Synthesis, crystal structure, and ADME prediction studies of novel imidazopyrimidines as antibacterial and cytotoxic agents

Article abstract of DOI:10.1002/ardp.201900271

In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a–u and 9a–d were efficiently constructed by a domino reaction between 2-imino-6-substituted-2,3-dihydropyrimidin-4(1H)-ones 4a–d or 8a–c and 2-bromoacetophenones 5a–i under mild basic conditions. The synthesized series were screened for their antibacterial activity against Staphylococcus aureus and Bacillus subtilis as Gram-positive (+) bacteria, as well as against Gram-negative (?) bacteria Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(?) bacteria over the Gram(+) ones. Compounds 6c, 6f, and 6g displayed potent and broad-spectrum antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising inhibitory activity on GryB ATPase from E. coli with IC₅₀ = 1.14 and 0.73 μM, respectively. Simultaneously, some of the synthesized imidazopyrimidines were screened for their antiproliferative activity against 60 cancer cell lines at a concentration of 10 μM. Compound 9d showed potent activity against most of the tested cell lines, with a mean growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and excretion) prediction study demonstrated that the synthesized hits have, in addition to their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a drug-likeness nature to be further developed.

Full text of DOI:10.1002/ardp.201900271

Received: 13 September 2019
DOI: 10.1002/ardp.201900271
Revised: 12 December 2019
Accepted: 21 December 2019
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F U L L P A P E R
Synthesis, crystal structure, and ADME prediction studies
of novel imidazopyrimidines as antibacterial and
cytotoxic agents
1
1
2
2
Heba T. Abdel‐Mohsen
|
Amira Abood
|
Keith J. Flanagan
|
Alina Meindl
|
2
1
Mathias O. Senge
|
Hoda I. El Diwani
1
Department of Chemistry of Natural and
Microbial Products, Division of
Abstract
Pharmaceutical and Drug Industries Research,
National Research Centre, Cairo, Egypt
In the present study, a novel series of polyfunctionalized imidazopyrimidines 6a–u and
a–d were efficiently constructed by a domino reaction between 2‐imino‐6‐substituted‐
9
2
Medicinal Chemistry, Trinity Translational
Medicine Institute, Trinity Centre for Health
Sciences, Trinity College Dublin, St. James's
Hospital, The University of Dublin, Dublin,
Ireland
2,3‐dihydropyrimidin‐4(1H)‐ones 4a–d or 8a–c and 2‐bromoacetophenones 5a–i under
mild basic conditions. The synthesized series were screened for their antibacterial
activity against Staphylococcus aureus and Bacillus subtilis as Gram‐positive (+) bacteria, as
well as against Gram‐negative (−) bacteria Escherichia coli, Klebsiella pneumoniae,
Pseudomonas aeruginosa, and Salmonella typhi. Most of the synthesized derivatives of
imidazopyrimidines 6 and 9 showed remarkable selectivity against Gram(−) bacteria over
the Gram(+) ones. Compounds 6c, 6f, and 6g displayed potent and broad‐spectrum
antibacterial activity against all tested strains. Compounds 6f and 6g displayed promising
inhibitory activity on GryB ATPase from E. coli with IC50 = 1.14 and 0.73 μM, respectively.
Simultaneously, some of the synthesized imidazopyrimidines were screened for their
antiproliferative activity against 60 cancer cell lines at a concentration of 10 μM.
Compound 9d showed potent activity against most of the tested cell lines, with a mean
growth inhibition of 37%. The ADME (absorption, distribution, metabolism, and
excretion) prediction study demonstrated that the synthesized hits have, in addition to
their promising chemotherapeutic activity, acceptable pharmacokinetic properties, and a
drug‐likeness nature to be further developed.
Correspondence
Heba T. Abdel‐Mohsen, Department of
Chemistry of Natural and Microbial Products,
Division of Pharmaceutical and Drug
Industries Research, National Research
Centre, El‐Buhouth St., Dokki, P.O. Box:
12622, Cairo, Egypt.
Email: hebabdelmohsen@gmail.com and
ht.abdel-mohsen@nrc.sci.eg
Funding information
Science Foundation Ireland,
Grant/Award Number: SFI IvP 13/IA/1894
K E Y W O R D S
ADME, antibacterial activity, antiproliferative activity, imidazopyrimidine
[3]
1
|
INTRODUCTION
urgently required.
Therefore, new modes of targeting drug‐
resistant bacteria are required. One such avenue is targeting the
DNA gyrase of bacteria. DNA gyrase, a bacterial type II topoisome-
rase, is involved in controlling the topological state of DNA in
Recently, the emergence of drug‐resistant infectious diseases has
become one of the most concerning global health problems, resulting
[
1]
[4]
in high rates of mortality due to treatment failure. Overprescrip-
tion of the currently available antibiotics and low discovery of new
antibiotics are the major factors that accelerate the evolution of
bacteria. Gryase enzyme consists of two catalytic subunits in a
2 2
heterodimer (A B ). GyrA is involved in the breaking and reunion of
the double‐stranded DNA and GyrB has the adenosine triphosphate
(ATP)‐binding site and is involved in the hydrolysis of ATP to provide
[
2]
drug‐resistant bacterial infections. Staphylococcus aureus, Klebsiella
pneumoniae, Pseudomonas aeruginosa, followed by Salmonella species,
are examples of multiresistant bacteria for which new antibiotics are
[4]
sufficient energy for DNA supercoiling. Hence, gyrase B is a well‐
established target for the development of potential novel
Arch Pharm Chem Life Sci. 2020;e1900271.
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ABDEL‐MOHSEN ET AL.
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[
5]
antibacterial agents. Over the last few years, different chemical
In this regard, pyrimidines mimic the molecules in the biological
classes of gyrase B inhibitors that act on ATP‐binding sites have been
systems, and hence, are regarded as important building blocks in the
[20–25]
[
6,7]
[8,9]
identified.
idines (such as II),
pyrazinones (such as IV),
Pyrrolopyrimidines (such as I),
imidazo[1,2‐a]pyr-
field of drug discovery and development.
[26]
Recently, Al‐Tel and
[
10]
[11]
benzimidazole ureas (such as III),
imidazo-
indazoles
Al‐Qawasmeh
reported the synthesis of a novel series of
[
12]
[13]
benzothiazoles (such as V),
[15]
imidazopyrimidines, for example, IX, of potent antibacterial activity.
[27]
[
14]
(such as VI),
4,5′‐bithiazoles (such as VII),
and aminopyrimi-
Meanwhile, Kamal et al.
demonstrated the promising anticancer
[
16]
dines (such as VIII),
are examples of reported ATP GyrB inhibitors
activity of some benzimidazole–imidazopyrimidine conjugates such
as compound X against different cell lines. On the basis of this
(Figure 1). Despite the achieved progress, many of the identified
derivatives fail in clinical trials because of unsatisfactory physico-
background and as a continuation of our efforts in the synthesis of
[20,21,23,24,28,29]
[
17]
chemical and pharmacokinetic properties.
new chemotherapeutic agents,
the main aim of this
Also, resistance to chemotherapeutic agents is regarded as one of
the major factors that reduce the efficacy of cancer therapy and lead
to the classification of cancer as the second most common cause of
study is to synthesize a novel series of polyfunctionalized imidazo-
pyrimidines 6 and 9 (Figure 2) that could provide other chemother-
apeutic opportunities in drug discovery. The synthesized compounds
were evaluated for their antibacterial activity against some Gram‐
positive (+) and Gram‐negative (−) bacteria. The most promising
candidates were further evaluated for their inhibitory activity on
gyrase B ATPase. Concurrently, some of the synthesized compounds
were selected by the National Cancer Institute (NCI) to be screened
for their in vitro cytotoxic activity. Besides, an in silico ADME
(absorption, distribution, metabolism, and excretion) prediction study
was carried out to predict pharmacokinetic parameters and the drug‐
likeness nature of the synthesized imidazopyrimidines.
[
18]
death worldwide.
More specifically, pharmacokinetic resistance is
responsible for the clinical failure of a high percentage of new and
[
19]
currently existing anticancer agents.
Considering these facts, there is a challenging requirement to
design and synthesize new chemotherapeutic agents with favorable
pharmacokinetic profiles to overcome the phenomena of numerous
drug resistances. Research is needed in this area to develop newer
and safer derivatives of known drugs, as well as to discover newer
scaffolds that may have different modes of action.
FIGURE 1 Examples of different classes of GyrB inhibitors I–VIII

