Synthesis and Computational Analysis of New Antioxidant and Antimicrobial Angular Chromenopyrimidines

Article abstract of DOI:10.1002/jhet.3686

A convenient synthetic protocol for the synthesis of novel chromenopyrimidine derivatives based on angular scaffold has been developed from the readily available enaminonitrile precursor 1. The skeleton of chromenopyrimidines has been decorated with different moieties in order to approach compounds with improved antioxidant and antimicrobial activities. Compound 1 was reacted with Ac₂O to yield benzochromenopyrimidine 6 that gave chloropyrimidine 7 via chlorination reaction. The reaction of chloropyrimidine 7 with different amines afforded a series of benzochromenopyrimidines 9–12. The hydrazine 11 and hydrazide 13 derivatives showed excellent antioxidant activity in addition to the potent antimicrobial activity revealed by aminopyrimidines 10 and 16. Computational docking studies indicated the potential recognition of compound 13 towards antioxidant binding site. Dual evaluations of the antimicrobial affinity of compound 16 indicated its promising activity as antimicrobial lead.

Full text of DOI:10.1002/jhet.3686

Month 2019
Synthesis and Computational Analysis of New Antioxidant and Antimi-
crobial Angular Chromenopyrimidines
Mohamed A. Abozeid,a
Mohamed R. El-Kholany,a
Laila A. Abouzeid,b,c Abdel-Rahman H. Abdel-Rahman,a and
a
*
El-Sayed I. El-Desoky
aDepartment of Chemistry, Faculty of Science, Mansoura University, El-Gomhoria Street, Mansoura 35516, Egypt
bDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, El-Gomhoria Street,
Mansoura 35516, Egypt
cDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Delta University, Mansoura-Gamasa, Egypt
*E-mail: desoky199@yahoo.com; prof.desoky.orgchem@gmail.com
Received January 18, 2019
DOI 10.1002/jhet.3686
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A convenient synthetic protocol for the synthesis of novel chromenopyrimidine derivatives based on an-
gular scaffold has been developed from the readily available enaminonitrile precursor 1. The skeleton of
chromenopyrimidines has been decorated with different moieties in order to approach compounds with im-
proved antioxidant and antimicrobial activities. Compound 1 was reacted with Ac2O to yield
benzochromenopyrimidine 6 that gave chloropyrimidine 7 via chlorination reaction. The reaction of
chloropyrimidine 7 with different amines afforded a series of benzochromenopyrimidines 9–12. The hydra-
zine 11 and hydrazide 13 derivatives showed excellent antioxidant activity in addition to the potent antimi-
crobial activity revealed by aminopyrimidines 10 and 16. Computational docking studies indicated the
potential recognition of compound 13 towards antioxidant binding site. Dual evaluations of the antimicrobial
affinity of compound 16 indicated its promising activity as antimicrobial lead.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
effectiveness including antihypertensive,[5] antiplatelet,
[6] antiviral,[7] antidiabetic,[8] antimicrobial, and
antioxidant[9] activities. In addition, many vital natural
products such as vitamin B1 contain pyrimidine nucleus.
Pyrimidine bases such as cytosine, uracil, and thymine
are utilized in constructing different nucleotides that are
the essential building blocks of the nucleic acid DNA.
In addition, chromene scaffolds became privileged
skeletons because of their wide medicinal activities.[10–13]
Because enhanced medicinal activity might be produced
via combining two or more biologically active segments,
pyrimidine and chromene units might be appropriate
candidates to build an elegant hydrid model.[14]
Herein, we disclose our results in the design of new
antimicrobial and antioxidant agents based upon an angular
chromenopyrimidine hydrid skeleton.
Microbial resistance to the common drugs is recognized
as one of the main public health issues in the world. The
World Health Organization has reported the microbial
resistance as one of the three most serious health threats
of the current century. The excessive and uncontrolled use
of antimicrobial drugs promoted the appearance of
multidrug-resistant microbes, which leaded to continuous
need for new drugs. In addition, reactive oxygen species
are deleterious oxygen radicals that can mutate DNA
as well as altering the cell components.[1] In this regard,
the human antioxidant defense system plays the main to
neutralize reactive oxygen species and consequently
protecting the human body from oxidative stress that is
responsible for many diseases such as cancer, hypertension,
diabetes, asthma, Alzheimer, and Parkinson.[2] As a result,
the development of efficient antioxidants became very
important in disease safeguard and medication.
RESULTS AND DISCUSSION
Pyrimidines play a crucial role in the human being life
because they are widely distributed in several important
organic compounds.[3,4] Many of these compounds
exhibit outstanding biological and pharmacological
Chemistry. The multicomponent reaction between 2,7-
dihydroxynaphthalene, benzaldehyde, and malononitrile
in the presence of piperidine afforded the angular
© 2019 Wiley Periodicals, Inc.

M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
Scheme 1. a. Benzaldehyde, malononitrile, piperidine; b. Ac2O, 1 h; c. Ac2O, 7 h; d. AcOH.
enaminonitrile 1 via a convenient and high yielding
protocol (Scheme 1).[15] The versatile precursor benzo[f]
chromeno[2,3-d]pyrimidine derivative 6 was synthesized
from the benzochromene derivative 1 through harsh
treatment with acetic anhydride under reflux conditions.
Interestingly, the aforementioned reaction was monitored,
and it was shown that the triacetylated product 2 was
obtained by refluxing for 1 h, whereas the yield of the
chromenopyrimidine product 6 increased concurrently
with increasing the reaction time that indicated to the
shorter time (entry 5).[16] However, the yield could be
mostly improved by the gradual upgrading of DBU up to
6 equivalents (entries 5–7); the reaction efficacy was
downgraded beyond 6 equivalent DBU because of the
production of the hydrolyzed phenol 8 (entries 8 and 9).
In addition, the nucleophilic bases would be non-efficient
in such transformations because of their competing
nucleophilic activity.[17]
The replacement of chlorine atom and deacetylation
of chloropyrimidine 7 were accomplished by the reaction
with piperidine, morpholine, aniline, and hydrazine
formation of the product
6 passing through the
triacetylated product 2.
hydrate
piperidine
yielding
or morpholine
chromenopyrimidinyl amine
N-(benzochromenopyrimidinyl)
The plausible reaction mechanism included the gradual
hydrolysis of the triacetylated product to give
O-acetyl-N-acetylbenzochromene derivative that
paved the way to undergo tautomerization giving the
nucleophilic hydroxyl group that attacked the carbonitrile
active center giving the benzochromeno[2,3-d]oxazine 5
that finally underwent Dimroth rearrangement giving the
desired benzochromenopyrimidine derivative 6 as shown
in Scheme 1.[16]
Meanwhile, it is important to finely tune the chlorination
reaction conditions of the chromenopyrimidine 6 in
order to obtain the corresponding chloropyrimidine 7 in
excellent yield as shown in Table 1. Although the
reaction did not proceed at all either in the absence of
base (entry 1) or in the presence of pyridine (entry 2),
triethylamine could promote the reaction upon 19% yield
of product 7. Among the tertiary amines we screened,
1,8-diazabicycloundec-7-ene (DBU) was the most
efficient to give the desired product in 60% yield in
9a,b,
N-phenyl-N-
and N-
2
10,
3
benzochromenopyrimidinyl hydrazine 11, respectively
(Scheme 2). Moreover, the deacetylation of
chloropyrimidine 7 could be carried out in the presence
of triethylamine to yield the hydrolyzed phenol 8 that
could afford hydrazine derivative 11 in a good yield by
treatment with hydrazine hydrate in ethanol.
The chromenopyrimidinyl hydrazine 11 was exploited to
construct different condensed and isolated heterocyclic
compounds (Scheme 3). By the reaction with different
aldehydes, the corresponding hydrazones 12a–d were
produced successfully. Moreover, the pendant hydrazinyl
moiety was acetylated in the presence of glacial
acetic acid to give the corresponding acetohydrazide
13. Additionally, the reaction of hydrazine 11 with
DMF–DMA or formic acid afforded the corresponding
benzochromenotriazolo pyrimidine derivative 14 in a
good yield. Moreover, compound 11 was reacted with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Bioactive Angular Chromenopyrimidines
Table 1
Optimization of chlorination reaction conditions.
