, ir (KBr): NH 3161, 3157, 5C=O 1708, 1674, 1665,
1649 C=C cm−1. 1H nmr (400 MHz, DMSO‐d6): δ 4.46 (s,
1H, CH pyran), 7.45–8.13 (m, 9H, ArH's), 11.09 (brs, 2H,
2NH), 10.94 (brs, 2H, 2NH). 13C nmr (75 MHz, DMSO‐
d6): δ 37.3 (CH pyran), 92.6 (2C=C alkene), 118.4, 123.7,
129.2, 134.5, 143.8, 148.1 (Ph‐carbons), 150.9 (2NC=ON),
156.6 (2C‐N), 166.0, (2C=O), 181.2 (PhC=O); Anal. Calcd.
for C22H14N6O7 (474.38): C, 55.79; H, 3.20; N, 17.77. Found:
C, 55.70; H, 2.97; N, 17.72.
1
1634 C=C cm−1. H nmr (400 MHz, DMSO‐d6): δ 4.45
(s, 1H, CH pyran), 7.28–7.52 (m, 4H, ArH's), 11.16 (brs,
2H, 2NH), 11.29 (brs, 2H, 2NH).13C nmr (75 MHz,
DMSO‐d6): δ 36.2 (CH pyran), 88.4 (2C=C alkene),
119.4, 124.3, 130.1, 135.2, 144.1, 147.7 (Ph‐carbons),
150.6 (2NC=ON), 153.6 (2C‐S), 163.4, (2C=O); Anal.
Calcd. for C15H9N5O6S (387.33): C, 46.62; H, 2.38; N,
18.21. Found: C, 46.51; H, 2.34; N, 18.08.
5.11 | 10‐Acetyl‐5‐(3‐nitrophenyl)‐1,3,5,7,9‐
pentahydropyrimidino[5′,4′‐5,6]pyridino
[2,3‐d]pyrimidine‐2,4,6,8‐tetraone (12)
5.14 | 10‐Phenyl‐5‐(3‐nitrophenyl)‐1,3,5,7,9‐
pentahydropyrimidino[5′,4′‐5,6]pyridino
[2,3‐d]pyrimidine‐2,4,6,8‐tetraone (15)
The crude product was crystallized from ethanol to give
compound 12 in 82% yield as pale white crystals, mp
274–275°C, ir (KBr): NH 3165, 3151, 5C=O 1702, 1667,
The crude product was crystallized from acetic acid to
give compound 15 in 75% yield as pale white crystals,
mp 242–243°C, ir (KBr): NH 3166, 3154, 4C=O 1697,
1
1664, 1648 C=C cm−1. H nmr (400 MHz, DMSO‐d6): δ
1
1.95 (s, 3H, CH3), 4.51 (s, 1H, CH pyran), 7.23–7.39 (m,
4H, ArH's), 11.24 (brs, 2H, 2NH), 11.38 (brs, 2H, 2NH).
13C nmr (75 MHz, DMSO‐d6): δ 35.8 (CH pyran), 89.6
(2C=C alkene), 118.4, 123.7, 129.2, 134.5, 143.8, 148.1
(Ph‐carbons), 152.3 (2NC=ON), 154.6 (2C‐N), 164.7,
(2C=O); Anal. Calcd. for C17H12N6O7 (412.31): C, 49.58;
H, 2.97; N, 20.45. Found: C, 49.52; H, 2.93; N, 20.38.
1669, 1655 C=C cm−1. H nmr (400 MHz, DMSO‐d6): δ
4.48 (s, 1H, CH pyran), 7.48–8.24. (m, 9H, ArH's), 11.08
(brs, 2H, 2NH), 11.26 (brs, 2H, 2NH); 13C nmr (75 MHz,
DMSO‐d6): δ 37.5 (CH pyran), 92.3 (2C=C alkene),
118.6, 122.3, 123.2, 128.7, 129.0, 129.5, 129.8, 134.3,
143.6, 148.2 (Ar‐carbons), 151.3 (2NC=ON), 156.2 (2C‐
N), 166.4, (2C=O), Anal. Calcd. for C21H14N6O6

8
HAGGAM ET AL.
(446.37): C, 46.78; H, 2.90; N, 25.55. Found: C, 56.51; H,
3.16; N, 18.83.
MGC‐803, followed by 24 h of incubation. The effect of
the vehicle solvent (DMSO) on the growth of these cell
lines was evaluated in all the experiments by exposing
untreated control cells to the maximum concentration
(0.5%) of DMSO used in each assay.
5.15 | 10‐[4‐(1H‐indol‐3‐yl)thiazol‐2‐yl]‐5‐
(3‐nitrophenyl)‐1,3,5,7,9‐
pentahydropyrimidino[5′,4′‐5,6]
pyridino[2,3‐d]pyrimidine‐2,4,6,8‐tetraone
(16)
ORCID
Reda A. Haggam https://orcid.org/0000-0001-8568-9668
The crude product was crystallized from ethanol to give
compound 15 in 92% yield as pale yellow crystals, mp
282–283°C, ir (KBr): NH 3160, 3155, 4C=O 1714, 1669,
1653 C=C cm−1. 1H nmr (400 MHz, DMSO‐d6): δ 4.48 (s,
1H, CH pyran), 7.14–7.63. (m, 10H, ArH's), 10.23 (s, 1H,
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