ABDEL‐MOHSEN ET AL.
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FIGURE 2 Rationale for the design of the new imidazopyrimidines 6a–u and 9a–d
3
2
2
|
RESULTS AND DISCUSSION
Chemistry
optimized for JCH = 8 Hz. A strong J correlation between three OMe
groups at ring A to C‐3ʺ, C‐4ʺ, and C‐5ʺ allowed the assignment of the
.1
|
latter at δ
C
152.49, 139.56, and 152.49 ppm, respectively. gHMBC
3
showed a strong J correlation between H‐2ʺ, H‐6ʺ, and C‐7, which
1
For the synthesis of the target compounds 6a–u, a series of
allows its assignment at 165.82 ppm. H‐NMR spectrum shows two
2
‐imino‐4‐oxo‐6‐(un)substituted‐phenyl‐1,2,3,4‐tetrahydropyrimidine‐
‐carbonitriles 4a–d were first synthesized by one‐pot reaction of
doublets at δ
H‐3′, H‐5′, respectively, of ring D. Using gHMBC and gHSQC
correlations C‐2′, C‐6′ and C‐3′, C‐5′ were assigned at δ 129.20
H
7.59 and 7.99 ppm corresponding to H‐2ʹ, H‐6ʹ and
5
guanidine hydrochloride (1), ethyl cyanoacetate (2), and aromatic
aldehydes 3a–d in the presence of anhydrous K CO to give the
corresponding 2‐imino‐4‐oxo‐6‐(un)substituted‐phenyl‐1,2,3,4‐tetra-
C
2
3
and 127.18 ppm, respectively. Strong correlations were seen from
H‐3′ and H‐5′ to C‐1′ with H‐2′, H‐6′, H‐3′, and H‐5′ correlating C‐4′,
[
28]
hydropyrimidine‐5‐carbonitriles 4a–d.
Compounds 4a–d were
which confirms the assignment of C‐1′ and C‐4′ at δ
134.01 ppm, respectively. A singlet at δ 8.49 ppm corresponds to
H‐3: Its directly bonded carbon was detected by gHSQC at δ
C
130.77 and
subsequently reacted with different 2‐bromoacetophenones 5a–i
H
under basic conditions to give the corresponding cyclized products
C
6
a–u in good yields under mild reaction conditions (Scheme 1).
105.12 ppm. The quaternary carbons C‐2 and C‐8a (ring C) were
[22,30]
3
On the basis of the higher reactivity of 3‐NH over 1‐NH
it is
identified by gHMBC correlations; the J correlation between H‐2′,
postulated that the reaction between 4 and 5 proceeds through the
initial base‐catalyzed nucleophilic substitution reaction of 3‐NH of
the pyrimidine moiety of 4 with 2‐bromoacetophenone 5 to give a
tautomeric mixture of the intermediates A and B. Subsequent
intramolecular condensation between the 2‐amino group of B with
C═O afforded the final product 6 exclusively (Scheme 2).
H‐6′ (δ
H
7.59 ppm) and C‐2 established its assignment at
δ
C
3
126.20 ppm whereas a J correlations from 3‐H to C‐8a confirm its
assignments at δ
ary carbon C‐6, C═O, and CN groups were assigned at δ
156.53, and 117.69 ppm, respectively, by exclusion (Figure 3).
C
146.99 ppm, respectively. The remaining quatern-
C
82.64,
In addition, unequivocal evidence for the structure of 6o was
provided by X‐ray crystal structure analysis, and the molecular
structure of 6o is depicted in Figure 4 (for full atom labeling, see
Figure S20). In this structure, there are a few features of key interest,
namely an intramolecular short hydrogen contact, the solvent
(MeOH) hydrogen‐bonding network formation, and π‐stacking inter-
actions. The intramolecular short hydrogen contact between
C14–H14…N4 (2.548[6] Å, 149.6[9]°) results from the almost
coplanar orientation of the A and B rings (angle between the planes
is 6.2[2]°). As the contact distance is larger than the expected
bonding length for a hydrogen bond and the cyano moiety is pointing
The structures of 6a–u were elucidated by NMR spectroscopic
methods including 2D NMR as well as X‐ray crystallographic study.
1
Analysis of the H‐NMR spectrum of the reaction between 4 and
2
‐bromoacetophenones 5 revealed the formation of 6 as an exclusive
1
product. Taking 6p as an example, H‐NMR spectrum showed the
H
presence of three singlets at δ 3.76, 3.85, and 7.23 ppm correspond-
ing to 4‐OMe, 3,5‐OMe, H‐2ʺ, and H‐6ʺ of ring A, respectively; their
corresponding directly bonded carbons were identified by gHSQC at
C
δ 60.18, 56.00, and 106.24 ppm, respectively. The complete assign-
1
13
ment of rings A–D were carried out by gHMBC H– C correlations

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ABDEL‐MOHSEN ET AL.
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SCHEME 1 Synthesis of imidazopyrimidines 6a–u
away from the CH group, it is clear that this interaction is
coincidental with the planar orientation and not its driving force.
When looking down the ac‐plane, a linear arrangement of individual
molecular units is formed. A linear hydrogen‐bonding network
centered on the imidazopyrimidine ring from the cyano group of
one molecule to the amine of its nearest neighbor can be observed.
This is facilitated by the incorporation of MeOH solvent molecule
between the imidazopyrimidine rings with the amine moiety bonding
SCHEME 2 Proposed mechanism for the synthesis of 6

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FIGURE 3 Important gHMBC correlations in 6p
to the oxygen of the MeOH and the cyano motif interacting with the
OH hydrogen atom (N2–H2…O1S [1.841{5} Å, 170.8{3}°] and
O1S–H1S…N4 [1.960{4} Å, 176.1{7}°]; Figure S21). In the crystal
packing, one of the major features observed is the extensive
π‐stacked system (Figure S22). This is due to the individual layers
of the crystal lattice being rotated at ~180° to each other, with the
tri‐methoxybenzene and imidazopyrimidine rings alternately stacking
with each other when viewed down the b‐axis. As a result of this high
planarity within these compounds, it is clear that the formation of
such π‐stacked networks is a favorable interaction.
SCHEME 3 Synthesis of the target imidazo[1,2‐a]pyrimidines
9a–d
8739], P. aeruginosa [ATCC 9027], S. typhi [ATCC 14028], and K.
pneumonia [ATCC 10131]) were performed employing the agar
[
31,32]
well‐diffusion technique.
Ampicillin and levofloxacin were
used as reference drugs for Gram(+) and Gram(−) bacteria,
respectively. The diameters of the inhibition zones (mm) subse-
quent to treatment with 100 μl of 10 mg/ml of 6a–u and 9a–d, as
well as the positive controls are presented in Table 1.
After the successful synthesis of 6a–u, the synthesis of 9a–d
was achieved by initial construction of crucial starting material
8
a–c through a base‐catalyzed condensation between guanidine
hydrochloride (1) and B‐ketoesters 7a–c in the presence of
From the results depicted in Table 1, most of the synthesized
imidazopyrimidines 6a–u and 9a–d showed promising zones of
inhibition against Gram(−) bacteria over Gram(+) ones. Concerning
the Gram(+) bacteria, B. subtilis is much more sensitive to the effect
of synthesized compounds rather than S. aureus. Most of the
compounds having unsubstituted phenyl group 6a–d, 6f, 6g at
position‐7 showed moderate to potent antimicrobial activity against
S. aureus, whereas complete loss of activity was observed upon
introducing methoxyphenyl groups in 6i, 6k–u. Compounds 6e, 6h,
and 6j are the only exceptions. Meanwhile, compounds 6i–k with a
4‐methoxyphenyl group at position‐7 were more potent than 6a–g
against B. subtilis. Compounds 6b–d, 6f, 6g, 6j, and 9b showed wider
zones of inhibition than ampicillin against S. aureus, whereas 6a–g,
6i–k, and 9d demonstrated larger inhibition zones than ampicillin
[
21]
KOH.
‐bromoacetophenones 5b,c to give the compounds 9a–d as
single products (Scheme 3).
Subsequently, 8a–c were reacted with different
2
2
.2
|
Biological evaluation
2
.2.1 | In vitro antimicrobial activity
In the present study, in vitro evaluation of the antimicrobial
activities of all the synthesized imidazopyrimidines 6a–u and 9a–d
against two Gram(+) bacteria (S. aureus [ATTCC 6538] and B.
subtilis [ATCC 663]) and four Gram(−) bacteria (E. coli [ATTCC
FIGURE 4 Molecular structure of
5
‐oxo‐2‐phenyl‐7‐(3,4,5‐trimethoxyphenyl)‐
,5‐dihydroimidazo[1,2‐a]pyrimidine‐6‐
1
carbonitrile (6o) (thermal displacement
50%)

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ABDEL‐MOHSEN ET AL.
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TABLE 1 Antimicrobial activities of 6a–u, 9a–d, and positive controls expressed as diameters of inhibition zone (mm)
Diameter of inhibition zone (mm)
Gram(+)
Gram(−)
Escherichia coli Pseudomonas aeruginosa Klebsiella pneumonae Salmonella typhi
Entry Product
Staphylococcus aureus Bacillus subtilis
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
6a
11 ± 0.0
14 ± 0.7
11.5 ± 0.7
35 ± 1.4
19 ± 5.7
15 ± 0.7
34.5 ± 3.5
16.5 ± 0.7
16 ± 2.8
14.5 ± 0.7
17.5 ± 2.1
16.5 ± 0.7
12 ± 0
14 ± 0.0
–
6b
15 ± 0.7
21 ± 0.7
16 ± 2.8
–
6c
16.5 ± 0.7
19 ± 0.0
20.5 ± 0.7
40 ± 0.7
23.5 ± 0.7
18.5 ± 0.7
15 ± 0.0
16.5 ± 0.7
15.5 ± 2.1
18 ± 2.8
–
6d
13 ± 0.0
20 ± 1.4
11 ± 0.0
–
6e
–
18 ± 1.4
12 ± 0.0
12 ± 0.0
6f
13 ± 0.0
17 ± 2.1
20.5 ± 0.7
16 ± 0.7
6g
13.5 ± 0.7
16 ± 0.7
17.5 ± 0.7
12 ± 0.7
6h
–
–
11 ± 0.0
15 ± 0.7
6i
–
32 ± 0.7
–
15 ± 1.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
6j
17 ± 2.1
25 ± 1.4
20 ± 0
–
20 ± 0.7
–
14 ± 0.7
–
6k
–
45 ± 0.7
–
–
6l
–
–
–
–
–
14 ± 1.4
20 ± 2.8
–
6m
–
–
–
–
12 ± 0
6n
–
–
–
–
–
6o
–
11 ± 0.7
–
–
16 ± 0.0
17 ± 0.0
15.5 ± 0.7
19 ± 0.0
18 ± 0.0
20 ± 0.0
16 ± 0.0
15.5 ± 0.7
11 ± 1.4
15.5 ± 0.7
14 ± 0
19.5 ± 0.7
16 ± 1.4
18 ± 1.4
16.5 ± 0.7
14.5 ± 0.7
14.5 ± 0.7
15 ± 1.4
14 ± 0.0
15 ± 0.7
16 ± 1.4
20 ± 1.4
nd
6p
–
–
–
–
6q
–
–
13 ± 0.0
11 ± 2.1
6r
–
12 ± 0.0
11.5 ± 0.7
–
6s
–
–
11 ± 0.0
–
6t
–
–
–
–
6u
–
–
–
–
9a
–
–
–
–
9b
20 ± 0.7
–
25 ± 1.4
17 ± 0
–
9c
–
–
–
9d
–
19 ± 2.1
13 ± 0.0
nd
–
15 ± 2.1
nd
Ampicillin
Levofloxacin
12 ± 0.7
nd
nd
nd
20 ± 0.0
14 ± 1.4
–
20 ± 2.0
–
11 ± 0.0
–
Dimethyl
sulfoxide
–
–
–
against B. subtilis. Regarding Gram(−) bacteria, most of the tested
compounds possess significant antibacterial activity against K.
pneumonia and S. typhi in comparison to their effect on E. coli and
P. aeruginose. Again, most of the compounds exhibiting unsubstituted
phenyl group at position‐7 6a–h showed moderate to potent
antimicrobial activity against E. coli and P. aeruginosa, whereas
decrease or complete loss of activity was observed upon introducing
methoxyphenyl groups. Compounds 6j and 6q are exceptions.
Compounds 6c, 6f, 6j, and 9b were equipotent or more potent than
levofloxacin against E. coli, whereas 6a, 6c, 6f, 6h, 6i, 9b, and 9d
showed wider zones of inhibition than levofloxacin against P.
aeruginosa. Nearly all of the tested imidazopyrimidines demonstrated
promising activity against K. pneumoniae and S. typhi in comparison to
levofloxacin. Compound 6c showed the widest zone of inhibition
against the two bacterial strains.
On the basis of the obtained results, the minimum inhibitory
concentration (MIC) of the synthesized imidazopyrimidines that
showed antimicrobial activity was determined by employing a
[31,32]
twofold serial dilution technique.
The lowest concentration
that showed no growth inhibition was determined as the MIC, and
the obtained results are presented in Table 2.
Analysis of the obtained results revealed that some imidazopyr-
imidines have significant inhibitory effects against Gram(+) and
Gram(−) bacteria with MIC up to 10 μg/ml. The effect of the
substituents at position‐2 demonstrated that compound 6c with
p‐chlorophenyl group exhibited promising antimicrobial activity
against all the tested bacteria.
None of the tested imidazopyrimidines showed higher activity
than ampicillin against S. aureus. From the obtained results, it is
obvious that introduction of the 4‐F phenyl group in 6b