Entry
Base
X equivalents
Time (h)
Yield 7 (%)
No reaction
Yield 8 (%)
1
2
3
4
5
6
7
8
9
—
—
1.5
1.5
1.5
1.5
3
6
8
10
48
48
7
Pyridine
Et3N
No reaction
19
28
60
75
96
63
40
Traces
DMA
DBU
DBU
DBU
DBU
DBU
7
Traces
Traces
Traces
Traces
20
1.5
1.5
1.5
1.5
1.5
55
DMA, N,N-dimethyl aniline; DBU, 1,8-diazabicycloundec-7-ene.
Scheme 2. a. 2 amine; b. 1) Et3N or DBU, EtOH, 2) HCl; c. aniline, EtOH; d. H2NNH2.xH2O, EtOH.
acetylacetone in the presence of acetic acid to give
pyrazolylpyrimidine 15.
against L-ascorbic acid as reference drug using
two different radical scavenging assays, namely, ABTS
[2,2′-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)]
and DPPH [2,2-diphenyl-1-picrylhydrazyl], as depicted
in Table 2. Although hydrazinyl 11 and hydrazide 13
derivatives exhibited excellent antioxidant activities,
other products manifested poor to moderate activities.
The advantage of merging chromene and pyrimidine
moieties in one scaffold could be observed by the
improvement of the antioxidant activities of the hybrid
compounds 11 and 13 over chromene-based compounds 1
and 2 (Table 2). Additionally, the presence of free
hydroxyl group is very crucial to impart high antioxidant
activity, and this could be seen in many cases. For
example, conversion of enaminonitrile 1 into compound 2
by full acetylation destroyed its antioxidant activity.
Moreover, chromenopyrimidine derivatives 6 and 7 with
Furthermore, chromenopyrimidine derivative 16
containing phenolic and heteroaryl primary amine groups
was synthesized via the treatment of the enaminonitrile 1
with formamide. Compound 16 was coupled with the
diazonium salts of different amines, namely, aniline,
4-methoxyaniline, 4-chloroaniline, and 3-aminopyridine
to afford the corresponding azo products 17a–d. Also, O-
alkylation of aminopyrimidine 16 with chloroacetone and
ethyl chloroacetate afforded the O-alkylated products 18
and 19 that could be cyclized into naphthofuran
derivatives 20 and 21, respectively, via heating in
polyphosphoric acid (Scheme 4).
Biological
evaluation
and
structure–activity
relationships. Antioxidant activity.
The antioxidant
activities of the synthesized compounds were assessed
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M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
Table 2
Scheme 3. a. ArCHO, EtOH; b. AcOH; c. Method A: DMF–DMA,
DMF, Method B: HCOOH; d. acetyl acetone, AcOH, EtOH.
Evaluation of antioxidant activity.
ABTS assay
DPPH assay
Inhibition (%)
Inhibition
(%)b
b
Compound
Aa
Aa
1
2
6
7
8
9a
9b
10
0.093
0.468
0.452
0.447
0.193
0.367
0.203
0.184
0.090
0.396
0.274
0.224
0.191
0.078
0.153
0.300
0.192
0.382
0.361
0.423
0.375
0.443
0.363
0.158
0.362
0.510
0.059
81.8
8.2
0.155
0.613
0.583
0.567
0.300
0.532
0.319
0.298
0.142
0.576
0.411
0.387
0.254
0.121
0.290
0.489
0.301
0.497
0.482
0.551
0.491
0.601
0.536
0.342
0.530
0.705
0.104
78.0
13.0
17.3
19.6
57.4
24.5
54.8
57.7
79.8
18.3
41.7
45.1
63.9
82.8
58.9
30.6
57.3
29.5
31.6
21.8
30.4
14.8
23.9
51.5
28.6
0.0
11.4
12.3
62.1
28.0
60.2
63.9
82.3
22.3
46.3
56.0
62.5
84.7
70.0
41.2
62.3
25.1
29.2
17.0
26.5
13.1
28.8
69.0
29.0
0.0
11
12a
12b
12c
12d
13
14
15
16
17a
17b
17c
17d
18
19
20
21
low antioxidant activities showed improved activities
(ABTS: 62.1%; DPPH: 57.4) by the removal of acetyl
protecting group as seen in compound 8. The thorough
comparison of hydroxychromenopyrimidine derivatives 8,
11, and 13 revealed the role of hydrazinyl or hydrazide
fragments to improve the antioxidant activity from 62.1%
(ABTS) or 57.4% (DPPH) in compound 8 to the range of
80–85% in hydrazinyl 11 and hydrazide 13 derivatives.
Also, the transformation of hydrazinyl moiety to other
skeletons such as compounds 12a–d, 14, and 15 leaded to
inferior results. Amino group (compound 16) failed to
enhance the net antioxidant activity as seen by hydrazinyl
and hydrazide functions (compounds 11 and 13). To sum
up the structure–activity relationships, the combination
Control
LAAc
88.4
85.3
aAbsorbance of the sample.
bInhibition (%) = (Acontrol ꢀ Atested)/Acontrol × 100.
c
L-ascorbic acid.
Scheme 4. a. HCONH2; b. ArNH2, pyridine, NaNO2, HCl; c. Chloroacetone, acetone, K2CO3; d. Ethyl chloroacetate, acetone, K2CO3; e. PPA.
Journal of Heterocyclic Chemistry
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Month 2019
Bioactive Angular Chromenopyrimidines
Table 3
Evaluation of antimicrobial activity.
E. carotovora
B. subtilis
C. albicans
Da
(mm)
AIb
(%)
Da
(mm)
AIb
(%)
Da
(mm)
AIb
(%)
Compound
1
2
6
7
9
8
60
10
9
9
67
60
60
53
9
9
7
9
56
56
44
56
53
NAc
9
NAc
60
8
8
9a
9
7
60
47
10
7
67
47
10
7
63
44
9b
10
11
12a
12b
12c
12d
13
14
15
8
53
8
53
10
17
10
8
8
8
63
106
63
50
50
16
14
NAc
9
9
8
11
10
7
107
93
15
13
NAc
9
100
87
NAc
60
NAc
60
60
53
73
67
9
60
50
NAc
10
11
8
NAc
67
NAc
11
10
9
NAc
69
73
53
63
56
47
16
17a
17b
17c
17d
18
19
20
21
17
7
13
NAc
10
7
113
47
15
8
100
53
19
NAc
12
NAc
10
10
NAc
15
10
NAc
119
NAc
75
87
11
NAc
10
8
73
NAc
67
NAc
67
NAc
63
47
67
80
53
63
10
12
7
NAc
12
8
NAc
80
NAc
94
47
53
63
Control
(DMSO)
Streptomycin
NAc
NAc
NAc
NAc
NAc
15
100
15
100
16
100
aDiameter of inhibition zone.
bActivity index (%) = (Diameter of the inhibition zone of the tested
Figure 1. (A) Putative binding complex of compound 13 at the binding
site of 1HD2. (B) Putative binding complex of compound 13 at the bind-
ing site of 4C1M. [Color figure can be viewed at wileyonlinelibrary.com]
compound/Diameter of the inhibition zone of the reference drug) × 100.
cNo activity.
against fungal strain C. albicans. In addition to the excellent
antifungal activity of azo derivative 17b, it has very good
activity against Gram-negative bacteria. The deep
speculation indicated that free amino and hydroxyl groups in
product 16 were attributed to the best activity against all
tested microbial strains.[19] However, capping of both
groups as in product 10 did not produce big change in the
antimicrobial activity; replacing one of them has an obvious
impact on the overall activity. By comparing the structures
of the best products 10, 11, 16, and 20 with those of the
inactive ones, we could observe that the absence of amino
moiety, protection of hydroxyl via methyl ketone fragment,
or coupling near hydroxyl group has harmful impact on the
net antimicrobial activity. Finally, we could conclude that
the combination of pyrimidine and chromene moieties
where each of them bears polar group is beneficial to create
promising antimicrobial compounds.
of chromene and pyrimidine pharmacophores in one scaffold
bearing free hydroxyl group as well as hydrazinyl or
hydrazide functionalities suggested a promising model to
build up new leads with enhanced antioxidant efficiency.[18]
Antimicrobial activity. The antibacterial activity of the
synthesized bundle was assessed against Erwinia
carotovora (Gram-negative bacteria) and Bacillus subtilis
(Gram-positive bacteria) (Table 3). They were also
screened for their antifungal activity against Candida
albicans. The activities of our products were compared
with Streptomycin as reference drug.
The results in Table 3 showed that the combination of
pyrimidine and chromene scaffolds in products 10 and 16
leaded to super antimicrobial activities. In addition to
the excellent antifungal activity of furo derivative
20, it has very good antibacterial activities against
both of E. carotovora (Gram-negative bacteria) and
B. subtilis (Gram-positive bacteria). However, the
hydrazinylpyrimidine 11 has very good to excellent activities
against both bacterial types; it showed moderate activity
Molecular docking. Antioxidant activity.
Docking
study of pyrimidinylacetohydyazide 13 was performed
using the crystal structure of human peroxiredoxin (code:
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
In conclusion, the 4-hydrazine is occupying strategic
location targeting the proper recognition with Arg239. It
is clear that bulk substitution on the 4-hydrazino function
interferes with its exposure and in turn dramatically
lowers the degree of recognition with the conserved
amino acid residues and consequently lowers the
corresponding antioxidant potency.
Antimicrobial activity.
Simulations were performed
using the crystal structure of glucosamine-6-phosphate
synthase (code: 2VF5) that catalyzes the first step in
hexamine biosynthesis converting D-fructose-6-phosphate
(Fru-6-P) into D-glucosamine-6-phosphate (GlcN-6-P)
using glutamine as the ammonia source. The amino sugars
are the significant building blocks of polysaccharides
found in the cell wall of most human pathogenic
microorganisms. Therefore, not surprising that a number
of GlcN-6-P synthase inhibitors of natural or synthetic
origin display bactericidal or fungicidal properties.[20] In
correlation to in vitro antimicrobial activity, it thought
worthwhile to carry out in silico studies of target
molecules to predict the binding affinity and their
recognition. Aminopyrimidine 16 performed proper
recognition by hydrophilic interaction between free amino
function and the facing conserved residues lining the
pocket wall Arg254 and Phe189 (Fig. 2).
In silico physicochemical evaluation. Drug-likeness is a
term used to define absorption, distribution, metabolism,
and excretion properties of a drug molecule.[21,22] The
absorption, distribution, metabolism, and excretion
properties were calculated by using Osiris Property
Explorer server and analyzed by applying Lipinski’s rule
of five, which is very important standard widely for
selecting of lead compounds that are promising for
advanced drug design programs (Table 4). As shown in
Table 4, chromenopyrimidine analogs exhibited proper
molecular properties that are important for a new drug’s
pharmacokinetics.[23] Most of chromenopyrimidines
have molecular weights less than 500 g/mol and logPo/w
with the acceptable range. The absorption percentage was
calculated based upon the values of polar surface area
(PSA) [ABS (%) = 109 ꢀ (0.345 × PSA)].[24] However,
the number of H-bond acceptors and number of H-bond
donors are below to 10 and 5, respectively; some of the
synthesized compound showed low levels of violation
from Lipinski’s rule of five. Water solubility and oral
absorption for half of the molecules is 100%.
Figure 2. (A) Crystallographic structure of glucose amine-6phosphate at
the binding site of 2VF5. (B) Putative binding complex of compound 16
at the binding site of 2VF5. [Color figure can be viewed at
wileyonlinelibrary.com]
1HD2), and the results indicated its vast selectivity as
antioxidant lead (Fig. 1A). Pro45, one of the essential key
binding amino acids, professionally hocked the
chromopyrimidine ring by the aromatic–hydrogen
interaction. Additionally, the reversible antioxidant
activity of compound 13 was examined by docking at
oxidoreductase (code: 4C1M). The docking performance
is promising as proper antioxidant lead where it
professionally was recognized from both chains A and B
where the hydroxyl function interacted properly with
the key amino acid: GluB242. Atom N1 of the
chromopyrimidine ring showed bifurcated hydrogen
bonds with both conserved amino acids GluA102 and
ProA103. One of the two nitrogen of the hydrazine
function stabilized the Van der Waals interaction with the
crucial amino acid: ArgB239 (Fig. 1B).
CONCLUSION
A
bundle of novel angular chromenopyrimidine
derivatives has been synthesized via efficient synthetic
plan with the aim to be evaluated as antioxidant and
antimicrobial agents. The chromenopyrimidine derivatives
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Bioactive Angular Chromenopyrimidines
Table 4
In silico drug like (physicochemical) properties.
Comp.
MW
LogP
PSA
ABS (%)
non-HAs
HBA
HBD
Violations
NoRB
1
2
6
7
314.34
440.45
398.42
416.86
374.83
423.52
425.49
73.35
370.41
458.52
474.52
504.5
501.59
412.45
380.41
434.50
341.37
445.48
475.51
479.93
510.56
397.43
427.46
379.42
381.39
3.40
2.77
3.61
4.96
4.93
5.26
4.20
6.27
3.49
5.54
5.06
4.88
5.65
3.23
3.76
4.84
3.65
6.03
6.08
6.71
5.91
3.73
4.42
4.80
3.50
79.28
96.71
81.29
61.32
55.25
58.48
67.72
73.35
93.30
79.64
99.86
109.10
82.88
96.37
72.55
73.07
81.27
106.00
115.23
106.00
118.36
87.35
96.58
74.18
87.35
81.65
75.63
80.95
87.84
89.93
88.82
85.64
83.69
76.81
81.52
74.55
71.36
80.41
75.75
83.97
83.79
80.96
72.43
69.25
72.43
68.17
78.86
75.68
83.41
78.86
24
33
30
30
27
32
32
36
28
35
36
38
38
31
29
33
26
34
36
35
39
30
32
29
29
4
7
6
5
4
5
6
6
6
6
7
8
7
7
6
6
5
7
8
7
8
6
7
5
6
3
0
1
0
1
1
1
1
4
2
3
3
2
3
1
1
3
3
3
3
3
2
2
2
2
0
0
0
0
0
1
0
1
0
1
1
1
2
0
0
0
0
1
1
1
2
0
0
0
0
1
4
3
3
1
2
2
5
2
4
4
5
5
3
1
2
1
3
4
3
4
4
6
1
1
8
9a
9b
10
11
12a
12b
12c
12d
13
14
15
16
17a
17b
17c
17d
18
19
20
21
MW, molecular weight; LogP, logarithm of partition coefficient of compound between n-octanol and water; PSA, polar surface area; ABS (%), absorption
percentage; non-HAs, number of non-hydrogen atoms; HBA, number of hydrogen bond acceptors; HBD, number of hydrogen bond donors; Violations,
number of rule of five violations; NoRB, number of rotatable bonds.
bearing hydrazine or hydrazide moieties (11 and 13)
revealed excellent antioxidant activities compared with the
reference L-ascorbic acid under ABTS and DPPH
screening assays and based on the computational
recognition at the binding active sites. In addition, the
biological evaluation and the docking study indicated that
7-hydroxy-2-methyl-5-phenyl-5H-4-phenylamin-N-
ylbenzo[f]chromeno[2,3-d]pyrimidine (10) and 4-amino-5-
phenyl-5H-benzo[f]chromeno[2,3-d]pyrimidin-7-ol (16)
possess super antimicrobial activities in comparison with
the reference antibiotic Streptomycin.
III 400 MHz (Beni Suef University), and JEOL ECA II
500 MHz (Mansoura University) using tetramethylsilane
as an internal standard in DMSO-d6 or CDCl3 solvents.
The signals’ multiplicities are reported as follows:
s = singlet, d = doublet, dd = doublet of doublets,
t = triplet, q = quartet, and m = multiplet. Exchangeable
protons were detected through D2O test. 13C NMR
spectra (δ, ppm) were measured on JEOL ECA II
125 MHz (Mansoura University). Electron impact mass
spectra (EIMS) were determined on Thermo Scientific
DSQ II S GC/MS with FOCUS GC (70 ev) (Mansoura
University) or Kratos MS-80 GC/MS, 70 eV (Al-Azhar
University). Elemental analyses (C, H, and N) were
executed at Cairo University. Biological screenings were
performed at Pharmacognosy Department, Faculty of
Pharmacy, Mansoura University. The compounds have
been evaluated for the degree of recognition at the
binding pockets of the 1HD2, 4C1M, and 2VF5 enzymes
using Molecular Operating Environment software
10.2008 (MOE) provided with chemical computing
group, Canada.