ABDEL‐MOHSEN ET AL.
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TABLE 2 Minimum inhibitory concentrations (μg/ml) of synthesized imidazopyrimidines compared to ampicillin and levofloxacin as positive
controls
Minimum inhibitory concentration (μg/ml)
Gram(+)
Gram(−)
Entry Product
Staphylococcus aureus Bacillus subtilis Escherichia coli Pseudomonas aeruginosa Klebsiella pneumoniae Salmonella typhi
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
6a
6b
6c
500
500
50
2,500
–
500
500
50
50
500
50
10
–
500
500
10
50
500
12.5
10
500
–
50
–
50
100
–
1,000
12.5
2,500
100
50
50
–
12.5
50
6d
6e
6f
100
12.5
50
500
500
–
50
50
500
–
25
6g
50
12.5
500
–
6h
6i
500
500
1,000
–
–
100
50
500
–
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
6j
500
–
50
–
500
–
6k
6l
–
–
–
–
–
25
6m
6n
6o
6p
6q
6r
–
–
–
–
2,500
–
500
–
–
–
–
–
–
500
–
–
–
500
50
100
25
–
–
–
–
–
1,000
500
500
–
1,000
–
1,000
500
500
50
100
100
100
12.5
100
1,000
1,000
100
12.5
nd
–
500
–
6s
–
–
6t
–
–
–
6u
9a
9b
9c
–
–
–
–
500
2,500
500
50
–
–
–
–
100
–
–
50
–
500
–
–
9d
Ampicillin
–
50
12.5
nd
–
–
50
nd
12.5
–
25
6.25
nd
6.25
–
nd
Levofloxacin nd
10
3.13
–
Dimethyl
sulfoxide
–
–
(
MIC = 500 μg/ml) or 3,4‐dichlorophenyl group in 6 g (MIC = 500
resulted in no change in the potency when compared to the
2‐phenyl derivative 6a (MIC = 500 μg/ml). Whereas compounds 6c,
6d, and 6f, which exhibit 4‐chlorophenyl, 4‐bromophenyl, and
2‐methoxyphenyl groups, respectively, showed a 10‐fold increase
in the activity (MIC = 50 μg/ml). Further, introduction of the
3,4‐dichlorophenyl group in 6g (MIC = 10 μg/ml) demonstrated a
fivefold increase in the potency in comparison to 6c (MIC = 50 μg/
ml). Replacement of the phenyl moiety in 6a with naphthyl moiety in
6h resulted in complete loss of activity. In series 6i–k, compound 6j
with the p‐chlorophenyl group at position‐2 showed MIC = 50 μg/
ml. Replacement of the 4‐chlorophenyl group in 6j (MIC = 50 μg/ml)
with 4‐fluorophenyl in 6i (MIC = 100 μg/ml) or 4‐methoxyphenyl
group in 6k (MIC = 500 μg/ml) resulted in twofold and tenfold
decrease in the potency, respectively.
μg/ml) resulted in no change in the antibacterial activity when
compared to 6a (MIC = 500 μg/ml), whereas introduction of the
4
‐Cl phenyl moiety in 6c (MIC = 50 μg/ml) or 2‐methoxyphenyl
group in 6f (MIC = 50 μg/ml) resulted in 10‐fold increase in the
potency. Replacement of the 4‐chlorophenyl group of 6c (MIC =
5
0 μg/ml) with 4‐bromo derivative in 6d (MIC = 2,500 μg/ml)
resulted in a 50‐fold decrease in the potency, whereas replacement
with 4‐tolyl moiety in 6e or naphthyl moiety in 6h showed total loss
of the antibacterial activity against S. aureus.
The MIC results of the synthesized imidazopyrimidines on B.
subtilis demonstrated that 6 g (MIC = 10 μg/ml) has a higher potency
than ampicillin (MIC = 12.5 μg/ml). Introduction of the 4‐F phenyl
group in 6b (MIC = 500 μg/ml), 4‐tolyl group in 6e (MIC = 500 μg/ml)

8
of 18
ABDEL‐MOHSEN ET AL.
|
Compounds 6c (MIC = 10 μg/ml), 6g (MIC = 10 μg/ml) with chlor-
position‐7 of 9b (MIC = 500 μg/ml) with a methyl group in 9a (MIC =
2,500 μg/ml) resulted in a fivefold decrease in the antibacterial activity.
S. typhi is also one of the most sensitive microorganisms to the
synthesized series. The imidazopyrimidines 6c, 6g, 6t, and 9d (MIC =
12.5 μg/ml) were the most potent derivatives. Replacement of the
2‐phenyl group of 6a (MIC = 100 μg/ml) with 4‐bromophenyl moiety in
6d (MIC = 50 μg/ml), 4‐tolyl in 6e (MIC = 50 μg/ml) resulted in a twofold
increase in the activity, whereas the incorporation of 2‐methoxyphenyl
substituent in 6f (MIC = 25 μg/ml) resulted in a fourfold increase in the
potency in comparison to 6a (MIC = 100 μg/ml), whereas introduction
of 4‐chlorophenyl substituent in 6c (MIC = 12.5 μg/ml) or 3,4‐
dichlorophenyl substituent in 6g (MIC = 12.5 μg/ml) showed a eightfold
increase in the potency. Replacement of the phenyl group of 6a with a
naphthyl moiety in 6h (MIC = 500 μg/ml) displayed a fivefold decrease
in the potency, whereas introduction of the 4‐fluorophenyl substituent
in 6b resulted in total loss of the activity. In series 6o–u, compound 6o
(MIC = 100 μg/ml) with 3,4,5‐trimethoxyphenyl group at the position‐7
has the same potency as 6a (MIC = 100 μg/ml) with a phenyl group
at position‐7. Replacement of the phenyl group at position‐7 of
6o (MIC = 100 μg/ml) with 4‐bromophenyl 6q, 4‐tolyl in 6r,
2‐methoxyphenyl in 6s, or naphthyl in 6u resulted in no change of the
potency, whereas replacement of phenyl group of 6o (MIC = 100 μg/ml)
with 4‐chlorophenyl in 6p (MIC = 25 μg/ml) or 3,4‐dichlorophenyl in 6t
(MIC = 12.5 μg/ml) resulted in a fourfold and eightfold increase in the
potency, respectively. In series 9, compounds 9a and 9b (MIC = 1,000
μg/ml) showed weak activity, whereas a 10‐fold increase in potency was
observed by replacement of the 4‐fluorophenyl group of 9b (MIC =
1,000 μg/ml) with 4‐chlorophenyl moiety in 9c (MIC = 100 μg/ml).
Further replacement of the aliphatic group at position‐7 of 9a–c
(MIC = 100–1,000 μg/ml) with a phenyl group in 9d showed more than
the eightfold increase in potency (MIC = 12.5 μg/ml).
ophenyl groups, and 6f (MIC = 12.5 μg/ml) with a 2‐methoxyphenyl
moiety at position‐2 are slightly less potent than levofloxacin
(
MIC = 6.25 μg/ml) against E. coli, whereas 6d, 6j, and 9b showed
moderate antibacterial activity (MIC = 50 μg/ml). Replacement of the
phenyl group at position‐2 of 6a (MIC = 500 μg/ml) with the 4‐F phenyl
group in 6b, 4‐tolyl group in 6e or naphthyl group in 6h resulted in no
change in the activity (MIC = 500 μg/ml), whereas a 10‐fold increase in
the potency was observed by introduction of 4‐Br phenyl group in 6d
(
MIC = 50 μg/ml). Further increase in the potency appeared in 6f
MIC = 12.5 μg/ml), which exhibits the 2‐methoxyphenyl group at
(
position‐2 and it reaches its maximum potency by the incorporation of
the p‐chlorophenyl group in 6c (MIC = 10 μg/ml) and the 3,4‐
dichlorophenyl group in 6g (MIC = 10 μg/ml).
Compound 6f (MIC = 12.5 μg/ml) demonstrated comparable
antibacterial activity to levofloxacin (MIC = 12.5 μg/ml) against P.
aeruginosa. Compound 6a displayed moderate inhibitory activity of
MIC = 50 μg/ml, replacement of the phenyl group at position‐2
with 4‐chlorophenyl group in 6c or 3,4‐dichlorophenyl in 6g
resulted in no change in the activity (MIC = 50 μg/ml), whereas its
replacement with 4‐tolyl moiety in 6e (MIC = 100 μg/ml) or
naphthyl group in 6h (MIC = 500 μg/ml) resulted in twofold and
tenfold decrease in the potency, respectively. Total loss of potency
was observed by introduction of the 4‐fluorophenyl group in 6b or
4
‐bromophenyl group in 6d.
K. pneumoniae is one of the most sensitive bacterial strains to the
synthesized imidazopyrimidines. Compounds 6c and 9d (MIC = 12.5 and
5 μg/ml, respectively) showed potent antibacterial activity against K.
2
pneumoniae, whereas compounds 6a, 6f, 6g, 6p, 6t, and 9c showed
moderate antibacterial activity (MIC = 50 μg/ml) in comparison to
levofloxacin (MIC = 10 μg/ml). In series 6a–h, replacement of the phenyl
group in 6a (MIC = 50 μg/ml) with the 2‐methoxyphenyl group in 6f or
the 3,4‐dichlorophenyl group in 6g (MIC = 50 μg/ml) resulted in no
change in the activity, whereas replacement of the phenyl group in 6a
2.2.2 | In vitro inhibitory activity on E. coli GyrB
(MIC = 50 μg/ml) with p‐chlorophenyl group in 6c displayed increase in
ATPase
the antibacterial activity (MIC = 12.5 μg/ml). On the contrary, introduc-
tion of 4‐fluorophenyl moiety in 6b (MIC = 1,000 μg/ml), 4‐bromophenyl
group in 6d (MIC = 2,500 μg/ml), 4‐tolyl group in 6e (MIC = 100 μg/ml), or
naphthyl group in 6h (MIC = 500 μg/ml) resulted in decrease in the
potency against K. pneumoniae. In series 6o–u, replacement of the phenyl
group at position‐2 of 6o (MIC = 500 μg/ml) with a 4‐tolyl moiety in 6r,
The most potent compounds 6c, 6d, 6f, 6g, and 9d, as well as
novobiocin, were evaluated for their GyrB ATPase inhibitory activity
using E. coli gyrase for ATPase assays kit according to the
manufacturers' protocol (Inspiralis Ltd, England) and the results are
presented in Table 3. From the obtained results, it is obvious that the
2‐methoxyphenyl in 6s, or naphthyl group in 6u resulted in no change in
the potency (MIC = 500 μg/ml), whereas 10‐fold increase in the activity
appeared upon introduction of the 4‐chlorophenyl group in 6p (MIC =
TABLE 3 Inhibitory activity of imidazopyrimidines on Escherichia
coli gyrase B ATPase
5
0 μg/ml) and 3,4‐dichlorophenyl group in 6t (MIC = 50 μg/ml). The
a
Entry
Compound
IC50 (μM) on GyrB ATPase
4‐bromophenyl derivative 6q (MIC = 1,000 μg/ml) has a twofold decrease
1
2
3
4
5
6
6c
1.52
>10
1.14
0.73
>10
0.05
in potency in comparison to 6o (MIC = 500 μg/ml). In series 9a–d,
compound 9d (MIC = 25 μg/ml) was the most potent compound in series
6d
6f
9, replacement of the phenyl group at position‐7 of 9d with ethyl group in
6g
9b (MIC = 500 μg/ml) resulted in 20‐fold decrease in the potency,
9d
whereas further replacement of the 4‐fluorophenyl group at position‐2
of 9b with 4‐chlorophenyl group in 9c (MIC = 50 μg/ml) resulted in 10‐
fold increase in the potency. Further replacement of the ethyl group at
Novobiocin
a
Results are average of two independent experiments.