EXPERIMENTAL
General.
All melting points are reported in degree
Celsius (°C) (uncorrected) and were measured on a
Gallenkamp electrical melting point apparatus. Ethanol
was dried prior to use based upon the standard
techniques. The other chemicals were purchased from
commercial suppliers and used without further
purification. IR spectra were measured using the KBr disc
technique on a Mattson 5000 or Thermo Scientific
Nicolet IS10 FTIR Spectrometers at Mansoura
University. The 1H NMR spectra were measured on
Bruker AC 300 MHz (Cairo University), Bruker Avance
Synthesis. 2-Amino-6-hydroxy-4-phenyl-4H-benzo[f]
chromene-3-carbonitrile (1).
A
mixture of 2,7-
dihydroxynaphthalene (480 mg, 3 mmol), malononitrile
(198 mg, 3 mmol), and benzaldehyde (0.32 mL,
3.2 mmol) in EtOH (30 mL) containing few drops of
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
piperidine was refluxed for 2 h. After cooling, the formed
precipitate was filtered off and recrystallized from EtOH
affording compound 1. Colorless crystals; yield (800 mg,
85%); mp = 150–151°C; IR (KBr, ν/cmꢀ1): 3487 (OH),
(400 MHz, CDCl3): δ (ppm) = 2.39 (s, 3H, CH3), 2.69 (s,
3H, CH3), 5.86 (s, 1H, H-5), 7.15–7.84 (m, 10H, ArH);
(EIMS) m/z (%): 416.1 [M+] (8.2), 418.1[M++2] (3.0),
402.0 (7.3), 333.0 (31.6), 332.0 (100.0), 331.0 (22.0),
105.9 (4.6), 90.9 (3.56); Anal.Calcd for C24H17ClN2O3
(416.86): C, 69.15; H, 4.11; N, 6.72%. Found: C, 69.02;
H, 4.05; N, 6.89%.
1
3381 and 3329 (NH2), 2189 (CN); H NMR (500 MHz,
DMSO-d6): δ (ppm) = 3.43 (brs, 1H, OH), 4.99 (s, 1H,
H-4), 6.91 (s, 2H, NH2), 6.94–7.76 (m, 10H, ArH);
(EIMS) m/z (%): 314.1 [M+] (15.9), 313.1 (1.9), 238.2
(16.1), 237.1 (100.0), 221.0 (3.7), 208.1 (3.2), 85.1
(20.4), 84.1 (41.5); Anal.Calcd for C20H14N2O2 (314.34):
C, 76.42; H, 4.49; N, 8.91%. Found: C, 76.31; H, 4.32;
*Note: The same compound 7 was prepared also in
different yields as mentioned in Table 1 using the same
procedure with replacement of the base catalyst.
4-Chloro-2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-d]
pyrimidin-7-ol (8). A mixture of compound 7 (833 mg,
N, 8.99%.
2 mmol) and Et3N or DBU (6 mmol) in EtOH (15 mL)
was refluxed for 30 min. Thereafter, the reaction mixture
was poured into cold water (150 mL) and neutralized
using conc. HCl. The formed precipitate was filtered off,
dried, and recrystallized from EtOH to afford the product
8. Colorless crystals; yield (726 mg, 97%); mp = 187–
3-Cyano-2-(N,N-diacetylamino)-4-phenyl-4H-benzo[f]
chromen-6-yl acetate (2).
A solution of compound 1
(1.8 g, 5.7 mmol) in acetic anhydride (20 mL) was
refluxed for 1 h. The reaction mixture was poured into
cold water (150 mL) and stirred vigorously for 1 h. The
formed precipitate was filtered off and purified by
column chromatography using petroleum ether : ethyl
acetate (70:30) to give the triacetylated product. Pale
yellow crystals; yield (2.31 g, 92%); mp = 189–190°C;
IR (KBr, ν/cmꢀ1): 2221 (CN), 1734 (COO), 1672
1
188°C; IR (KBr, ν/cmꢀ1): 3407 (OH), 1579 (C═N); H
NMR (400 MHz, CDCl3): δ (ppm) = 2.65 (s, 3H, CH3),
5.74 (s, 1H, H-5), 7.07–7.74 (m, 11H, ArH, OH); (EIMS)
m/z (%): 374.0 [M+] (16.8%), 375.0 [M++1] (4.0), 376.0
[M++2] (4.5), 307.0 (7.1), 300.0 (4.5), 299.0 (45.0),
297.0 (100.0), 279.0 (4.8), 193.0 (10.7), 164.0 (9.3);
Anal. Calcd for C22H15ClN2O2 (374.82): C, 70.50; H,
4.03; N, 7.47%. Found: C, 70.29; H, 3.89; N, 7.59%.
1
(C═O); H NMR (300 MHz, DMSO-d6): δ (ppm) = 2.28
(s, 3H, CH3COO), 2.37 (s, 6H, (CH3CO)2N), 5.81 (s, 1H,
H-4), 7.25–8.06 (m, 10H, ArH); Anal. Calcd for
C26H20N2O5 (440.46): C, 70.90; H, 4.58; N, 6.36%.
Synthesis of compounds 9a,b.
A suspension of
Found: C, 70.72; H, 4.47; N, 6.51%.
7-Acetoxy-2-methyl-4-oxo-5-phenyl-5H-benzo[f]
chromeno[2,3-d]pyrimidine (6). A solution of compound 1
compound 7 (416 mg, 1 mmol) in piperidine or
morpholine (6 mmol) was heated at 80°C for 45 min.
Thereafter, the mixture was poured into cold water
(100 mL) and neutralized by using few drops from conc.
HCl. The formed products 9a,b were filtered off, dried,
and recrystallized from EtOH to give the products 9a or
9b, respectively.
(1.8 g, 5.7 mmol) in acetic anhydride (20 mL) was refluxed
for 7 h. The reaction mixture was left to stand overnight.
The formed precipitate was filtered off and washed well
with hot EtOH several times to afford the desired
product. Colorless crystals; yield (2.02 g, 89%);
mp = 250–251°C; IR (KBr, ν/cmꢀ1): 3448 (NH), 1758
1
N-(7-Hydroxy-2-methyl-5-phenyl-5H-benzo[f]
(COO), 1643 (C═O); H NMR (300 MHz, DMSO-d6): δ
chromeno[2,3-d]pyrimidin-4-yl)piperidine
(9a).
(ppm) = 2.280 (s, 3H, CH3), 2.283 (s, 3H, CH3), 5.66 (s,
1H, H-5), 7.08–7.98 (m, 10H, ArH), 12.49 (s, 1H, NH);
(EIMS) m/z (%): 398.2 [M+] (44.7), 397.6 (42.3), 396.8
(100.0), 392.9 (11.8), 362.9 (46.2), 362.0 (79.6), 352.2
(28.1), 332.0 (29.6), 283.1 (37.3), 237.8 (19.6), 179.8
(17.0), 138.6 (16.1), 106.0 (27.6), 90.8 (39.9); Anal.
Calcd for C24H18N2O4 (398.42): C, 72.35; H, 4.55; N,
Colorless crystals; yield (400 mg, 95%); mp = 262°C
(Decomp); IR (KBr, ν/cmꢀ1): 3447 (OH), 1584 (C═N);
1H NMR (500 MHz, DMSO-d6): δ (ppm) = 1.67–1.84
(m, 6H, H-3′, H-4′, H-5′), 2.40 (s, 3H, CH3), 3.24–3.49
(m, 4H, H-2′, H-6′), 5.67 (s, 1H, H-5), 6.98–7.82 (m,
10H, ArH), 10.00 (s, 1H, OH); (EIMS) m/z (%): 423.0
[M+] (16.8), 421.9 (24.9), 409 (25.3), 403.8 (39.9), 402.9
(100.0), 399.0 (42.6), 392.8 (27.5), 384.8 (18.8), 371.0
(49.9), 369.0 (57.1), 366.9 (42.9), 362.8 (25.1), 343.8
(22.1), 300.7 (4.5), 196.7 (15.5), 143.0 (11.6), 42.9
(45.0); Anal.Calcd for C27H25N3O2 (423.52): C, 76.57;
H, 5.95; N, 9.92%. Found: C, 76.66; H, 5.69; N, 10.13%.