ABDEL‐MOHSEN ET AL.
9 of 18
|
imidazopyrimidine derivatives 6c, 6f, and 6g bearing 4‐chlorophenyl,
dichlorophenyl, or 2‐methoxyphenyl substituents at position‐2
showed GyrB ATPase inhibitory activity of IC50 = 1.52, 1.14, and
TABLE 4 In vitro growth inhibition % of the selected compounds
against a panel of tumor cell lines at 10 µM
Growth inhibition %
0.73 μM, respectively in comparison to novobiocin (IC50 = 0.05 μM),
Subpanel
6a 6b 6c 6d 6f 6g 6h 6p 9d
whereas compounds 6d and 9d showed IC50 > 10 μM.
Leukemia
CCRF‐CEM
HL‐60(TB)
K‐562
MOLT‐4
PRMI‐8226
SR
–a
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
44
20 13
13 11
11 81
14 81
11 60
.2.3 | In vitro antiproliferative activity against NCI
0‐cell line panel
–
24 14
2
6
–
13
–
–
–
–
–
–
–
20
–
25
10 11 13 16 18 17
27 84
Some of the synthesized imidazopyrimidines were screened for their
in vitro antiproliferative activity through the Developmental Ther-
apeutics Program of NCI in the division of cancer treatment and
diagnosis (NIH, Bethesda, MD; www.dtp.nci.nih.gov). This involved
screening the synthesized compounds at a single dose of 10 μM
against a full‐NCI 60‐cell panel including leukemia, melanoma, lung,
colon, brain, ovary, kidney, prostate, and breast cancers. The results
are presented in Table 4.
Non‐small‐cell lung cancer
A549/ATTC
EKVX
–
–
–
–
–
–
12
30
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
34
12
25 24
HOP‐62
24 39 14 19 13
13 32
17 45
–
HOP‐92
19 35
14 24
23 23
11
–
–
–
–
–
–
–
10
–
NCI‐H226
NCI‐H23
NCI‐H322M
NCI‐H460
NCI‐H522
10
–
13
26
11
25
12 13 28
–
–
–
–
–
–
–
–
–
53
23 17 20 19 34 19 21 27 64
From the obtained results, it was clear that each of the
synthesized imidazopyrimidine has a different degree of efficiency
against 60 cancer cell lines. NCI‐H522 from non‐small‐cell lung
cancer, SNB‐75 from central nervous system (CNS) cancer, UO‐31
from renal cancer, and MCF‐7 and T‐47D from breast cancer are
the most sensitive cell lines to the tested imidazopyrimidines
Colon cancer
COLO‐205
HCC‐2998
HCT‐116
HCT‐15
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
23
24
49
62
17 15
20
13
–
–
–
–
18 21 11
–
–
33
20
–
–
–
–
HT29
–
12 59
KM12
10 13
10 25
–
–
56
60
SW‐620
–
–
–
–
6
a–d, 6f–h, 6p, and 9d. Compound 9d showed a broad spectrum of
CNS cancer
SF‐268
SF‐295
SF‐539
SNB‐19
SNB‐75
U251
promising antiproliferative activity against several NCI cell panels
with a mean growth inhibition percentage of 37%. At 10 μM
concentration, 9d exerted 44%, 81%, 81%, 60%, and 84% growth
inhibition against the leukemia cell lines CCRF‐CEM, HL‐60,
K‐562, MOLT‐4, and SR, respectively; 45%, 53%, and 64% of
inhibition against non‐small‐cell lung cancer cell lines HOP‐92,
NCI‐H460, and NCI‐H522, respectively; 49%, 62%, 59%, 56%, and
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
19
22 17 10
10
–
38
16
12
15 54
24 26
–
–
15
–
–
32
32 32
44
21 20 23 30 30 26
–
11
–
–
14
–
–
Melanoma
LOX IMVI
MALME‐3M
M14
13 11
–
–
20
–
–
–
–
–
–
–
–
–
–
11 34
–
–
19 13 20
–
–
–
22
50
6
0% of inhibition against HCT‐116, HCT‐15, HT29, KM12, and
SW‐620, respectively, from colon cancer; 54% and 44% against SF‐
95 and U251 from CNS cancer; 50%, lethal effect, 45%, and 63%
of inhibition against M14, MDA‐MB‐435, SK‐MEL‐5, and UACC‐
2, respectively, from melanoma cell lines; 46% and 55% against
–
12 10
–
–
–
–
18
–
–
MDA‐MB‐435
SK‐MEL‐2
SK‐MEL‐28
SK‐MEL‐5
UACC‐257
UACC‐62
–
–
–
–
–
–
–
–
–
–
–
16 lethal
2
27
–
22
14
14
10
–
–
–
–
–
26
27
45
17
6
12 11
16 26
–
–
–
–
13
39
–
OVCAR‐3 and NCI/ADR‐RES, respectively, from ovarian cancer
cell lines; 41% and 52% of inhibition against A498 and CAKI‐1,
respectively from renal cancer; 43% of inhibition against PC‐3
from prostate cancer and 42% of inhibition against MCF7 cell line
from breast cancer. Compound 6f is the second most potent
compound with a mean growth inhibition percentage of 18%. 6f
exerted 40%, 46%, 44%, and 49% growth inhibition against
IGROV1, A498, MCF‐7, and T‐47D cell lines, respectively.
12 15
–
18 63
Ovarian cancer
IGROV1
49 21 20 25 40
14 11 13 11 13
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
33
OVCAR‐3
OVCAR‐4
OVCAR‐5
OVCAR‐8
NCI/ADR‐RES
SK‐OV‐3
13 46
–
–
–
–
–
16
13
–
–
–
–
–
–
–
–
–
–
14
–
–
10
55
–
–
23 30 13 18 26
15 18
Renal cancer
7
86‐0
–
–
–
–
–
–
–
–
–
–
20
46
15
–
–
–
–
–
–
–
–
–
11 21
16 41
13 12
27 52
A498
–
2
.3 Estimation of physicochemical,
|
ACHN
CAKI‐1
RXF 393
SN 12C
TK‐10
17 14
–
pharmacokinetic, and ADME properties
17 31 19 23
10
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
28
11
–
10
–
–
–
Estimation of the physicochemical and pharmacokinetic properties,
as well as ADME parameters of the synthesized imidazopyrimidines,
–
–
UO‐31
35 39 35 30 33 19 13 33 31
Continues)
[
33]
was carried out using SwissADME free web tool.
Selected results
(