7.03%. Found: C, 72.22; H, 4.31; N, 7.12%.
7-Acetoxy-4-chloro-2-methyl-5-phenyl-5H-benzo[f]
chromeno[2,3-d]pyrimidine (7). A mixture of compound 6
(398 mg, 1 mmol), phosphorus oxychloride (3 mL,
20 mmol), and DBU (0.9 mL, 6 mmol) was refluxed for
2 h. After cooling, it was carefully poured into crushed
ice (150 g). The formed precipitate was filtered off and
washed well with water. The crude product was
recrystallized from EtOH to afford the product 7. White
crystals; yield (401 mg, 96%); mp = 252–253°C; IR
(KBr, ν/cmꢀ1): 1761 (COO), 1585 (C═N); 1H NMR
N-(7-Hydroxy-2-methyl-5-phenyl-5H-benzo[f]
chromeno[2,3-d]pyrimidin-4-yl)morpholine (9b).
Pale
yellow crystals; yield (400 mg, 94%); mp = 296°C
(Decomp); IR (KBr, ν/cmꢀ1): 3425 (OH), 1580 (C═N);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Bioactive Angular Chromenopyrimidines
1H NMR (500 MHz, DMSO-d6): δ (ppm) = 2.38 (s, 3H,
CH3), 3.17–3.21 (m, 2H, morpholinyl–CH2), 3.60–3.63
(m, 2H, morpholinyl–CH2), 3.71–3.74 (m, 2H,
morpholinyl–CH2), 3.84–3.87 (m, 2H, morpholinyl–
CH2), 5.67 (s, 1H, H-5), 7.77–7.72 (m, 10H, ArH), 9.95
(s, 1H, OH); Anal. Calcd for C26H23N3O3 (425.49): C,
73.39; H, 5.45; N, 9.88%. Found: C, 73.27; H, 5.21; N,
(EIMS) m/z (%): 458.4 [M+] (3.7), 451.2 (8.8), 447.7
(5.5), 407.3 (14.7), 383.0 (10.8), 373.0 (19.3), 371.0
(20.1), 369.3 (33.3), 368.1 (100.0), 365.9 (28.4), 349.0
(23.2), 326.0 (37.3), 324.9 (52.6), 305.1 (25.0), 56.8
(25.8), 42.8 (26.6); Anal.Calcd for C29H22N4O2 (458.52):
C, 75.97; H, 4.84; N, 12.22%. Found: C, 75.82; H, 4.61;
N, 12.41%.
9.97%.
4-((4-Hydroxybenzaldehyde)hydrazono-1-yl)-2-methyl-5-
phenyl-5H-benzo[f]chromeno[2,3-d]pyrimidin-7-ol
7-Hydroxy-2-methyl-5-phenyl-5H-4-phenylamin-N-
ylbenzo[f]chromeno[2,3-d]pyrimidine (10).
A mixture of
compound 7 (833 mg, 2 mmol) and aniline (0.2 mL,
2.2 mmol) was refluxed in EtOH (10 mL) for 5 h. The
mixture was poured into cold water (100 mL) and
neutralized using few drops from conc. HCl. The formed
precipitate was filtered off and recrystallized from EtOH
(80%) to give the product 10. Dark brown crystals; yield
(739 mg, 78%); mp = 236–237°C; IR (KBr, ν/cmꢀ1):
3409 (OH, NH), 1597 (C═N); 1H NMR (400 MHz,
DMSO-d6): δ (ppm) = 2.39 (s, 3H, CH3), 6.33 (s, 1H, H-
5), 7.06–7.83 (m, 15H, ArH), 9.15 (s, 1H, NH); Anal.
Calcd for C28H21N3O2 (431.50): C, 77.94; H, 4.91; N,
(12b).
Brown crystals; yield (788 mg, 83%); mp = 295–
296°C; IR (KBr, ν/cmꢀ1): 3100–3550 (br, OH, NH), 1580
1
(C═N); H NMR (500 MHz, DMSO-d6): δ (ppm) = 2.35
(s, 3H, CH3), 6.86–7.82 (m, 15H, ArH, H-5), 8.20 (s, 1H,
–CH═N–), 9.92, 9.94, 10.99 (3s, 3H, 2OH, NH); Anal.
Calcd for C29H22N4O3 (474.52): C, 73.40; H, 4.67; N,
11.81%. Found: C, 71.29; H, 4.45; N, 11.95%.
4-((4-Hydroxy-3-methoxybenzaldehyde)hydrazono-1-yl)-
2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-d]
pyrimidin-7-ol (12c).
Gray crystals; yield (737 mg,
73%); mp = 251°C; IR (KBr, ν/cmꢀ1): 3100–3550 (br,
9.74%. Found: C, 77.75; H, 4.78; N, 9.61%.
N-(7-Hydroxy-2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-
d]pyrimidin-4-yl)hydrazine (11). A mixture of compound 7
1
OH, NH), 1582 (C═N); H NMR (500 MHz, DMSO-d6):
δ (ppm) = 2.36 (s, 3H, CH3), 3.77 (s, 3H, CH3), 6.87–
7.81 (m, 14H, ArH, H-5), 8.20 (s, 1H, –CH═N–), 9.52,
9.93, 10.98 (3s, 3H, 2OH, NH); Anal.Calcd for
C30H24N4O4 (504.55): C, 71.42; H, 4.79; N, 11.10%.
Found: C, 71.33; H, 4.63; N, 11.29%.
or 8 (1 mmol) and hydrazine hydrate 80% (2 mL) in EtOH
(10 mL) was heated with stirring at 70°C for 1 h. The
mixture was poured into crushed ice (100 g). The formed
precipitate was filtered off, washed with water, and
recrystallized from EtOH to yield compound 11 (293 mg,
79%) or (319 mg, 86%), respectively; pale brown
needles; mp = 260–261°C; IR (KBr, ν/cmꢀ1): 3250–3490
4-((N,N-Dimethyl-4-aminobenzaldehyde)hydrazono-1-yl)-
2-methyl-5-phenyl-5H-benzo[f]chromeno[2,3-d]
pyrimidin-7-ol (12d).
1
(br, OH, NH, NH2), 1596 (C═N); H NMR (500 MHz,
Pale yellow crystals; yield
DMSO-d6): δ (ppm) = 2.33 (s, 3H, CH3), 4.43 (s, 2H,
NH2), 5.87 (s, 1H, H-5), 6.99–7.73 (m, 10H, ArH); 8.62,
9.86 (2s, 2H, NH, OH); Anal.Calcd for C22H18O2N4
(370.41): C, 71.34; H, 4.90; N, 15.13%. Found: C, 71.27;
H, 4.78; N, 15.22%.
(601 mg, 60%); mp = 279°C (Decomp); IR (KBr,
1
ν/cmꢀ1): 3446 (OH), 3284 (NH), 1557 (C═N); H NMR
(500 MHz, DMSO-d6): δ (ppm) = 2.34 (s, 3H, CH3–2),
2.97 (s, 6H, –N (CH3)2), 4.43 (s, 1H, H-5), 6.79–7.81 (m,
14H, ArH), 8.25 (s, 1H, –CH═N–), 10.13, 11.07 (2s, 2H,
OH, NH); Anal.Calcd for C31H27N5O2 (501.59): C,
74.23; H, 5.43; N, 13.96%. Found: C, 74.11; H, 5.30; N,
14.12%.
Synthesis of compounds 12a–d. A mixture of compound
11 (740 mg, 2 mmol) and the appropriate aldehydes,
namely, benzaldehyde, 4-hydroxybenzaldehyde, vanillin
or 4-(dimethylamino)benzaldehyde (2 mmol) in EtOH
(20 mL) was refluxed in water bath for 1–4 h (TLC
control). After cooling, it was poured into cold water
(100 mL). The formed precipitate was filtered off, dried,
and recrystallized from EtOH (80%) to form the desired
products.
N′-(7-Hydroxy-2-methyl-5-phenyl-5H-benzo[f]
chromeno[2,3-d]pyrimidin-4-yl)acetohydrazide
(13).
A
solution of compound 11 (740 mg, 2 mmol) in glacial
acetic acid (5 mL) was refluxed for 30 min. After
finishing the reaction, it was poured into crushed ice
(150 g) followed by stirring for additional 30 min. The
formed precipitate was filtered off, washed well with
water, dried, and recrystallized from EtOH to afford
compound 13. Gray crystals; yield (750 mg, 91%);
mp = 240–241°C; IR (KBr, ν/cmꢀ1): 3100–3550 (br,
4-(Benzaldehydehydrazono-1-yl)-2-methyl-5-phenyl-5H-
benzo[f]chromeno[2,3-d]pyrimidin-7-ol
(12a).
Buff
crystals; yield (551 mg, 60%); mp = 257°C (Decomp);
IR (KBr, ν/cmꢀ1): 3447 (OH), 3202 (NH), 1552 (C═N);
1H NMR (500 MHz, DMSO-d6): δ (ppm) = 2.38 (s, 3H,
CH3), 4.35 (s, 1H, H-5), 7.05–7.97 (m, 15H, ArH), 8.31
(s, 1H, –CH═N–), 10.00, 11.22 (2s, 2H, NH, OH);
1
OH, 2NH), 1680 (C═O), 1577 (C═N), 1232 (C–O); H
NMR (400 MHz, DMSO-d6): δ (ppm) = 1.54 (s, 3H,
CH3), 2.34 (s, 3H, CH3), 6.08 (s, 1H, H-5), 7.05–7.81
(m, 10H, ArH), 9.28, 9.78, 9.86 (3s, 3H, OH, 2NH);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
Anal. Calcd for C24H20N4O3 (412.45): C, 69.89; H, 4.89;
Synthesis of compounds 17a–d. A cold solution (temp.
0–5°C) of aryl diazonium chloride (2 mmol) [prepared by
mixing aromatic amine (2 mmol), sodium nitrite
(207 mg, 3 mmol), and conc. HCl (0.6 mL, 6 mmol) in
5 mL water] was added to a cold solution of compound
16 (682 mg, 2 mmol) in 10 mL pyridine with continuous
stirring for 1–2 h (TLC control). The formed precipitate
washed well with water and recrystallized from EtOH to
afford the desired products.
N, 13.58%. Found: C, 69.78; H, 4.73; N, 13.77%.
5-Methyl-14-phenyl-14H-benzo[f]chromeno[2,3-e][1,2,4]
triazolo[3,4-c]pyrimidin-12-ol (14).
Procedure (A): A mixture of compound 11 (370 mg,
1 mmol) and DMF–DMA (0.22 mL, 1.5 mmol) in dry
DMF (10 mL) was refluxed for 4 h. After finishing the
reaction, it was poured into crushed ice (100 g) and stirred
for 30 min. The formed precipitate was filtered off, dried,
and recrystallized from EtOH to afford the product 14
(240 mg, 63%).
4-Amino-5-phenyl-6-(phenyldiazenyl)-5H-benzo[f]
chromeno[2,3-d]pyrimidin-7-ol (17a).
Red crystals;
Procedure (B): A mixture of compound 11 (370 mg,
1 mmol) and formic acid (7 mL) was refluxed for 3 h,
poured into cold water (100 mL), and neutralized using
sodium carbonate. The formed precipitate was filtered off,
dried, and recrystallized from EtOH to afford compound
14. Pale brown crystals; yield (340 mg, 89%); mp = 219–
yield (739 mg, 83%); mp = 281–282°C; IR (KBr,
ν/cmꢀ1): 3461 (OH), 3301, 3126 (NH2), 1564 (C═N),
1426 (N═N), 1242 (C–O); 1H NMR (500 MHz,
DMSO-d6): δ (ppm) = 6.65 (s, 1H, H-5), 6.77 (d, 1H, H-
8, J = 9 Hz), 6.99 (s, 2H, NH2), 7.02–7.27 (m, 11H,
ArH, OH), 7.42 (d, 1H, H-11, J = 8 Hz), 7.85 (d, 1H, H-
10, J = 8 Hz), 7.95 (d, 1H, H-9, J = 9 Hz), 8.11 (s, 1H,
H-2); Anal. Calcd for C27H19N5O2 (445.48): C, 72.80; H,
4.30; N, 15.72%. Found: C, 72.66; H, 4.21; N, 15.89%.
1
220°C; IR (KBr, ν/cmꢀ1): 3425 (OH), 1599 (C═N); H
NMR (500 MHz, DMSO-d6): δ (ppm) = 2.50 (s, 3H, CH3),
5.95 (s, 1H, H-5), 6.99–7.83 (m, 10H, ArH); 8.76 (s, 1H,
H-3), 9.98 (s, 1H, OH); Anal. Calcd for C23H16N4O2
(380.41): C, 72.62; H, 4.24; N, 14.73%. Found: C, 72.46;
H, 4.03; N, 14.91%.
4-(3′,5′-Dimethyl-1H-pyrazol-1-yl)-2-methyl-5-phenyl-5H-
benzo[f]chromeno[2,3-d]pyrimidin-7-ol (15). A solution of
4-Amino-5-phenyl-6-(4-methoxyphenyldiazenyl)-5H-
benzo[f]chromeno[2,3-d]pyrimidin-7-ol
(17b).
Red
crystals; yield (846 mg, 89%); mp = 272°C; IR (KBr,
ν/cmꢀ1): 3486 (OH), 3387, 3319 (NH2), 1564 (C═N),
compound 11 (370 mg, 1 mmol) in EtOH (10 mL) was
added to a solution of acetyl acetone (0.1 mL, 1 mmol) in
glacial acetic acid (15 mL). The reaction mixture was
refluxed at 80°C for 1 h; thereafter, it was poured into
cold water (100 mL). The formed precipitate was filtered
off, dried, and recrystallized from EtOH (70%) to give
compound 15. Colorless crystals; yield (312 mg, 72%);
mp = 242–243°C; IR (KBr, ν/cmꢀ1): 3447 (OH), 1596
1
1429 (N═N), 1248 (C–O); H NMR (400 MHz, CDCl3):
3.93 (s, 3H, CH3), 5.11 (s, 1H, H-5), 6.84–7.70 (m, 16H,
ArH, NH2, OH), 8.34 (s, 1H, H-2); Anal.Calcd for
C28H21N5O3 (475.51): C, 70.73; H, 4.45; N, 14.73%.
Found: C, 70.61; H, 4.32; N, 14.81%.
4-Amino-5-phenyl-6-(4-chlorophenyldiazenyl)-5H-
benzo[f]chromeno[2,3-d]pyrimidin-7-ol (17c).
Reddish
1
(C═N), 1631 (C═C); H NMR (500 MHz, DMSO-d6): δ
brown crystals; yield (873 mg, 91%); mp = 282–283°C; IR
(ppm) = 1.69 (s, br, 1H, OH), 1.82 (s, 3H, CH3), 2.56 (s,
3H, CH3), 2.67 (s, 3H, CH3), 6.11 (s, 1H, H-5), 6.19 (s,
1H, H-4′), 6.53–7.42 (m, 10H, ArH); Anal. Calcd for
C27H22N4O2 (434.50): C, 74.64; H, 5.10; N, 12.89%.
Found: C, 74.42; H, 5.01; N, 12.97%.
4-Amino-5-phenyl-5H-benzo[f]chromeno[2,3-d]pyrimidin-7-
ol (16). A solution of compound 1 (628 mg, 2 mmol) in
(KBr, ν/cmꢀ1): 3481 (OH), 3312, 3108 (NH2), 1563
1
(C═N), 1429 (N═N), 1244 (C–O); H NMR (400 MHz,
CDCl3): δ (ppm) = 5.06 (s, 1H, H-5), 6.67–7.61 (m, 16H,
ArH, NH2, OH), 8.34 (s, 1H, H-2); (EIMS) m/z (%):
478.9 [M+] (8.3), 481.0 [M++2] (3.1), 451.0 (3.5), 376.0
(10.9), 373.9 (37.9), 354.0 (18.8), 352.9 (100.0), 338.0
(19.2), 335.0 (16.0), 326.0 (22.0), 311.0 (17.5), 263.9
(46.6), 127.0 (23.8); Anal.Calcd for C27H18ClN5O2
(479.52): C, 67.57; H, 3.78; N, 14.59%. Found: C, 67.41;
H, 3.62; N, 14.70%.
excess formamide (15 mL) was refluxed for 4 h.