10 of 18
ABDEL‐MOHSEN ET AL.
|
TABLE 4 (Continued)
3 CONCLUSION
|
Growth inhibition %
In summary, we have presented a simple and efficient method for
the synthesis of a new series of imidazopyrimidines 6 and 9 by a
domino reaction between 2‐imino‐4‐oxo‐6‐substituted‐1,2,3,4‐
tetrahydropyrimidines 4 or 8 and 2‐bromoacetophenone 5. The
newly synthesized compounds 6 and 9 showed promising activity
against Gram(−) bacteria over Gram(+) ones. Generally, com-
pounds exhibiting a phenyl group at position‐7 6a–g demon-
strated promising antibacterial activity over compounds having
methoxyphenyl groups 6i–u. Compounds 6c, 6f, and 6g showed a
potent and broad spectrum of antibacterial activity over the
tested microorganisms. Both 6c and 6g with chlorophenyl groups
at position‐2 showed MIC of 10.0 and 12.5 μg/ml against E. coli
and S. typhi, respectively, whereas compound 6f with
2‐methoxyphenyl group at position‐2 displayed MIC of 12.5,
12.5 and 25 μg/ml against E. coli, P. aeruginosa and S. typhi,
respectively. In addition, 6f and 6g displayed IC50 of 1.14 and
0.73 μM in GyrB ATPase assay. The synthesized compounds
revealed promising antiproliferative activity against NCI cancer
cell lines. Compound 9d showed a broad spectrum of cytotoxic
activity between 10% to lethal effect against the tested cell lines.
In silico prediction of physicochemical and pharmacokinetic
properties of the new imidazopyrimidines showed that they are
promising candidates to be further optimized for the discovery of
oral chemotherapeutic agents.
Subpanel
6a 6b 6c 6d 6f 6g 6h 6p 9d
Prostate cancer
PC‐3
DU‐145
25 25
–
–
10 32
–
–
–
–
–
–
43
–
–
–
–
–
Breast cancer
MCF7
29 20 17 26 44
–
–
–
17 13 42
MDA‐MB‐231/ATTC 24 28 16
–
–
–
–
–
–
–
–
–
12 38
10 32
11 36
22 26
HS 578T
11 16
–
BT‐549
T‐47D
MDA‐MB‐468
11
–
–
16 30 11
28 45 23 28 49 12
28
–
–
–
–
–
–
17
a
%
of growth inhibition is <10%.
are depicted in Table 5. Analysis of the obtained results revealed that
the synthesized imidazopyrimidines 6a–u and 9a–d have acceptable
physicochemical properties such as molecular weights between
2
5
57–481 g/mol, topological polar surface areas (TPSA) ranging from
[34]
0.16 to 110.87 Å, iLOGP (octanol‐water partition coefficient)
between 2.43 and 3.63 and an acceptable number of hydrogen‐bond
donors and acceptors.
The imidazopyrimidines have moderate water solubility and all of
them are predicted to be well absorbed from GIT. With the exception
of compounds 6a–e, 6h, and 9a–d, the rest of compounds do not have
the probability to penetrate the blood–brain barrier; therefore, no
side effects are expected to occur in the CNS. Moreover, most of the
examined compounds are nonsubstrates for the most important
efflux transporter P‐glycoprotein, which exerts a predominate role in
pumping xenobiotics outside the cells. Hence, the imidazopyrimidines
are expected to be well absorbed and controlled excreted from the
site of action.
4
|
EXPERIMENTAL
|
Chemistry
4.1
[
33]
Bioavailability radar provided from SwissADME web tool
4.1.1 | General remarks
showed that most of the tested compounds exhibited promising
predicted physicochemical properties for oral bioavailability. For
instance, Figure 5 displays the bioavailability radar chart of
compounds 6f, 6g, and 9d (for the bioavailability radar for the
rest of compounds; check Supporting Information). The ideal space
of six physicochemical parameters, for example, size, polarity,
lipophilicity, solubility, flexibility, and saturation for oral bioavail-
All chemicals were purchased from commercial suppliers. Analy-
tical thin‐layer chromatography was performed on precoated
silica gel 60 F245 aluminum plates (Merck) with visualization
under ultraviolet (UV) light. Melting points were determined on a
Stuart SMP30 melting point apparatus with open capillary tubes
and are uncorrected. Elemental analysis and spectral data
analysis of the compounds were performed in the Microanalytical
Labs, National Research Centre, Cairo, Egypt. Infrared (IR)
[
33]
ability are located in the pink‐colored area.
All the synthesized
imidazopyrimidines are almost present in the pink area; the
3
−1
fraction of sp hybridized carbons is <0.25 in some cases, hence
spectra (4,000–400 cm ) were recorded using KBr pellets in a
it is deviated out from the pink zone. It is interesting to mention
Jasco FT/IR 6100E Fourier transform infrared spectrophot-
1
13
that none of 6a–u and 9a–d violated the drug‐likeness rules
ometer. H‐NMR and C‐NMR spectra were recorded at 400
[
35]
[36]
[37]
including Lipinski's rule,
Veber rule,
Ghose‐filter,
(100) and 300 (75) MHz on Bruker, Agilent and a Varian
Unity
[
38]
[39]
Egan,
and Muegge's
filter and they do not exhibit any of
Inova instrument, respectively, using dimethyl sulfoxide
as a solvent. Chemical shifts are given in parts per
[
40]
Pan Assay Interference subcompounds.
(DMSO)‐d
6
From results of the ADME prediction study, it was interesting to
summarize that the synthesized imidazopyrimidines not only have
promising chemotherapeutic properties but also satisfy the essential
physicochemical, pharmacokinetic, and drug‐likeness parameters for
future discovery of chemotherapeutic agents.
million (ppm) relative to tetramethylsilane as internal standards.
Coupling constants are reported in Hertz (Hz).
The original spectra of the investigated compounds are provided
as Supporting Information, as are their InChI codes together with
some biological activity data.

ABDEL‐MOHSEN ET AL.
11 of 18
|
TABLE 5 Selected calculated physicochemical and pharmacokinetic properties of 6a–u and 9a–d from SwissADME free web tool
Product MW Rotatable bonds H‐bond Acc. H‐bond Don. MR TPSA Log P GI absorption BBB permeant Pgp substrate
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
9
9
9
9
a
b
c
d
e
f
312.32
330.32
346.77
391.22
326.35
342.35
381.21
362.38
360.34
376.8
2
2
2
2
2
3
2
2
3
3
4
4
4
5
5
5
5
5
6
5
5
1
2
2
2
3
4
3
3
3
4
3
3
5
4
5
6
5
6
6
6
6
6
7
6
6
2
3
2
3
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
91.4
91.36
96.41
99.1
73.95 2.51
73.95 2.56
73.95 2.72
73.95 2.84
73.95 2.79
83.18 2.9
73.95 2.88
73.95 2.91
83.18 2.95
83.18 3.07
92.41 3.1
92.41 3.13
92.41 3.32
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
High
Yes
Yes
Yes
Yes
Yes
No
No
Yes
No
No
No
No
No
No
No
No
No
No
No
No
No
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
Yes
No
No
No
No
No
Yes
Yes
No
No
Yes
Yes
No
Yes
No
No
No
No
96.37
97.89
101.42
108.91
97.85
102.9
104.38
104.34
109.39
g
h
i
j
k
l
372.38
390.37
406.82
402.4
m
n
o
p
q
r
110.88 101.64 3.31
110.88 101.64 3.19
115.89 101.64 3.41
118.58 101.64 3.56
115.84 101.64 3.43
117.37 110.87 3.63
402.4
436.85
481.3
416.43
432.43
471.29
452.46
259.69
257.26
273.72
305.31
s
t
120.9
101.64 3.49
u
a
b
c
d
128.38 101.64 3.53
71.22
70.98
76.03
86.64
50.16 2.43
50.16 2.53
50.16 2.7
50.16 2.76
Abbreviations: ADME, absorption, distribution, metabolism, and excretion; BBB, blood–braib barrier; GI, gastrointestinal; MR: molecular refractivity; MW,
molecular weights; Pgp, p‐glycoprotein; TPSA, topological polar surface areas.
4
.1.2 | Synthesis of 4a–d and 8a–c
4.1.3 | General procedure for the synthesis of 6a–u
and 9a–d
The starting 2‐imino‐4‐oxo‐6‐substituted‐1,2,3,4‐tetrahydropyrimidine‐5‐
carbonitriles and 2‐imino‐6‐substituted‐2,3‐dihydropyrimidin‐
(1H)‐ones 8 were synthesized according to the previously reported
4
A mixture of equivalent amounts of 4 or 8, 2‐bromoacetophenones 5
4
3
and NaHCO was stirred in ethanol under reflux for 4 hr. The
[21,28]
procedure.
reaction mixture was then cooled to room temperature followed by
6g
9d
6
f
FIGURE 5 Bioavailability radar plot from SwissADME online web tool for 6f, 6g, and 9d

12 of 18
ABDEL‐MOHSEN ET AL.
|
filtration and the filter was washed with ethanol. The filtrate was
concentrated to one‐third its original volume and poured on to ice/
water and neutralized with 2N HCl. The precipitated product was
filtered and dried to give the crude product, which was further
purified by crystallization from methanol or by column chromato-
graphy to give analytically pure products.
(100 MHz; DMSO‐d
128.38, 128.49, 129.20, 130.63, 133.89, 135.38, 147.45, 154.46, and
166.60 ppm; Anal. calcd. for C19 11ClN O: C, 65.81; H, 3.20; N, 16.16.
Found: C, 65.58; H, 3.55; N, 16.03.
6
) 82.14, 105.02, 113.23, 117.65, 127.22, 128.20,
H
4
2‐(4‐Bromophenyl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
pyrimidine‐6‐carbonitrile (6d)
5
‐Oxo‐2,7‐diphenyl‐1,5‐dihydroimidazo[1,2‐a]pyrimidine‐6‐
carbonitrile (6a)
−1
White powder; yield: 56%; mp, >300°C; ύ max (atr) cm 3,200, 3,056,
1
2
,220, 1,652, 1,575, and 1,482; H‐NMR (400 MHz; DMSO‐d
6
) 7.49–7.57
1
3
White powder; yield: 56%; mp >300°C; H‐NMR (400 MHz; DMSO‐d
6
)
(3H, m, H‐3ʺ, H‐4ʺ, H‐5ʺ), 7.72 (2H, d, J = 7.5 Hz, H‐2′, H‐6′), 7.85–7.86
3
7.42–7.46 (1H, m, H‐4ʺ), 7.49–7.53 (2H, m, H‐3ʺ, H‐5ʺ), 7.55–7.57 (3H,
(2H, m, H‐2ʺ, H‐6ʺ), 7.92 (2H, d, J = 7.6 Hz, H‐3′, H‐5′), and 8.49 ppm (1H,
1
3
m, H‐3′, H‐4′, H‐5′), 7.86–7.88 (2H, m, H‐2ʺ, H‐6ʺ or H‐2′, H‐6′), 8.00
s, H‐3); C‐NMR (100 MHz; DMSO‐d ) 82.71, 105.14, 113.33, 117.50,
6
3
(
1
2H, d, J =7.2 Hz, H‐2ʺ, H‐6ʺ or H‐2′, H‐6′), and 8.42 ppm (1H, s, H‐3);
122.66, 127.45, 128.40, 128.49, 130.69, 131.01, 132.13, 135.41, 147.16,
3
C‐NMR (100 MHz; DMSO‐d
28.39, 128.50, 129.16, 129.50, 130.69, 131.58, 136.84, 147.14,
56.53, and 166.52 ppm; Anal. calcd. for C19 O: C, 73.07; H,
.87; N, 17.94. Found: C, 73.35; H, 3.48; N, 17.63.
6
) 82.91, 104.55, 117.50, 125.47, 127.04,
156.59, and 165.45 ppm; Anal. calcd. for C19H11BrN O: C, 58.33; H, 2.83;
4
1
1
3
N, 14.32. Found: C, 58.71; H, 2.53; N, 14.64.
12 4
H N
5‐Oxo‐7‐phenyl‐2‐(p‐tolyl)‐1,5‐dihydroimidazo[1,2‐a]pyrimidine‐6‐
carbonitrile (6e)
2
‐(4‐Fluorophenyl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
pyrimidine‐6‐carbonitrile (6b)
−1
White powder; yield: 39%; mp, >300°C; ύ max (atr) cm 3,300,
1
3
,118, 2,217, 1,646, 1,562, and 1,480; H‐NMR (400 MHz; DMSO‐d
6
)
1
3
White powder; yield: 54%; mp, >300°C; H‐NMR (400 MHz; DMSO‐d
6
)
2.32 (3H, s, CH
3
), 7.27 (2H, d, J = 7.8 Hz, H‐3′, H‐5′), 7.54–7.55 (3H,
3
3
7
.38 (2H, t, J = 8.8 Hz, H‐3′, H‐5′), 7.56–7.57 (3H, m, H‐3ʺ, H‐4ʺ, H‐5ʺ),
.86–7.88 (2H, m, H‐2′, H‐6′), 8.00–8.03 (2H, m, H‐2ʺ, H‐6ʺ), 8.43 (1H, s,
H‐3), and 14.27 ppm (1H, br., NH); Anal. calcd. for C19 11FN O: C, 69.09;
H, 3.36; N, 16.96. Found: C, 69.39; H, 3.12; N, 16.60.
m, H‐3ʺ, H‐4ʺ, H‐5ʺ), 7.79 (2H, d, J = 7.8 Hz, H‐2′, H‐6′), 7.84 (2H, d,
3
13
7
J = 7.1 Hz, H‐2ʺ, H‐6ʺ), and 8.27 ppm (1H, s, H‐3);
(100 MHz; DMSO‐d ) 20.91, 82.72, 103.89, 117.59, 124.36, 125.42,
128.38, 128.49, 129.70, 130.63, 131.88, 136.93, 139.23, 147.13,
C‐NMR
H
4
6
14 4
156.57, and 166.30 ppm; Anal. calcd. for C20H N O: C, 73.61; H,
4.32; N, 17.17. Found: C, 73.37; H, 4.11; N, 17.45.
2
‐(4‐Chlorophenyl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
pyrimidine‐6‐carbonitrile (6c)
2‐(2‐Methoxyphenyl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
pyrimidine‐6‐carbonitrile (6f)
−1
White powder; yield: 50%; mp, >300°C; ύ max (atr) cm 3,137, 2,214,
1
1
,654, 1,578, and 1,484; H‐NMR (400 MHz; DMSO‐d
6
) 7.56–7.59 (5H,
1
3
6
White powder; yield: 66%; mp, >300°C; H‐NMR (400 MHz; DMSO‐d )
m, H‐2ʺ, H‐3ʺ, H‐4ʺ, H‐5ʺ, H‐6ʺ), 7.86 (2H, d, J = 6.8 Hz, H‐2′, H‐6′), 7.98
3
3
3
13
3
3.99 (3H, s, OCH ), 7.11 (1H, t, J = 7.6 Hz, H‐5′), 7.28 (1H, d, J = 8.4 Hz,
(
2H, d, J = 6.8 Hz, H‐3′, H‐5′), and 8.47 ppm (1H, s, H‐3); C‐NMR

ABDEL‐MOHSEN ET AL.
13 of 18
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3
−1
H‐3′), 7.46 (1H, t, J = 8.4 Hz, H‐4′), 7.55–7.57 (3H, m, H‐3ʺ, H‐4ʺ, H‐5ʺ),
Pale yellow powder; yield: 43%; mp, >300°C; ύ max (atr) cm 3,379,
13
1
7
.85–7.89 (3H, m, H‐2ʺ, H‐6ʺ, H‐6′), and 8.02 ppm (1H, s, H‐3); C‐NMR
100 MHz; DMSO‐d ) 55.82, 82.77, 106.42, 111.99, 115.17, 117.53,
20.83, 127.24, 128.37, 128.52, 129.63, 130.66, 130.87, 136.89, 146.47,
56.50, 156.53, and 166.58 ppm; Anal. calcd. for C20 : C, 70.17;
H, 4.12; N, 16.37. Found: C, 70.38; H, 4.45; N, 16.08.
3,145, 3,005, 2,218, 1,678, 1,566, and 1,489; H‐NMR (400 MHz;
3
(
6
DMSO‐d
6
) 3.80 (3H, s, OCH
3
), 7.03 (2H, d, J = 8.8 Hz, H‐3ʺ, H‐5ʺ),
1
7.60 (2H, dd, J = 8.4 Hz, J = 5.6 Hz, H‐3′, H‐5′), 7.86 (2H, d, J = 9.0 Hz,
H‐2ʺ, H‐6ʺ), 8.13 (2H, dd, J = 8.8 Hz, J = 5.6 Hz, H‐2′, H‐6′), and
1
14 4 2
H N O
8.18 ppm (1H, s, H‐3); Anal. calcd. for C20
H13FN
4 2
O : C, 66.66; H,
3.64; N, 15.55. Found: C, C, 66.42; H, 3.43; N, 15.87.
2
‐(3,4‐Dichlorophenyl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
2
‐(4‐Chlorophenyl)‐7‐(4‐methoxyphenyl)‐5‐oxo‐1,5‐dihydroimidazo‐
pyrimidine‐6‐carbonitrile (6g)
[1,2‐a]pyrimidine‐6‐carbonitrile (6j)
−1
White powder; yield: 39%; mp, >300°C; ύ max (atr) cm 3,400, 3,122,
1
Pale yellow powder; yield: 42%; mp, >300°C; H‐NMR (400 MHz;
1
2
,213, 1,692, 1,589, and 1,491; H‐NMR (400 MHz; DMSO‐d
6
) 7.55–7.57
3
DMSO‐d
6
) 3.83 (3H, s, OCH
3
), 7.09 (2H, d, J = 8.8 Hz, H‐3ʺ, H‐5ʺ), 7.54
3
(
3H, m, H‐3ʺ, H‐4ʺ, H‐5ʺ), 7.77 (1H, d, J = 8.4 Hz, H‐5′), 7.84–7.87 (2H, m,
3
3
(
2H, d, J = 8.4 Hz, H‐2′, H‐6′), 7.87 (2H, d, J = 8.4 Hz, H‐2ʺ, H‐6ʺ), 7.92
3
4
H‐2ʺ, H‐6ʺ), 7.93 (1H, dd, J = 8.4 Hz, d, J = 2.0 Hz, H‐6′), 8.27 (1H, d,
3
13
(
2H, d, J = 8.4 Hz, H‐3′, H‐5′), and 8.37 ppm (1H, s, H‐3); C‐NMR
100 MHz; DMSO‐d ) 55.42, 82.73, 99.59, 111.12, 113.81, 114.69,
27.18, 128.80, 129.23, 130.17, 130.32, 130.79, 134.00, 147.01,
59.63, and 161.32 ppm; Anal. calcd. for C20 13ClN : C, 63.75;
4
13
J = 2.0 Hz, H‐2′), and 8.58 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐
) 82.61, 106.14, 117.45, 125.50, 127.26, 128.24, 128.45, 128.53,
28.65, 130.80, 131.39, 131.78, 132.15, 136.65, 147.23, 156.56, and
66.44 ppm; Anal. calcd. for C19 10Cl O: C, 59.86; H, 2.64; N, 14.70.
Found: C, 59.54; H, 2.33; N, 14.92.
(
6
d
6
1
1
1
H
4 2
O
1
H
2 4
N
H, 3.48; N, 14.87. Found: C, 63.48; H, 3.75; N, 14.51.
2
,7‐Bis(4‐methoxyphenyl)‐5‐oxo‐1,5‐dihydroimidazo[1,2‐a]‐
2
‐(Naphthalen‐2‐yl)‐5‐oxo‐7‐phenyl‐1,5‐dihydroimidazo[1,2‐a]‐
pyrimidine‐6‐carbonitrile (6k)
pyrimidine‐6‐carbonitrile (6h)
1
1
Pale yellow powder; yield: 33%; mp, >300°C; H‐NMR (400 MHz; DMSO‐
White powder; yield: 75%; mp, >300°C; H‐NMR (400 MHz;
3
d
6
) 3.80 (3H, s, OCH
3
), 3.84 (3H, s, OCH
3
), 7.05 (2H, d, J = 8.8 Hz, H‐3ʺ,
DMSO‐d
6
)
7.57–7.59 (5H, m, H‐2ʺ, H‐3ʺ, H‐4ʺ, H‐5ʺ, H‐6ʺ),
3
3
3
H‐5ʺ), 7.10 (2H, d, J = 8.8 Hz, H‐3′, H‐5′), 7.88 (2H, ov. d‐like, J = 8.8 Hz,
7
.87–7.96 (4H, m, H‐5′, H‐6′, H‐7′, H‐8′), 8.03 (1H, d, J = 8.4 Hz,
3
3
4
H‐2ʺ, H‐6ʺ or H‐2′, H‐6′), 7.89 (2H, ov. d‐like, J = 8.4 Hz, H‐2ʺ, H‐6ʺ or H‐
H‐4′), 8.09 (1H, dd, J = 8.8 Hz, J = 1.6 Hz, H‐3′), 8.50 (1H, s, H‐3 or
13
1
3
2′, H‐6′), 8.24 (1H, s, H‐3), and 13.93 ppm (1H, br., NH); C‐NMR
100 MHz; DMSO‐d ) 55.80, 56.01, 82.65, 106.27, 111.95, 117.72,
20.81, 125.40, 127.17, 130.85, 131.31, 132.10, 139.52, 146.18, 155.48,
56.52, and 165.94 ppm; Anal. calcd. for C21 : C, 67.73; H, 4.33;
N, 15.05. Found: C, 67.43; H, 4.65; N, 15.35.
H‐1′), and 8.52 ppm (1H, s, H‐3 or H‐1′); C‐NMR (100 MHz;
DMSO‐d ) 82.89, 105.07, 117.52, 123.05, 124.51, 124.57, 127.09,
27.11, 127.78, 128.15, 128.40, 128.51, 128.84, 130.69, 131.76,
32.70, 132.98, 136.86, 147.25, 156.54, and 166.48 ppm; Anal.
O: C, 76.23; H, 3.89; N, 15.46. Found: C, 76.53;
(
6
6
1
1
1
1
16 4 3
H N O
calcd. for C23
14 4
H N
H, 3.65; N, 15.78.
7‐(2,5‐Dimethoxyphenyl)‐2‐(4‐fluorophenyl)‐5‐oxo‐1,5‐
2‐(4‐Fluorophenyl)‐7‐(4‐methoxyphenyl)‐5‐oxo‐1,5‐dihydroimidazo‐
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6l)
[
1,2‐a]pyrimidine‐6‐carbonitrile (6i)

14 of 18
ABDEL‐MOHSEN ET AL.
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1
Pale yellow powder; yield: 25%; mp, >300°C; H‐NMR (400 MHz;
5‐Oxo‐2‐phenyl‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐dihydroimidazo‐
[1,2‐a]pyrimidine‐6‐carbonitrile (6o)
DMSO‐d
4
6
) 3.74 (3H, s, OCH
3
), 3.77 (3H, s, OCH
3
), 6.98 (1H, d,
3
4
J = 3.2 Hz, H‐6ʺ), 7.07 (1H, dd, J = 8.8 Hz, J = 3.2 Hz, H‐4ʺ), 7.12
3
3
(
1H, d, J = 9.0 Hz, H‐3ʺ), 7.37 (2H, t, J = 8.8 Hz, H‐3′, H‐5′),
7
.99–8.02 (2H, m, H‐2′, H‐6′), 8.43 (1H, s, H‐3), and 14.26 ppm (1H,
13
br., NH); C‐NMR (100 MHz; DMSO‐d
6
) 55.64, 55.97, 85.83, 104.55,
1
1
1
13.17, 115.05, 116.33 (d, J = 21.8 Hz), 116.76 (d, J = 21.2 Hz),
24.06, 126.83, 127.98 (d, J = 8.6 Hz), 131.36, 147.12, 150.42,
52.86, 154.23, 155.89, 162.69 (d, J = 245.6 Hz), and 165.15 ppm;
1
Anal. calcd. for C21
H
15FN
4
3
O : C, 64.61; H, 3.87; N, 14.35. Found: C,
White powder; yield: 66%; mp, >300°C; H‐NMR (400 MHz; DMSO‐
64.92; H, 3.65; N, 14.68.
d ) 3.76 (3H, s, OCH ), 3.84 (6H, s, OCH ), 7.23 (2H, s, H‐2ʺ, H‐6ʺ),
6
3
3
3
7.42–7.52 (3H, m, H‐3′, H‐4′, H‐5′), 7.95 (2H, d, J = 7.6 Hz,
1
3
H‐2′, H‐6′), and 8.40 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐
) 56.04, 60.23, 82.73, 104.55, 106.29, 117.77, 125.48, 127.04,
29.18, 129.53, 131.67, 131.80, 139.58, 146.98, 152.53, 156.58, and
65.89 ppm; Anal. calcd. for C, 65.66; H, 4.51;
2
‐(4‐Chlorophenyl)‐7‐(2,5‐dimethoxyphenyl)‐5‐oxo‐1,5‐
d
6
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6m)
1
1
22 18 4 4
C H N O :
N, 13.92. Found: C, 65.34; H, 4.31; N, 13.71.
2‐(4‐Chlorophenyl)‐5‐oxo‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6p)
−1
Pale yellow powder; yield: 46%; mp, >300°C; ύ max (atr) cm 3,475,
1
3
,136, 3,044, 2,222, 1,663, 1,578, and 1,489; H‐NMR (400 MHz;
DMSO‐d
6
) 3.74 (3H, s, OCH
3
3
), 3.77 (3H, s, OCH ), 6.98 (1H, d,
4
3
4
J = 3.2 Hz, H‐6ʺ), 7.07 (1H, d, J = 9.2 Hz, J = 3.2 Hz, H‐4ʺ), 7.12 (1H,
3
3
d, J = 9.2 Hz, H‐3ʺ), 7.58 (2H, d, J = 8.4 Hz, H‐2′, H‐6′), 7.97 (2H, d,
3
J = 8.4 Hz, H‐3′, H‐5′), 8.48 (1H, s, H‐3), and 14.24 ppm (1H, br., NH);
1
1
3
White powder; yield: 72%; mp, >300°C; H‐NMR (300 MHz; DMSO‐
6
C‐NMR (100 MHz; DMSO‐d ) 55.58, 55.91, 82.41, 105.13, 113.10,
d
6
) 3.76 (3H, s, OCH
3
), 3.85 (6H, s, OCH
3
), 7.23 (2H, s, H‐2ʺ, H‐6ʺ),
1
1
14.98, 115.88, 116.57, 116.81, 127.28, 129.21, 129.65, 133.95,
47.15, 150.36, 152.78, 155.84, 156.60, and 164.50 ppm; Anal. calcd.
3
3
7
.59 (2H, d, J = 8.7 Hz, H‐2′, H‐6′), 7.99 (2H, d, J = 8.4 Hz,
13
H‐3′, H‐5′), 8.49 (1H, s, H‐3), and 14.29 ppm (1H, br., NH); C‐
NMR (75 MHz; DMSO‐d ) 56.00, 60.18, 82.64, 105.12, 106.24,
17.69, 126.20, 127.18, 129.20, 130.77, 131.68, 134.01, 139.56,
46.99, 152.49, 156.53, and 165.82 ppm; Anal. calcd. for
17ClN : C, 60.49; H, 3.92; N, 12.83. Found: C, 60.17; H,
.67; N, 12.54.
for C21
H
15ClN
4 3
O : C, 62.00; H, 3.72; N, 13.77. Found: C, 62.32; H,
6
3.93; N, 13.90.
1
1
7
‐(2,5‐Dimethoxyphenyl)‐2‐(4‐methoxyphenyl)‐5‐oxo‐1,5‐
C
22
H
4 4
O
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6n)
3
2‐(4‐Bromophenyl)‐5‐oxo‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6q)
1
Pale yellow powder; yield: 37%; mp, >300°C; H‐NMR (400 MHz;
DMSO‐d
6 3 3 3
) 3.74 (3H, s, OCH ), 3.77 (3H, s, OCH ), 3.81 (3H, s, OCH ),
4
6
.98 (1H, d, J = 2.8 Hz, H‐6ʺ), 7.06–7.08 (3H, m, H‐4ʺ, H‐3′, H‐5′), 7.12
−1
3
3
White powder; yield: 76%; mp, 295–297°C; ύ max (atr) cm 3,200,
(1H, d, J = 9.1 Hz, H‐3ʺ), 7.89 (2H, d, J = 8.8 Hz, H‐2′, H‐6′), 8.30 (1H, s,
1
13
3,111, 2,215, 1,660, 1,575, and 1,486; H‐NMR (400 MHz; DMSO‐d )
H‐3), and 14.12 ppm (1H, br., NH); C‐NMR (100 MHz; DMSO‐d
5.98, 56.02, 82.09, 106.14, 113.17, 115.21, 116.02, 116.21, 116.36,
16.43, 122.31, 126.79, 131.59, 132.99, 146.33, 150.27, 152.75, 155.35,
6
) 55.47,
6
3
.76 (3H, s, OCH
3
), 3.84 (6H, s, OCH
3
), 7.22 (2H, s, H‐2ʺ, H‐6ʺ), 7.59
5
3
3
(2H, d, J = 8.8 Hz, H‐2′, H‐6′), 7.99 (2H, d, J = 8.8 Hz, H‐3′, H‐5′), and
1
1
3
8.48 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐d
6
) 56.01, 60.19,
18 4 4
and 165.73 ppm; Anal. calcd. for C22H N O : C, 65.66; H, 4.51; N, 13.92.
82.64, 105.13, 106.25, 117.71, 126.21, 127.20, 128.96, 129.22,
Found: C, 65.41; H, 4.88; N, 13.65.

ABDEL‐MOHSEN ET AL.
15 of 18
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1
31.69, 134.03, 139.57, 147.01, 152.50, 156.55, and 165.40 ppm;
Anal. calcd. for C22 17BrN : C, 54.90; H, 3.56; N, 11.64. Found: C,
4.71; H, 3.23; N, 11.35.
(400 MHz; DMSO‐d
6 3 3
) 3.76 (3H, s, OCH ), 3.85 (6H, s, OCH ),
3
H
4 4
O
7.22 (2H, s, H‐2ʺ, H‐6ʺ), 7.79 (1H, d, J = 8.4 Hz, H‐5′), 7.96
3
4
4
5
(1H, dd, J = 8.4 Hz, J = 2.1 Hz, H‐6′), 8.30 (1H, d, J = 1.8 Hz,
1
3
6
H‐2′), and 8.60 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐d )
5
1
1
6.02, 60.20, 82.65, 106.14, 106.27, 117.64, 125.43, 127.22,
5
‐Oxo‐2‐(p‐tolyl)‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐dihydroimidazo‐
29.89, 131.35, 131.76, 132.12, 134.34, 139.63, 146.99,
52.51, 156.52, 161.97, and 165.71 ppm; Anal. calcd. for
[
1,2‐a]pyrimidine‐6‐carbonitrile (6r)
C
22
H
16Cl
2 4 4
N O : C, 56.07; H, 3.42; N, 11.89. Found: C, 56.33; H,
3
.76; N, 11.60.
2‐(Naphthalen‐2‐yl)‐5‐oxo‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6u)
1
White powder; yield: 64%; mp, >300°C; H‐NMR (400 MHz; DMSO‐d
.33 (3H, s, CH ), 3.75 (3H, s, OCH ), 3.84 (6H, s, OCH ), 7.21 (2H, s, H‐2ʺ,
H‐6ʺ), 7.46 (2H, d, J = 8.4 Hz, H‐3′, H‐5′), 7.92 (2H, d, J = 8.8 Hz,
6
)
2
3
3
3
3
3
1
3
H‐2′, H‐6′), and 8.10 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐d
0.88, 55.96, 60.16, 95.03, 103.29, 104.22, 106.17, 118.68, 125.30,
26.88, 128.69, 129.50, 132.12, 139.12, 152.40, 157.06, 157.39, and
64.24 ppm; Anal. calcd. for C23 : C, 66.34; H, 4.84; N, 13.45.
Found: C, 66.01; H, 4.54; N, 13.12.
6
)
2
1
1
H N
20 4
O
4
1
White powder; yield: 60%; mp, >300°C; H‐NMR (400 MHz; DMSO‐
d
6
) 3.77 (3H, s, OCH
.56–7.60 (2H, m), 7.91–7.99 (3H, m), 8.11–8.12 (1H, m), 8.54 (1H, s,
H‐3 or H‐1′), 8.55 (1H, s, H‐3 or H‐1′), and 14.38 ppm (1H, br., NH);
Anal. calcd. for C26 : C, 69.02; H, 4.46; N, 12.38. Found: C,
3 3
), 3.86 (6H, s, OCH ), 7.25 (2H, s, H‐2ʺ, H‐6ʺ),
7
2
‐(2‐Methoxyphenyl)‐5‐oxo‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐
20 4 4
H N O
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6s)
69.38; H, 4.65; N, 12.05.
2‐(4‐Chlorophenyl)‐7‐methylimidazo[1,2‐a]pyrimidin‐5(1H)‐one (9a)
−1
White powder; yield: 61%; mp, >300°C; ύ max (atr) cm 3,400, 3,120,
1
2
,942, 2,214, 1,671, 1,594, and 1,492; H‐NMR (300 MHz; DMSO‐d
6
)
−1
White powder; yield: 48%; mp, >300°C; ύ max (atr) cm 3,310, 2,960,
3
3 3 3
.76 (3H, s, OCH ), 3.85 (6H, s, OCH ), 3.99 (3H, s, OCH ), 7.11 (1H, t,
1
1
,675, 1,563, and 1,479; H‐NMR (400 MHz; DMSO‐d
6
) 2.29 (3H, s, CH
3
),
3
3
J = 7.2 Hz), 7.22–7.24 (3H, m), 7.46 (1H, t, J = 7.2 Hz), 7.91 (1H, d,
3
5
3
.47 (1H, s, H‐6), 7.42 (2H, d, J = 8.4 Hz, H‐2′, H‐6′), 7.90 (2H, d,
3
13
J = 7.8 Hz), 8.02 (1H, s, H‐3), and 14.01 ppm (1H, br., NH); C‐NMR
13
J = 8.4 Hz, H‐3′, H‐5′), and 7.97 ppm (1H, s, H‐3); C‐NMR (100 MHz;
DMSO‐d ) 21.14, 93.43, 103.06, 126.75, 128.52, 131.50, 132.69, 137.97,
47.15, 155.17, and 157.60 ppm; Anal. calcd. for C13 10ClN O: C, 60.13;
H, 3.88; N, 16.18. Found: C, 60.37; H, 3.98; N, 16.40.
(
75 MHz; DMSO‐d
6
) 55.80, 56.00, 60.17, 82.54, 106.26, 106.42, 111.96,
15.15, 117.76, 120.80, 127.19, 130.82, 131.84, 139.50, 146.29,
52.47, 156.52, and 165.94 ppm; Anal. calcd. for C23 : C,
3.88; H, 4.66; N, 12.96. Found: C, 63.64; H, 4.92; N, 12.72.
6
1
1
6
1
H
3
20 4 5
H N O
7‐Ethyl‐2‐(4‐fluorophenyl)imidazo[1,2‐a]pyrimidin‐5(1H)‐one (9b)
2
‐(3,4‐Dichlorophenyl)‐5‐oxo‐7‐(3,4,5‐trimethoxyphenyl)‐1,5‐
dihydroimidazo[1,2‐a]pyrimidine‐6‐carbonitrile (6t)
1
White powder; yield: 48%; mp, >300°C; H‐NMR (400 MHz; DMSO‐d
6
)
3
3
1
.22 (3H, t, J = 7.2 Hz, CH
3
), 2.57 (2H, q, J = 7.2 Hz, CH
2
), 5.65 (1H, s, H‐
3
6
), 7.25 (2H, t, J = 8.8 Hz, H‐3′, H‐5′), 7.92–7.96 (2H, m, H‐2′, H‐6′), and
−
1
3
8.10 ppm (1H, s, H‐3); Anal. calcd. for C14H12FN O: C, 65.36; H, 4.70; N,
White powder; yield: 73%; mp, 198–200°C; ύ max (atr) cm
1
16.33. Found: C, 65.61; H, 4.52; N, 16.61.
3
,300, 3,117, 2,942, 2,208, 1,661, 1,592, and 1,478; H‐NMR

16 of 18
ABDEL‐MOHSEN ET AL.
|
2
‐(4‐Chlorophenyl)‐7‐ethylimidazo[1,2‐a]pyrimidin‐5(1H)‐one (9c)
refinement can be found in Tables S1 and S2. All images were
[
45]
prepared by using Olex2.
CCDC 1951700 contains the
Supporting Information crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.
−1
White powder; yield: 36%; mp, >300°C; ύ max (atr) cm 3,426, 3,120,
4
.3 Biological evaluation
|
1
2
,928, 1,686, 1,600, 1,566, and 1,443; H‐NMR (400 MHz; DMSO‐d
6
)
3
3
1.21 (3H, t, J = 7.6 Hz, CH
3
), 2.57 (2H, q, J = 7.6 Hz, CH
2
), 5.65 (1H, s, H‐
Antimicrobial activity and MIC of the synthesized compounds and
positive control (ampicillin and levofloxacin) were evaluated by well
[31,32]
3
3
6
), 7.46 (2H, d, J = 8.4 Hz, H‐2′, H‐6′), 7.91 (2H, d, J = 8.8 Hz, H‐3′, H‐5′),
13
and 8.10 ppm (1H, s, H‐3); C‐NMR (100 MHz; DMSO‐d
3.75, 104.16, 126.91, 128.75, 129.21, 130.18, 130.65, 156.59, 157.34,
and 168.67 ppm; Anal. calcd. for C14 12ClN O: C, 61.43; H, 4.42; N,
6
) 12.72, 39.96,
diffusion method.
9
H
3
15.35. Found: C, 61.74; H, 4.71; N, 15.00.
4
.3.1 | Tested microbes
The Gram(+) bacterial strains S. aureus (ATTCC 6538), and B. subtilis
ATCC 663) were used for the experiment, whereas E. coli (ATTCC
739), P. aeruginosa (ATCC 9027), K. pneumoniae (ATCC 10131) and
2
‐(4‐Fluorophenyl)‐7‐phenylimidazo[1,2‐a]pyrimidin‐5(1H)‐one (9d)
(
8
S. typhi (ATCC 14028) were selected as Gram(−) bacterial strains for
this study.
4
.3.2 | Preparation of inoculums
1
White powder; yield: 33%; mp, >300°C; H‐NMR (400 MHz; DMSO‐
d
6
) 5.88 (1H, s, H‐6), 7.32–7.36 (3H, m, H‐3ʺ, H‐4ʺ, H‐5ʺ), 7.62 (2H, dd,
J = 8.4 Hz, J = 5.2 Hz, H‐3′, H‐5′), 7.49–7.50 (2H, m, H‐2ʺ, H‐6ʺ), 8.16
2H, dd, J = 8.4 Hz, J = 5.2 Hz, H‐2′, H‐6′), 8.21 (1H, s, H‐3), and
Bacterial inoculums were prepared by growing bacteria in nutrient
broth (Sigma‐Aldrich) for 24 hr at 37°C. These cell suspensions were
diluted with sterile nutrient broth to provide initial cell counts of
(
1
3
3.40 ppm (1H, br., NH); Anal. calcd. for C18H12FN O: C, 70.81; H,
4
about 10 CFU/ml.
3
.96; N, 13.76. Found: C, 70.58; H, 3.65; N, 13.43.
4
.3.3 | Preparation of synthetic compounds
4
.2
|
X‐ray crystallographic study
A stock solution of 10 mg/ml in DMSO of each compound was prepared.
Crystals were grown following the protocol developed by Hope
by dissolving the compound in CH Cl and layering with a MeOH
Single crystal X‐ray diffraction data for all
compounds were collected on Bruker APEX DUO
CCD diffractometer by using graphite‐monochromated Mo K
λ = 0.71073 Å) radiation. Crystals were mounted on a MiTeGen
2
2
[
41]
for liquid.
4.3.4 | Determination of the antibacterial activity
a
2
α
The well‐diffusion assay was used to determine and screen the
[31,32]
(
antimicrobial activity of all compounds.
Petri dishes containing
MicroMount and collected at 100(2) K by using an Oxford
Cryosystems Cobra low‐temperature device. Data were collected
by using ω and ϕ scans and were corrected for Lorentz and
20 ml nutrient agar culture medium at 50–70°C was left to solidify
under UV light (265 nm wavelength) for 15 min. Then, they were
inoculated with 0.2 ml of an overnight bacterial cell suspension
matching a 0.5‐McFarland standard solution. The suspension was
uniformly spread using a sterile swab over the surface of the medium.
Wells of 8 mm in diameter were made in the agar plates with a sterile
glass Pasteur pipette and 0.1 ml of each compound of the stock
solution was added into the wells. DMSO was used as a negative
control, whereas ampicillin and levofloxacin (10 mg/ml) were used as
positive controls. The plates were then incubated at 37°C for 24 hr.
The antimicrobial activity was assayed by measuring the diameters of
the inhibition zone formed around the wells in mm. Each assay was
performed at least in triplicate.
[
42–44]
polarization effects by using the APEX software suite.
Using Olex2, the structure was solved with the XT structure
solution program, using the intrinsic phasing solution method and
refined against │F2│ with XL using least‐squares minimiza-
[
45,46]
tion.
Hydrogen atoms were generally placed in geometri-
cally calculated positions and refined using a riding model. The
phenyl ring at C7 was modeled over two positions in a 50:50%
occupancy using the restraint SADI. The methoxy group at C16
were modeled over two positions in a 50:50% occupancy using
the constraint EADP. Further details of data collection and

ABDEL‐MOHSEN ET AL.
17 of 18
|
4
.3.5 | Determination of the minimal inhibitory
ORCID
concentration
Heba T. Abdel‐Mohsen
http://orcid.org/0000-0002-7610-8312
Amira Abood
http://orcid.org/0000-0003-0712-9889
http://orcid.org/0000-0003-1656-3177
http://orcid.org/0000-0002-7467-1654
http://orcid.org/0000-0001-7525-9437
Minimum inhibitory concentration studies of isolated compounds
were performed according to the standard reference method for
Keith J. Flanagan
Mathias O. Senge
Hoda I. El Diwani
[
31,32]
bacteria.
The Petri dishes were inoculated with the strains as
[
31,32]
described before using the microdilution method.
The tested
compounds and the positive control (ampicillin and levofloxacin)
were diluted at different concentrations ranging from 10 to 0.05 mg/
ml, and each concentration was placed in a separate well. The Petri
dishes were incubated for 24 hr at 37°C. The MIC was defined as the
lowest concentration of the compound capable of preventing the
microbial growth in the culture medium.
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Bioorganische Chemie, Institut für Chemie, Universität Hohenheim
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How to cite this article: Abdel‐Mohsen HT, Abood A,
Flanagan KJ, Meindl A, Senge MO, El Diwani HI. Synthesis,
crystal structure, and ADME prediction studies of novel
imidazopyrimidines as antibacterial and cytotoxic agents. Arch
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