Thereafter, the mixture was poured into cold water
(100 mL) and was stirred for 6 h. The formed precipitate
was filtered off, dried, and recrystallized from EtOH to
give the desired compound. Reddish brown crystals;
yield (546 mg, 80%); mp = 288°C (Decomp); IR (KBr,
ν/cmꢀ1): 3220–3500 (br, OH, NH2), 1590 (C═N), 1231
4-Amino-5-phenyl-6-(pyridin-3-yldiazenyl)-5H-benzo[f]
chromeno[2,3-d]pyrimidin-7-ol (17d).
Reddish brown
crystals; yield (839 mg, 94%); mp = 287–288°C; IR
1
(C–O); H NMR (500 MHz, DMSO-d6): δ (ppm) = 5.83
(KBr, ν/cmꢀ1): 3452 (OH), 3296, 3132 (NH2), 1567
(s, 1H, H-5), 7.15 (s, 2H, NH2), 7.00–7.77 (m, 10H,
ArH), 8.06 (s, 1H, H-2), 9.87 (s, 1H, OH); Anal. Calcd
for C21H15N3O2 (341.37): C, 73.89; H, 4.43; N, 12.31%.
Found: C, 73.79; H, 4.26; N, 12.53%.
1
(C═N), 1426 (N═N), 1241 (C–O); H NMR (400 MHz,
CDCl3): 5.10 (s, 1H, H-5), 6.69–8.91 (m, 16H, ArH,
NH2, OH), 8.34 (s, 1H, H-2); Anal. Calcd for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Bioactive Angular Chromenopyrimidines
C26H18N6O2 (446.47): C, 69.95; H, 4.06; N, 18.82%.
Found: C, 69.82; H, 3.88; N, 18.95%.
heated in water bath at 100°C. After 30 min, compound
19 (854 mg, 2 mmol) was added with stirring. The
reaction mixture was heated in water bath for 2 h. After
finishing the reaction, it was carefully poured into
crushed ice (100 g), and the medium was neutralized
using sodium acetate. The formed precipitate was filtered
off, dried, and recrystallized from EtOH (85%) to give
the product 21. Black crystals; yield (496 mg, 65%);
mp = 293°C (Decomp.); IR (KBr, ν/cmꢀ1): 3458, 3350
Synthesis of compounds 18 and 19.
A mixture of
compound 16 (682 mg, 2 mmol) and chloroacetone
(0.3 mL, 3.6 mmol) or ethyl chloroacetate (0.3 mL,
2.8 mmol) was refluxed in dry acetone (20 mL) in the
presence of anhydrous K2CO3 (1 g) for 7 h. Thereafter,
the mixture was poured into cold water (150 mL) and
neutralized by using few drops of conc. HCl. The formed
precipitate was filtered off, dried, and recrystallized from
EtOH to give compounds 18 or 19, respectively.
1
(NH2), 1725 (C═O), 1567 (C═N), 1228 (C–O); H NMR
(500 MHz, DMSO-d6): δ (ppm) = 4.81 (s, 2H, H-8), 5.84
(s, 1H, H-5), 7.05 (br, 2H, NH2), 7.05–7.82 (m, 9H,
ArH), 8.08 (s, 1H, H-2); Anal. Calcd for C23H15N3O3
(381.39): C, 72.43; H, 3.96; N, 11.02%. Found: C, 72.33;
H, 3.72; N, 11.15%.
1-((4-Amino-5-phenyl-5H-benzo[f]chromeno[2,3-d]
pyrimidin-7-yl)oxy)propan-one (18).
Gray crystals;
yield (683 mg, 86%); mp = 220–221°C; IR (KBr,
ν/cmꢀ1): 3530, 3456 (NH2), 1734 (C═O), 1230 (C–O);
1H NMR (500 MHz, DMSO-d6): δ (ppm) = 2.22
(s, 3H, CH3CO), 4.93 (s, 2H, CH3COCH2), 5.85
(s, 1H, H-5), 7.06–7.86 (m, 12H, ArH, NH2), 8.09
(s, 221H, H-2); Anal.Calcd for C24H19N3O3 (397.43):
C, 72.53; H, 4.82; N, 10.57%. Found: C, 72.40; H,
4.67; N, 10.71%.
Biological
evaluation. Antioxidant
activity.ABTS
assay.
The reaction mixture consisted of 2 mL of
ABTS[25] solution (60 μM) was added to MnO2 (3 mL,
25 mg/mL) solution, all prepared in aqueous phosphate
buffer solution (PH 7, 0.1M). The mixture was shaken,
centrifuged, and filtered. The absorbance (Acontrol) of the
resulting bluish green solution at 734 nm was adjusted to
approximately 0.5. Then, the absorbance was measured
upon the addition of 50 μL of (2 mM) solution of the
Ethyl 2-((4-amino-5-phenyl-5H-benzo[f]chromeno[2,3-d]
pyrimidin-7-yl)oxy)acetate (19).
Gray crystals; yield
(743 mg, 87%); mp = 170°C; IR (KBr, ν/cmꢀ1): 3392,
tested
compounds
in
spectroscopic
grade
1
MeOH/phosphate buffer (1:1) (Atested). The inhibition
ratio was calculated using the following equation:
3188 (NH2), 1738 (C═O), 1587 (C═N), 1220 (C–O); H
NMR (500 MHz, DMSO-d6): δ (ppm) = 1.19 (t, 3H,
J = 7 Hz, CH3CH2O), 4.15 (q, 2H, J = 7 Hz, CH3CH2O),
4.93 (s, 2H, CH3CH2OCOCH2), 5.88 (s, 1H, H-5), 7.16–
7.87 (m, 12H, ArH, NH2), 8.09 (s, 1H, H-2); Anal.Calcd
for C25H21N3O4 (427.46): C, 70.25; H, 4.95; N, 9.83%.
Inhibition ð%Þ ¼ ðAcontrol ꢀ AtestedÞ=Acontrolꢁ100
L-Ascorbic acid (Vitamin C) was used as standard antiox-
idant (positive control). Blank sample was run without
ABTS and using MeOH/phosphate buffer (1:1) instead of
the tested samples. Negative control sample was run with
ABTS and MeOH/phosphate buffer (1:1) only instead of
the tested samples.
Found: C, 70.11; H, 4.72; N, 9.98%.
9-Methyl-5-phenyl-5H-1-benzofuro[6,5-f]chromeno[2,3-d]
pyrimidin-4-amine (20).
A mixture of phosphorus
pentoxide (26 g) in phosphoric acid 85% (15 mL) was
heated in water bath at 100°C. After 30 min, compound
18 (794 mg, 2 mmol) was added with stirring. The
reaction mixture was heated in water bath for 1 h. After
finishing the reaction, it was carefully poured into
crushed ice (100 g), and the medium was neutralized
using sodium acetate. The formed precipitate was filtered
off, dried, and purified by preparative chromatography
using petroleum ether : ethyl acetate (50:50) to obtain the
product 20. Pale yellow powder; yield (395 mg, 52%);
mp = 264°C (Decomp); IR (KBr, ν/cmꢀ1): 3270, 3144
DPPH assay.
Solutions of the synthesized compounds
were prepared in methanol at concentration of 60 μg/mL,
and then 1 mL of each sample was transferred to 1 mL of
0.012% DPPH[26] in methanol. The mixture was
incubated in dark for 30 min at room temperature, and
then the absorbance of each mixture was measured at
517 nm. The inhibition percentage of the samples was
calculated using the following equation:
Inhibition ð%Þ ¼ ðAcontrol ꢀ AtestedÞ=Acontrolꢁ100
1
(NH2), 1561 (C═N), 1245 (C–O); H NMR (500 MHz,
L-Ascorbic acid was used as a reference to compare the
activities of the newly screening compounds. Negative
control sample was run with DPPH solution only without
the tested compounds.
DMSO-d6): δ (ppm) = 1.20 (s, 3H, CH3), 5.99 (s, 1H, H-
5), 7.10–7.27 (br, 2H, NH2), 7.01–7.81 (m, 9H, ArH),
8.05, 8.07 (2s, 2H, H-8, H-2); Anal. Calcd for
C24H17N3O2 (379.42): C, 75.98; H, 4.52; N, 11.08%.
Found: C, 75.73; H, 4.43; N, 11.21%.
4-Amino-5-phenyl-5H-1-benzofuro[6,5-f]chromeno[2,3-d]
Antimicrobial activity.
The antimicrobial activity of
chromenopyrimidines was estimated by filter paper disc
method using inoculums containing 106 bacterial and
fungal cells/mL to spread on nutrient agar.[27] The
pyrimidin-9(8H)-one (21).
A mixture of phosphorus
pentoxide (26 g) in phosphoric acid 85% (15 mL) was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Abozeid, M. R. El-Kholany, L. A. Abouzeid, A.-R. H. Abdel-Rahman, and E.-S. I. El-Desoky Vol 000
[2] Patlevič, P.; Vašková, J.; Švorc, P.; Vaško, L. Integr Med Res
2016, 5, 250.
[3] Lagoja, I. M. Chem Biodivers 2005, 2, 1.
[4] Bhat, A. R.; Dongre, R. S.; Naikoo, G. A.; Hassan, I. U.; Ara,
T. J Taibah Univ Sci 2017, 11, 1047.
[5] Alam, O.; Khan, S. A.; Siddiqui, N.; Ahsan, W.; Verma, S. P.;
Gilani, S. J. Eur J Med Chem 2010, 45, 5113.
[6] Bruno, O.; Schenone, S.; Ranise, A.; Bondavalli, F.; Barocelli,
E.; Ballabeni, V.; Chiavarini, M.; Bertoni, S.; Tognolini, M.; Impicciatore,
M. Biorg Med Chem 2001, 9, 629.
[7] Perlíková, P.; Hocek, M. Med Res Rev 2017, 37, 1429.
[8] Barakat, A.; Soliman, S. M.; Al-Majid, A. M.; Lotfy, G.;
Ghabbour, H. A.; Fun, H.-K.; Yousuf, S.; Choudhary, M. I.; Wadood,
A. J Mol Struct 2015, 1098, 365.
[9] Padmaja, A.; Payani, T.; Reddy, G. D.; Padmavathi, V. Eur J
Med Chem 2009, 44, 4557.
[10] Bingi, C.; Emmadi, N. R.; Chennapuram, M.; Poornachandra,
Y.; Kumar, C. G.; Nanubolu, J. B.; Atmakur, K. Bioorg Med Chem Lett
2015, 25, 1915.
sterilized filter paper discs (Whatman no. 1, 6 mm in
diameter) were saturated with the solution of the tested
compounds in DMSO (0.01 g/mL), and another filter
paper disc was saturated with DMSO to serve as control.
The discs were placed on the surface of the agar plates
seeded with the tested organisms. The plates were
incubated at 28°C for fungi and at 37°C for bacteria.
Diameters of the inhibition zone (mm) were measured
after 18–24 h. The stock cultures of the tested organisms
were obtained from the microbiological lab at the Faculty
of Medicine in Mansoura University.
Molecular
docking.
Docking
chromenopyrimidine analogs into the binding active site
of human peroxiredoxin (code: 1HD2),[28]
of
the
oxidoreductase (code: 4C1M),[29] and glucosamine-6-
phosphate synthase (code: 2VF5)[30] has been performed
to examine the degree of recognition as antioxidant and
antimicrobial leads. The X-ray crystal structure of the
1HD2, 4C1M, and 2VF5 was obtained from the RCSB
Protein Data Bank of Brookhaven National Laboratory.
The tested compounds were prepared by partial charges
and energy minimized using the molecular mechanics
force field “AMBER” until the RMS deviation was
0.01 Kcal/mol Å. The docking was carried out on using
MOE.
[11] Reddy, B. S.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J.;
Vardhan, M. Bioorg Med Chem Lett 2012, 22, 1995.
[12] El-Desoky, S. I.; Badria, F. A.; Abozeid, M. A.; Kandeel, E.
A.; Abdel-Rahman, A. H. Med Chem Res 2013, 22, 2105.
[13] Abozeid, M. A.; El-Kholany, M. R.; Abdel-Rahman, A. H.;
El-Desoky, S. I. Int J Modern Org Chem 2018, 5, 1.
[14] Bonacorso, H. G.; Rosa, W. C.; Oliveira, S. M.; Brusco, I.;
Brum, E. S.; Rodrigues, M. B.; Frizzo, C. P.; Zanatta, N. Bioorg Med
Chem Lett 2017, 27, 1551.
[15] Okasha, R. M.; Albalawi, F. F.; Afifi, T. H.; Fouda, A. M.; Al-
Dies, A.-A. M.; El-Agrody, A. M. Molecules 2016, 21, 1450.
[16] Zeng, Q.; Huang, B.; Danielsen, K.; Shukla, R.; Nagy, T. Org
Process Res Dev 2004, 8, 962.
[17] Schenone, S.; Bruno, O.; Bondavalli, F.; Ranise, A.; Mosti, L.;
Menozzi, G.; Fossa, P.; Donnini, S.; Santoro, A.; Ziche, M. Eur J Med
Chem 2004, 39, 939.
In
silico
physicochemical
evaluation.
The
physicochemical properties such as molecular weight,
partition coefficient value (LogP), which indicates the
lipophilicity of the ligand, number of hydrogen bond
donor and number of hydrogen bond acceptor, PSA,
number of rotatable bonds, and volume for the ligands
were obtained as shown in Table 4. For a drug molecule
to be orally bioavailable in the systemic circulation,
Lipinski’s rule of five should apply: “The drug must have
molecular weight value of ≤500, hydrogen bond donor
≤5, hydrogen bond acceptor ≤10, and partition coefficient
(LogP) value ≤5.” From the results in Table 4, the
synthesized compounds are in agreement with the
Lipinski’s rule of five because there was no more than
two parameter violations. In addition, the PSA, which
reflects the ligand hydrophilicity, is very vital in protein–
ligand interaction.
[18] Zhong, Z.; Zhong, Z.; Xing, R.; Li, P.; Mo, G. Int J Biol
Macromol 2010, 47, 93.
[19] Benveniste, R.; Davies, J. Antimicrob Agents Chemother
1973, 4, 402.
[20] Venkatesh, T.; Bodke, Y.; Kenchappa, R.; Telkar, S. Med
Chem 2016, 6, 440.
[21] Pontiki, E.; Hadjipavlou-Litina, D.; Litinas, K.; Geromichalos,
G. Molecules 2014, 19, 9655.
[22] Kauthale, S.; Tekale, S.; Damale, M.; Sangshetti, J.; Pawar, R.
Bioorg Med Chem Lett 2017, 27, 3891.
[23] Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J
Adv Drug Deliv Rev 1997, 23, 3.
[24] Ertl, P.; Rohde, B.; Selzer, P. J Med Chem 2000, 43, 3714.
[25] Pisoschi, A. M.; Negulescu, G. P. Biochem Anal Biochem
2011, 1, 1.
[26] Miceli, M.; Roma, E.; Rosa, P.; Feroci, M.; Loreto, M.; Tofani,
D.; Gasperi, T. Molecules 2018, 23, 710.
[27] Burt, S. A.; Reinders, R. D. Lett Appl Microbiol 2003, 36,
162.
[28] Declercq, J.-P.; Evrard, C.; Clippe, A.; Vander Stricht, D.; Ber-
nard, A.; Knoops, B. J Mol Biol 2001, 311, 751.
[29] Forbes, L. V.; Sjögren, T.; Auchère, F.; Jenkins, D. W.;
Thong, B.; Laughton, D.; Hemsley, P.; Pairaudeau, G.; Turner, R.;
Eriksson, H. J Biol Chem 2013, 288, 36636.
REFERENCES AND NOTES
[1] Rowe, L. A.; Degtyareva, N.; Doetsch, P. W. Free Radic Biol
Med 2008, 45, 1167.
[30] Bahare, R. S.; Ganguly, S.; Choowongkomon, K.; Seetaha, S.
DARU J Pharm Sci 2015, 23, 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet