Synthesis of hydantoin alkynes through palladium-catalyzed reaction, antibacterial evaluation, and molecular docking studies

Article abstract of DOI:10.1002/jccs.202000475

Novel 3-(3-(aryl)prop-2-yn-1-yl)-5,5-diphenylimidazolidine-2,4-diones were synthesized through the reaction of 5,5-diphenyl-3-(prop-2-yn-1-yl)imidazolidine-2,4-dione and aryl iodides in the presence of a palladium-copper catalytic in CH₃CN at r

Full text of DOI:10.1002/jccs.202000475

Received: 27 October 2020
DOI: 10.1002/jccs.202000475
Revised: 20 January 2021
Accepted: 21 January 2021
A R T I C L E
Synthesis of hydantoin alkynes through
palladium-catalyzed reaction, antibacterial evaluation,
and molecular docking studies
Ali Keivanloo1
| Saeed Lashkari1 | Saghi Sepehri2 | Mohammad Bakherad1
|
Sima Abbaspour1
1Faculty of Chemistry, Shahrood
Abstract
University of Technology, Shahrood, Iran
2Department of Medicinal Chemistry,
School of Pharmacy, Ardabil University of
Medical Sciences, Ardabil, Iran
Novel 3-(3-(aryl)prop-2-yn-1-yl)-5,5-diphenylimi- dazolidine-2,4-diones were
synthesized through the reaction of 5,5-diphenyl-3-(prop-2-yn-1-yl)imidazolidine-
2,4-dione and aryl iodides in the presence of a palladium-copper catalytic in
CH3CN at room temperature. All prepared compounds were examined against
the two bacterial strains, Micrococcus luteus and Pseudomonas aeruginosa and
subjected by molecular docking studies. The in silico study carried out to predict
the conformation of the examined compounds recommended that these com-
pounds could bind noticeably to key the residues at the active site of
dihydropteroate synthase. The interactive, biochemical, and in silico studies were
in concordance with each other.
Correspondence
Ali Keivanloo, Faculty of Chemistry,
Shahrood University of Technology,
Shahrood 36199-95161, Iran.
Email: akeivanloo@yahoo.com
Saghi Sepehri, Department of Medicinal
Chemistry, School of Pharmacy, Ardabil
University of Medical Sciences, Ardabil,
Iran.
Email: sepehri.saghi@yahoo.com
K E Y W O R D S
antibacterial activity, aryl iodide, imidazolidine-2,4-dione, molecular docking, palladium catalyst
Funding information
the Research Council
1 | INTRODUCTION
a hydantoin nucleus with substituents at various positions.
Thus, the synthesis of hydantoins is an extremely active
The palladium-catalyzed reaction of terminal acetylenic
compounds with aryl and vinyl halides catalyzed by
copper(I) salt in the presence of amine base has been
known as Sonogashira coupling. The Sonogashira cou-
pling is one of the most important and powerful
approaches for C C bond-forming and construction of
aryl alkynes.[1,2] Aryl alkynes are valuable intermediates
in organic synthesis and are applied for the preparation
of natural products,[3] biologically active compounds,[4]
molecular electronics,[5] and polymers.[6]
Imidazoledin-2,4-diones (hydantoins) have been
known compounds for more than a century since their
discovery.[7] Hydantoins are important nitrogen heterocy-
clic compounds in organic synthesis and pharmaceutical
chemistry. Diverse procedures have been extended for the
synthesis of hydantoins,[8] which have essentially created
area of investigation,[9] and it is necessary to develop effec-
tive methods for construction of a variety of hydantoin
derivatives with substituents at the favorite positions. It is
well-known that hydantoins are important biologically
active compounds display properties, including anti-ulcer,[10]
antitumor,[11] antiviral,[12] antibacterial,[13] antidiabetic,[14]
antiarrhythmic,[15] and anticonvulsant[16] activities. They also
have herbicidal and antifungal properties and are used for
agrochemical applications.[17] For example, hydantoins A1,
A2, and A3 used as anticonvulsant,[18] fungicidal,[16,19] and
antibacterial agents, [20] respectively (Figure 1).
Previously we reported the synthesis of new biologically
active compounds via Sonogashira reactions,[21,22] in this
research, we present the synthesis of novel 3-(3-(aryl)prop-
2-yn-1-yl)-5,5-diphenylimidazolidine-2,4-dione derivatives
through Sonogashira coupling reaction. The newly
J Chin Chem Soc. 2021;1–11.
http://www.jccs.wiley-vch.de
© 2021 The Chemical Society Located in Taipei & Wiley-VCH GmbH
1

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KEIVANLOO ET AL.
SCHEME 2 Synthesis of 5,5-diphenyl-3-(prop-2-yn-1-yl)
imidazolidine-2,4-dione (3) from the reaction of
5,5-diphenylimidazolidine-2,4-dione (1) with 3-bromoprop-1-yne
(2) in the presence of K2CO3
FIGURE 1 Examples of biologically active molecules
containing a hydantoin core
The results are outlined in Table 1. The solvents, includ-
ing CH3CN, DMSO, THF, and DMF, and the organic and
inorganic bases, including K2CO3, Cs2CO3, Et3N, and
morpholine were investigated. It was realized that
CH3CN was the best solvent and Et3N was the most effec-
tive and suitable base for the coupling reaction. More-
over, we studied several palladium catalysts, including
Pd(OAc)2, Pd(PPh3)2Cl2, and Pd/C in the presence and
absence of a copper co-catalyst. Pd(PPh3)2Cl2 was found
to be the efficient catalytic system and gave the target
product with a high reaction yield. Besides, the use of
CuI was found to be necessary for reaction progress.
When the base Et3N was replaced by K2CO3 or the sol-
vent CH3CN was replaced by DMSO, the reaction yields
decreased to 69 and 65%, respectively (Table 1, entries
1 and 7). As shown in Table 1, the desired product 5c
was produced in a 70% yield when the reaction was
accomplished in the presence of Et3N and Pd(PPh3)2Cl2/
CuI in DMF at r.t. (entry 5). In addition, the desired prod-
uct 5c was formed in a 60% yield when the reaction was
done in the presence of Cs2CO3 and Pd(OAc)2/CuI in
DMF at r.t. (entry 10). Besides, the convenient reaction
temperature was room temperature.
SCHEME 1 Synthesis of 3-(3-(aryl)prop-2-yn-1-yl)-
5,5-diphenylimidazolidine-2,4-dione (5) from the reaction of
5,5-diphenyl-3-(prop-2-yn-1-yl)imidazolidine-2,4-dione (3) and an
Aryl iodide (4)
synthesized compounds were examined for their
antibacterial activities and were exposed to the molecular
docking studies.
2 | RESULTS AND DISCUSSION
In this study, we describe the preparation of novel 3-(3-(aryl)
prop-2-yn-1-yl)-5,5-diphenylimidazolidine-2,4-dione deriva-
tives 5 by coupling reaction of 5,5-diphenyl-3-(prop-2-yn-
1-yl)imidazolidine-2,4-dione 3 with aryl iodides 4 catalyzed
by Pd(Ph3P)2Cl2 and CuI in CH3CN at room temperature
(Scheme 1).
With the results of our optimization reaction in hand,
we then investigated the scope and generality of the reac-
tion, by the reaction of 5,5-diphenyl-3-(prop-2-yn-1-yl)
imidazolidine-2,4-dione (3), with aryl iodides 4a–g in the
presence of Pd(PPh3)2Cl2 at room temperature to afford
3-(3-(aryl)prop-2-yn-1-yl)-5,5-diphenylimidazolidine-
2,4-diones 5a–g. The results are shown in Table 2.
The reaction of benzil and urea in alkaline EtOH
afforded 5,5-diphenylimidazolidine-2,4-dione (1) as
starting material.[23] the reaction of compound 1 with
propargyl bromide (2) in the presence of K2CO3 in
DMF as solvent yielded 5,5-diphenyl-3-(prop-2-yn-1-yl)
imidazolidine-2,4-dione 3 in high yield (Scheme 2).
For optimization of the reaction conditions, we
selected the reaction of 5,5-diphenyl-3-(prop-2-yn-1-yl)
imidazolidine-2,4-dione (3) and 1-iodo-4-nitrobenzene 4c
as a model system. First, we carried out the reaction
of 5,5-diphenyl-3-(prop-2-yn-1-yl)imidazolidine-2,4-dione
(1.0 mmol) with 1-iodo-4-nitrobenzene (1.2 mmol) in the
presence of Pd(Ph3P)2Cl2/CuI and Et3N, in CH3CN at
room temperature. Under this condition, the desired
product, 3-(3-(4-nitrophenyl)prop-2-yn-1-yl)-5,5-diphenyl
imidazolidine-2,4-dione 5c, was prepared in a 96% yield
(Table 1, entry 4). The effects of solvents, bases, catalysts,
and temperatures on the reaction were further examined.
The structure of new compounds 5a–g was character-
ized by spectroscopic data, mass, and elemental analysis.
1
For example, in the H-NMR spectrum for 5c, the NH
proton of imidazole ring appeared as a singlet at
δ(H) 9.79, which disappeared upon deuteration. Two
doublets were observed at δ(H) 8.18 and 7.65 characteris-
tics of the aryl group. Two phenyl groups appeared as a
multiplet at δ(H) 7.37–7.47 with 10 protons area. In the
aliphatic region, the methylene group protons appeared
as a singlet at δ(H) 4.31. In addition, the 13C NMR spec-
trum of 4a presented 14 peaks, accounting for all carbon
atoms. Molecular ion peak at m/z 411 was recorded by

KEIVANLOO ET AL.
3
TABLE 1 Effects of solvent,
catalysts, base, and temperature on the
reaction of 5,5-diphenyl-3-(prop-2-yn-
1-yl)imidazolidine-2,4-dione and 1-iodo-
4-nitrobenzene afford
Entry
1
Catalyst
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
DMF
Base
T/ꢀC
r.t
r.t
r.t
r.t
r.t
50
r.t
50
50
r.t
50
r.t
50
r.t
40
r.t
r.t
40
50
40
Yield (%)
69
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(PPh3)2Cl2/CuI
Pd(OAc)2/CuI
Pd(OAc)2/CuI
Pd(OAc)2/CuI
Pd(OAc)2/CuI
Pd(OAc)2/CuI
Pd(OAc)2/CuI
Pd(PPh3)2Cl2
K2CO3
Morpholine
Cs2CO3
Et3N
2
75
3
81
3-(3-(4-nitrophenyl)prop-2-yn-1-yl)-
5,5-diphenylimidazolidine-2,4-dionea
4
96
5
Et3N
70
6
DMF
Morpholine
Et3N
71
7
DMSO
DMSO
DMF
65
8
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Et3N
72
9
68
10
11
12
13
14
15
16
17
18
19
20
DMF
60
DMSO
DMSO
CH3CN
CH3CN
CH3CN
DMF
64
72
Cs2CO3
K2CO3
Morpholine
Et3N
65
61
54
Pd(PPh3)2Cl2
50
Pd(PPh3)2Cl2
THF
K2CO3
Cs2CO3
Morpholine
K2CO3
47
Pd(PPh3)2Cl2
DMSO
CH3CN
DMF
51
Pd/C, CuI
46
Pd/C, CuI
41
aReaction conditions: A mixture of 3 (1.2 mmol), 4 (1.0 mmol), Pd(PPh3)2Cl2 (0.05 mmol), CuI (0.1 mmol),
and base (10 mmol) in solvent (4 ml) stirred for 10 hr.
the mass spectrometer. The FT-IR and microanalysis data
were consistent with the proposed structure.
of 1,000 μg/ml in DMSO and the results were reported as
the inhibition zone in mm. All compounds showed
antibacterial activities against M. luteus and
P. aeruginosa. The structure–activity relationship in com-
pounds 5a–g showed that 5d and 5f have better inhibi-
tory activity than the others against M. luteus and
P. aeruginosa. In addition, 5b, 5d, 5e, and 5f has better
inhibitory activity than the others against M. luteus, 5d
and 5f have better inhibitory activity against
P. aeruginosa.
Mechanistically, Sonogashira coupling reaction com-
prises a general multi-step process as shown in Scheme 3.
First, the Pd(0) was formed by the in situ reductions of
Pd(II) in the reaction mixture. In continuing, oxidative
addition of aryl iodide by Pd(0) produces complex
intermediate A, followed by trans-metalation from cop-
per acetylide (B), trans-cis isomerization (C), and
reduction-elimination (D) afford final product 5.
2.1 | Antibacterial assay
2.2 | The molecular docking simulation
studies
All newly synthesized 3-(3-(aryl)prop-2-yn-1-yl)-5,-
5-diphenylimidazolidine-2,4-diones 5a–g were examined
for in vitro antibacterial activities against tow bacterial
strains, Micrococcus luteus and Pseudomonas aeruginosa
by the well diffusion method. DMSO was selected as the
negative control, displaying without activity against the
bacterial strains examined, and tetracycline was selected
as a positive control. The obtained results are shown in
Table 3. The evaluation was performed at a concentration
A crucial stage in the biosynthesis of dihydropteroate and
pyrophosphate is the condensation of 6-hydroxymethyl-7,-
8-dihydropterin pyrophosphate with para-aminobenzoic
acid (pABA) that is catalyzed by the enzyme
dihydropteroate synthase (DHP), which is a significant
biosynthetic process for micro-organisms. In the biosyn-
thesis of pyrimidines, purines, and certain amino acids in
living cells, folate derivatives are critical cofactors.[24]

4
KEIVANLOO ET AL.
TABLE 2 Synthesis of 3-(3-(aryl)prop-2-yn-1-yl)-5,5-diphenylimidazolidine-2,4-diones (5)a
Entry
Aryl iodide
Product
Melting point (ꢀC)
Yield (%)
1
105–106
90
2
3
102–103
110–111
87
96
4
98–100
82
5
6
7
106–107
115–118
120–121
80
83
81
aReaction conditions: A mixture of 5 (1.0 mmol), 6 (1.2 mmol), Pd(PPh3)2Cl2 (0.05 mmol), CuI (0.1 mmol), and base (10 mmol) in solvent (4 ml) stirred at r.t
for 12 hr.
Thus, significant goals for the design and development of
new antibacterial drugs, are most of the enzymes in the
folate biosynthesis pathway. The first efficient synthetic
antimicrobial drugs that are still extensively used in clini-
cal, are sulphonamide drugs. These drugs group as analogs
of pABA for DHP enzyme inhibit folate biosynthesis and
can so efficiently diminish the cell of folate cofactors.[25]
The synthesized compounds in this research have struc-
tural similarity with sulphonamide drugs, for example,
sulfamethoxazole (Figure 2).
2.3 | Validation of molecular docking
The presentation of a public docking technique can be
verified through testing its validation to predict the most
essential affinity of
a cognate (co-crystallographic)
ligand.[26] This technique was the presentation using
eliminating the cognate ligand and re-docking it into its
protein (self-docking). The rule of the docking validation
is Root-mean-square deviation (RMSD) of the Cartesian
coordinates of the atoms of the compound in the docked

KEIVANLOO ET AL.
5
and crystallographic conformations (RMSD < 2 Å). In
this research, sulfamethoxazole (co-crystallographic)
ligand of DHP was re-docked into protein and RMSD
value of validation of molecular docking for protein with
Protein Data Bank (PDB) ID: 3TYE obtained 0.49 Å. The
descriptions of sulfamethoxazole interaction with the
DHP active site showed six hydrogen bonds including:
Two hydrogen bonds between NH2 group at para phenyl
ring of sulfamethoxazole and carboxyl of ASP184 and car-
bonyl group of ASN120 residues, two hydrogen bonds
between oxygen atom of SO2 of ligand and amine groups
of ARG254 residue, a hydrogen bond between NH of
ligand and carboxyl group of ASP110 residue and a
hydrogen bond between NH at oxazole ring of sulfameth-
oxazole and hydroxyl group of THR67 residue. In
addition, MET145, ILE122, PHE189, and GLY64 residues
exhibited hydrophobic interactions with ligand. Suitable
interactions and strong binding with main amino acid
residues at the active site of DHP is designated by the free
binding energy values (ΔGbinding), expressed in term
kcal/mol.
2.4 | Binding mode of studied
compounds
Molecular docking results exhibited that screened com-
pounds 5a–g could inhibit DHP by hydrophobic and
hydrogen bond interactions (Tables 4 and 5).
Among the docked compounds, compounds 5e hav-
ing a methyl group at the para position of the phenyl
rings revealed the best docking score and the highest
antibacterial activity (Tables 3–5). The binding mode of
compound 5e into DHP active site was revealed in
Figure 3. The hydantoin moiety of 5e situated at the
hydrophobic pocket, enclosed using the amino acids
GLU65, ASP101, ASP61, GLY63, GLY64, ASN27, ILE25,
LEU26, and ILE62 making a strong hydrophobic binding.
Comprehensive investigation indicated that the phenyl
group of 5e made two cation-π stacking interactions
through the amino acids ARG254 and LYS220. It was
SCHEME 3 Proposed mechanism for formation of 3-(3-(aryl)
prop-2-yn-1-yl)-5,5-diphenylimidazolidine-2,4-diones from the
reaction of 5,5-diphenyl-3-(prop-2-yn-1-yl)imidazolidine-2,4-dione
and aryl iodides
FIGURE 2 Synthesized compounds (5a–g) with structural
similar to sulfamethoxazole
TABLE 3 Antibacterial activities of
Entry
Compound
Micrococcus luteus
Pseudomonas aeruginosa
selected compounds (1,000 μg/ml) as
inhibition zone in mm
1
2
3
4
5
6
7
8
9
5a
8
6
5b
41
24
41
42
41
31
—
41
12
9
5c
5d
16
10
14
9
5e
5f
5g
DMSO
Tetracycline
—
13

6
KEIVANLOO ET AL.
TABLE 4 Docking results of 5a–g derivatives docked into DHP target
Compound
5a
Hydrogen bond
Hydrophobic interaction
π-π
Cation-π
NH2 of ARG254
with O of NO2
SER218, HIS256, GLY188, THR67, LYS220, ASP101,
PHE189, ILE122, ASN120, MET145, GLY216, ASP184
—
ARG254 with ph
5b
5c
NH2 of ARG254
ILE25, LEU26, GLY63, ASN27, ILE62, ASP61, GLU65,
GLY64, ASP101, SER66, PHE189, ASN120, THR67,
ILE122, MET145
—
ARG254 with ph
LYS220 with ph
with O of C
O
NH2 of ARG254
with O of NO2
PHE222, GLY188, ASN196, ARG234, PHE189, LYS220,
ARG219, SER218, HIS256, ILE25
HIS256 with ph
PHE189 with ph
—
NH of SER221 with
O of C
O
5d
5e
NH2 of ARG254
LEU26, ILE25, GLY63, ILE62, ASN27, GLU65, THR67,
ASP61, SER66, GLY64, PHE189, ASP101, MET145,
ASN120, ILE122, ILE143, ASP184
—
—
—
with O of C
O
NH2 of ARG254
ILE25, ASN27, LEU26, ILE62, GLY64, GLU65, GLY63,
ASP61, ASP101, SER66, THR67, ILE122, PHE189,
ASN120, MET145, ASP184
ARG254 with ph
LYS220 with ph
with O of C
O
5f
NH2 of ARG254
with O of NO2
ASN196, SER221, PHE222, GLY188, LYS220, PHE189,
GLY216, ASP101, ILE122
—
—
—
5g
NH2 of ARG254
with O of NO2
NH2 of LYS220
with O of NO2
GLY188, ASN196, PHE222, PHE189, SER218, LYS220,
ARG219, HIS256
PHE189 with ph
TABLE 5 Docking results of lead compounds docked into theDHP
Compound
ΔGbind (kcal/mol)
−6.95
VHDEa (kcal/mol)
−7.64
EEb (kcal/mol)
IEc (kcal/ol)
−8.44
5a
5b
5c
5d
5e
5f
−0.80
−1.26
−1.03
−1.67
−1.27
−1.04
−0.94
−7.69
−8.52
−9.78
−7.13
−7.89
−8.92
−7.92
−8.34
−10.01
−10.22
−9.61
−8.13
−8.95
−7.52
−8.58
5g
−7.35
−7.90
−8.84
aVanderWaals-Hbond-Desolvation-Energy.
bElectrostatic Energy.
cIntermolecular Energy.
exposed that the residue ARG254 (bond length: 1.90 Å)
made a hydrogen bond with 5e, which was the main
interaction of 5e with DHP. All these interactions aided
5e to stability in the DHP active site.
According to docking results, compounds 5d and 5e
exposed the lowest free binding energy among com-
pounds. These compounds are having methoxy and
methyl groups at the para position of the phenyl
ring, respectively. Compound 5d indicated weaker
antibacterial activity and free binding energy than 5e. It
seems that the existence of hydrophilic group at the para
position of phenyl ring declines antibacterial activity and
free binding energy due to the reduction of lipophilicity.
In addition, compound 5e exhibited two cation-π stac-
king interactions with LYS220 and ARG254 residues
while compound 5d did not show any cation-π stacking
interaction. LYS220 residue in loop 2 of DHP has an
important role to stabilize the binding of pABA at the
active site.[27]
Compound 5b showed antibacterial activity and free
binding energy as well as 5d. Compound 5b is without
group on para position of the phenyl ring and decreases
lipophilicity in compared to 5d and 5e. On the other
hand, compound 5b formed two cation-π stacking inter-

KEIVANLOO ET AL.
7
FIGURE 3 Binding mode of compound 5e in the dihydropteroate synthase active site
FIGURE 4 Binding mode of
compounds 5f (a) and 5g (b) with
dihydropteroate synthase active site
actions with key residues (LYS220 and ARG254).
Whereas, 5d did not form any cation-π stacking
interaction.
phenyl ring (Figure 4). Thus, the position of groups on
the phenyl ring might be important for activity and score
docking. In addition, compound 5g formed π-π stacking
interaction with PHE189 and two hydrogen bonds with
ARG254 (bond length: 1.73 Å) and LYS220 (bond length:
2.79 Å) residues. It seems that π-π stacking interaction
and extra hydrogen bond has a negative effect.
Compounds 5a and 5c having a strong electron-
withdrawing group with the hydrophilic character on
phenyl ring displayed the weakest antibacterial activity
and free binding energy among compounds. There is
NO2 group on meta and para positions on phenyl ring in
5a and 5c, respectively (Figure 5). Compound 5a formed
a cation-π stacking interaction with ARG254 residue and
two hydrogen bonds with LYS220 (bond length: 2.12 Å)
and ARG254 (bond length: 1.83 Å) residues. Compound
5c formed two hydrogen bonds with ARG254 (bond
length: 1.61 Å) and SER221 (bond length: 2.01 Å) resi-
dues and two π-π stacking interactions with HIS256 and
PHE189 amino acids.
Compound 5f having two groups of chlorine and
nitro on para and meta position, respectively, showed
antibacterial activity similar to compounds 5b and 5d
and free binding energy lower than these two com-
pounds. Compound 5f has two electron-withdrawing
groups with lipophilic and hydrophilic characters while
compounds 5d and 5e have electron-donating group
(methyl and methoxy). Moreover, compound 5f did not
show any cation-π and π-π stacking interactions with
active site amino acids.
Compound 5g revealed poor antibacterial activity and
free binding energy than compound 5f. Both compounds
have similar groups on phenyl ring (Cl and NO2) but
positions of two groups on phenyl ring are different. In
compound 5f, chlorine and nitro groups are on para and
meta positions, respectively, while in compound 5g, chlo-
rine and nitro groups are on ortho and para positions of

8
KEIVANLOO ET AL.
FIGURE 5 Binding mode of
compounds 5a (a) and 5c (b) with
dihydropteroate synthase active site
In summary, the formation of π-π stacking interaction
Elemental analyses were performed on an Eager 300 for
EA1112 microanalyzer.
and extra hydrogen bond decreases antibacterial activity
and free binding energy of compounds (e.g., compounds
5c and 5g). While the presence of cation-π stacking inter-
action has a positive effect (e.g., compounds 5b and 5e).
All compounds formed a hydrogen bond with ARG254
residue. According to in vitro and in silico results, the
presence of electron-withdrawing and hydrophilic group
decreases antibacterial activity and free binding energy
whereas, electron-donating and the lipophilic group has
a positive effect. In addition, the position of groups on
the phenyl ring is important for activity and score dock-
ing. Finally, compounds 5b, 5d, and 5e revealed more
electrostatic interaction than other compounds (Table 5).
Then, the existence of electrostatic interaction also has a
positive effect on activity and score docking. Further-
more, the achieved in silico results mention that LYS220
and ARG254 residue were significant residues in keeping
the energetic conformations of the screened compounds
into DHP enzyme.
3.2 | Synthesis of 5,5-diphenyl-3-(prop-
2-yn-1-yl)imidazolidine-2,4-dione (3)
3-Bromoprop-1-yne (4) (1.2 mmol) was added slowly to a
stirring mixture of 5,5-diphenylimidazolidine-2,4-dione
(1) (1 mmol) and K2CO3 (1.2 mmol) in dry DMF (3 ml) at
room temperature, and stirring was continued till the dis-
appearance of compound 1 (monitored by TLC). The sol-
vent was evaporated to dryness, the residue was washed
with H2O, and dried.[28] White powder solid (95% yield):
mp, 194–195ꢀC.
3.3 | General procedure for synthesis of
3-(3-(aryl)prop-2-yn-1-yl)-
5,5-diphenylimidazolidine-2,4-dione (5a–g)
To a mixture of aryl iodides 4 (1.0 mmol) and Et3N
(4 mmol) in CH3CN (4 ml) was added 5,5-diphenyl-
3-(prop-2-yn-1-yl)imidazolidine-2,4-dione 3 (1.2 mmol)
and stirred at room temperature for 10 hr. Upon comple-
tion of the reaction (TLC), the solvent was evaporated
and solid obtained was washed with H2O and subse-
quently dried. The crude product was purified by column
chromatography (silica gel 100) using n-hexane/ethyl
acetate (97:3) as the eluent.
3 | EXPERIMENTAL
3.1 | Palladium(II) chloride and
propargyl bromide were purchased from
Sigma-Aldrich
Triphenylphosphine, N,N-dimethylformamide, triethyla-
mine, thin-layer chromatography (TLC) plates, silica gel
(particle size, 100–200 mesh), and all the solvents used
for the reactions were purchased from Merck. NMR spec-
tra were recorded on a Bruker 300 MHz 1H NMR,
75 MHz 13C spectrometer. 1H NMR spectra were reported
relative to residual CHCl3 (δ 7.26). 13C NMR spectra were
reported relative to CDCl3 (δ 77.16). IR spectra were
recorded on a Shimadzu IR-435 grating spectrophotome-
ter. Mass spectra were recorded on a 5975C spectrometer
manufactured by Agilent Technologies Company.
3.3.1 | 3-(3-(3-Nitrophenyl)prop-2-yn-
1-yl)-5,5-diphenylimidazolidine-
2,4-dione (5a)
White powder solid (90% yield): mp, 105–107ꢀC; IR
(KBr): 3,297 (NH), 3,082, 2,975, 2,926, 1,772 (C O), 1,714
(C O), 1,530 (NO2), 1,446, 1,414, 1,348 (NO2), 1,257,

KEIVANLOO ET AL.
9
1
1,200, 1,120, 870, 767 cm−1; H-NMR (300 MHz, CDCl3):
δ 4.62 (s, 2H, CH2), 7.39–7.48 (m, 11H, PhH, and ArH),
7.52 (d, J = 8.1 Hz, 1H, ArH), 7.71 (d, J = 7.8 Hz, 1H,
ArH), 8.18–8.22 (m, 1H, ArH), 8.26 (s, 1H, NH) ppm; 13C-
NMR (75 MHz, CDCl3): δ 28.9, 70.5, 81.0, 85.0, 123.4,
124.0, 126.8, 126.9, 128.8, 128.9, 129.3, 137.6, 138.8, 148.0,
155.5, 172.3 ppm; m/z [M]+ 411. Anal. calcd. for
C24H17N3O4: C, 70.07; H, 4.17; N, 10.21; found: C,
70.12; H, 4.19; N, 10.25%.
9.77 (s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ
34.2, 58.8, 69.8, 82.7, 85.9, 125.2, 127.2, 128.7, 129.0,
136.1, 140.0, 148.5, 155.3, 157.6, 173.3 ppm; m/z [M]+
396. Anal. calcd. for C25H20N2O3: C, 75.74; H, 5.09; N,
7.07; found: C, 75.82; H, 5.10; N, 7.03%.
3.3.5 | 5,5-Diphenyl-3-(3-(p-tolyl)prop-
2-yn-1-yl)imidazolidine-2,4-dione (5e)
Yellow powder solid (80% yield): mp, 106–107ꢀC; IR
(KBr): 3,312 (NH), 3,082, 2,995, 1,769 (C O), 1,712
(C O), 1,600, 1,550, 1,488, 1,446, 1,331, 1,254, 1,209,
3.3.2 | 5,5-Diphenyl-3-(3-phenylprop-
2-yn-1-yl)imidazolidine-2,4-dione (5b)
1
1,120, 1,046, 940 cm−1; H-NMR (300 MHz, DMSO-d6): δ
Yellow powder solid (87% yield): mp, 102–103ꢀC; IR
(KBr): 3,310 (NH), 3,070, 2,925, 2,847, 1,771 (C O), 1,715
(C O), 1,559, 1,532, 1,490, 1,443, 1,350, 1,252, 1,209,
2.30 (s, 3H, CH3), 4.31 (s, 2H, CH2), 7.37–7.55 (m, 14H,
PhH, and ArH), 9.79 (s, 1H, NH) ppm; 13C-NMR (75 MHz,
DMSO-d6): δ 22.8, 33.7, 69.8, 82.8, 86.1, 128.9, 131.2, 132.1,
134.8, 135.0, 137.5, 144.3, 149.0, 156.7, 173.6 ppm; m/z
[M]+ 380. Anal. calcd. for C25H20N2O2: C, 78.93; H,
5.30; N, 7.36; found: C, 78.90; H, 5.33; N, 7.40%.
1
1,174, 940, 707 cm−1; H-NMR (300 MHz, DMSO-d6): δ
4.54 (s, 2H, CH2), 7.36–7.47 (m, 15H, ArH, and ArH),
9.85 (s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ
28.9, 69.8, 82.6, 84.3, 122.0, 127.1, 128.8, 129.1, 129.2,
129.4, 131.9, 139.8, 154.7, 172.9 ppm; m/z [M]+ 366. Anal.
calcd. for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65;
found: C, 78.64; H, 4.97; N, 7.60%.
3.3.6 | 3-(3-(4-Chloro-3-nitrophenyl)prop-
2-yn-1-yl)-5,5-diphenylimidazolidine-
2,4-dione (5f)
3.3.3 | 3-(3-(4-Nitrophenyl)prop-2-yn-
1-yl)-5,5-diphenylimidazolidine-
2,4-dione (5c)
White powder solid (83% yield): mp, 115–118ꢀC; IR
(KBr): 3,300 (NH), 3,075, 2,928, 1,772 (C O), 1,712
(C O), 1,589, 1,580, 1,500 (NO2), 1,461, 1,345 (NO2),
12,365, 1,208, 1,139, 1,112, 873, 779 cm−1 1H-NMR
;
Yellow powder solid (96% yield): mp, 110–111ꢀC; IR
(KBr): 3,300 (NH), 3,050, 2,987, 1,769 (C O), 1,718
(C O), 1,597, 1,520 (NO2), 1,433, 1,345 (NO2), 1,107,
(300 MHz, DMSO-d6): δ 4.84 (s, 2H, CH2), 7.35–7.45 (m,
10H, PhH), 8.03 (d, J = 8.7 Hz, 1H, ArH), 8.30 (dd,
J = 8.8, 2.5 Hz, 1H, ArH), 8.72 (d, J = 2.4 Hz, 1H, ArH),
9.75 (s, 1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ
33.8, 69.9, 84.1, 87.5, 122.5, 125.0, 125.2, 127.2, 128.7,
129.0, 136.9, 139.4, 144.0, 148.5, 155.9, 173.3 ppm; m/z
[M]+ 445. Anal. calcd. for C24H16ClN3O4: C, 64.65; H,
3.62; N, 9.42; found: C, 64.69; H, 3.60; N, 9.45%.
1
1,043, 985, 851, 774 cm−1; H-NMR (300 MHz, DMSO-
d6): δ 4.31 (s, 2H, CH2), 7.37–7.47 (m, 10H, ArH), 7.65 (d,
J = 9 Hz, 2H, ArH), 8.18 (d, J = 8.7 Hz, 2H, ArH), 9.79 (s,
1H, NH) ppm; 13C-NMR (75 MHz, DMSO-d6): δ 28.6,
71.4, 83.5, 86.1, 128.8, 131.2, 131.4, 134.8, 135.0, 141.2,
144.5, 147.3, 156.7, 173.1 ppm; m/z [M]+ 411. Anal. calcd.
for C24H17N3O4: C, 70.07; H, 4.17; N, 10.21; found: C,
70.01; H, 4.13; N, 10.20%.
3.3.7 | 3-(3-(2-Chloro-4-nitrophenyl)prop-
2-yn-1-yl)-5,5-diphenylimidazolidine-
2,4-dione (5g)
3.3.4 | 3-(3-(4-Methoxyphenyl)prop-2-yn-
1-yl)-5,5-diphenylimidazolidine-
2,4-dione (5d)
Yellow powder solid (81% yield): mp, 120–122ꢀC; IR
(KBr): 3,298 (NH), 3,065, 2,980, 1,775 (C O), 1,712
(C O), 1,590, 1,530 (NO2), 1,491, 1,447, 1,350, 1,235,
1
White powder solid (82% yield): mp, 98–100ꢀC; IR (KBr):
3,335 (NH), 3,020, 2,965, 1,764 (C O), 1,720 (C O),
1,598, 1,530, 1,458, 1,348, 1,230, 1,100, 1,051, 980, 840,
1,134, 1,048, 820, 776 cm−1; H-NMR (300 MHz, DMSO-
d6): δ 4.88 (s, 2H, CH2), 7.37–7.43 (m, 10H, PH), 8.03 (d,
J = 9 Hz, 1H, ArH), 8.41 (dd, J = 8.7, 2.4 Hz, 1H, ArH),
8.63 (d, J = 1.8 Hz, 1H, ArH), 9.72 (s, 1H, NH) ppm; 13C-
NMR (75 MHz, DMSO-d6): δ 33.7, 69.6, 84.8, 88.2, 124.1,
126.3, 126.8, 127.8, 129.7, 129.8, 131.3, 139.5, 143.3, 148.8,
1
765 cm−1; H-NMR (300 MHz, DMSO-d6): δ 3.90 (s, 3H,
OCH3), 4.54 (s, 2H, CH2), 7.19 (d, J = 8.7 Hz, 2H, ArH),
7.35–7.38 (m, 10H, PhH), 7.99 (d, J = 9 Hz, 2H, ArH),

10
KEIVANLOO ET AL.
153.9, 173.8 ppm; m/z [M]+ 445. Anal. calcd. for
C24H16ClN3O4: C, 64.65; H, 3.62; N, 9.42; found: C,
64.72; H, 3.65; N, 9.40%.
the synthesized compounds were examined against the
tow bacterial strains Micrococcus luteus and Pseudomonas
aeruginosa. According to the results obtained, com-
pounds 5b, 5d, 5e, and 5f have the most inhibitory activ-
ity against M. luteus and 5d and 5f have better inhibitory
activity than the others against P. aeruginosa. The molec-
ular docking study carried out to predict the conforma-
tion of the tested compounds recommended that these
compounds could bind noticeably to key the residues at
the active site of DHP.
3.4 | Molecular docking study
Computer-simulated docking studies were accomplished
by the AutoDock 4.2.[29] Lamarckian Genetic Algorithm of
the AutoDock 4.2 program was used as the search algo-
rithm.[30] The Graphical User Interface program
AutoDock Tools 1.5.6 (ADT) was used to prepare, run,
and analyze the docking simulations. Molecular docking
of compounds was performed with crystal structure DHP
(PDB ID: 3TYE) by the Auto-Dock Tool 1.5.6. All two-
dimensional (2D) structures of the compounds were built
using the ChemDraw program (ChemDraw Ultra 10.0,
Cambridge soft.), and then moved into the Hyperchem 8.0
software (HyperChem, Release 8.0 for Windows, Molecu-
lar Modeling System: HyperCube, 2007). Molecules were
subjected to energy minimization with MM+ force field
and then PM3 semi-empirical technique. Then the partial
charges of atoms were calculated by the Gasteiger–Marsili
procedure implemented in the AutoDock Tools package.
The non-polar hydrogens of compounds were merged.
The crystal structures of protein were taken from the Pro-
tein Data Bank (www.rcsb.org). All bound water and
ligands were eliminated from the protein, and polar
hydrogen atom was added to the protein as it was required
for the electrostatic interactions, and then non-polar
hydrogen atoms were merged. In all dockings, a grid map
with 60 grid points in the X, Y, and Z directions was built.
Among the three different search algorithms offered by
AutoDock 4.2, the Lamarckian genetic algorithm
approach was applied. For all docking procedures,
150 independent runs with the step sizes of 0.2 Å for trans-
lations and 5ꢀ for orientations and torsions were consid-
ered. For the Lamarckian GA method, a maximum
number of 25 × 105 energy evaluations; 27,000 maximum
generations; a gene mutation rate of 0.02; and a cross-over
rate of 0.8 were used. At the end of the docking, the struc-
tures were ranked by energy. Ligand-receptor interactions
were all visualized based on docking results using Discov-
ery Studio Visualizer 4.0 and Ligplus 2012.
ACKNOWLEDGMENTS
The authors wish to express their thanks to the Research
Council of Shahrood University of Technology for the
financial support of this research work.
ORCID
Ali Keivanloo https://orcid.org/0000-0003-1430-7399
REFERENCES
[1] K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett.
1975, 16, 4467.
[2] T. Hundertmark, A. F. Littke, S. L. Buchwald, G. C. Fu, Org.
Lett. 2000, 2, 1729.
[3] I. Paterson, R. D. M. Davies, R. Marquez, Angew. Chem. 2001,
113, 623.
[4] M. Kort, V. Correa, A. R. P. M. Valentijn, G. A. Marel, B. V. L.
Potter, C. W. Taylor, J. H. Boom, J. Med. Chem. 2000, 43, 3295.
[5] O. Mongin, L. Porres, L. Moreaux, J. Mertz, M. Blanchard-
Desce, Org. Lett. 2002, 4, 719.
[6] O. Mongin, C. Papamicael, N. Hoyler, A. Gossauer, J. Org.
Chem. 1998, 63, 5568.
[7] A. Baeyer, Justus Liebigs Ann. Chem. 1861, 119, 126.
[8] (a) D. M. Whitehead, F. L. Strat, S. J. Conway, Org. Biomol.
Chem. 2008, 6, 988. (b) D. Sergent, Q. Wang, A. N. Sasaki, J.
Ouazzani, Bioorg. Med. Chem. Lett. 2008, 18, 4332.
[9] (a) S. M. Dumbris, D. J. Díaz, L. McElwee-White, J. Org. Chem.
2009, 74, 8862. (b) S. Werner, D. M. Turner, P. G. Chambers,
K. M. Brummond, Tetrahedron 2008, 64, 6997.
[10] D. Zhang, D. Ye, E. Feng, J. Wang, J. Shi, H. Jiang, H. Liu,
J. Org. Chem. 2010, 75, 3552.
[11] C. A. Kumar, S. N. Swamy, K. Sugahara, K. S. Rangappa, Bio-
org. Med. Chem. 2009, 17, 4928.
[12] P. T. Todorov, E. D. Naydenova, C. R. Chim. 2010, 13, 1424.
[13] A. Mandal, R. S. G. Krishnan, S. Thennarasu, S. Panigrahi,
A. B. Mandal, Colloids Surf. B Biointerfaces 2010, 79, 136.
[14] A. Volonterio, A. C. de Ramirez, M. Zanda, J. Org. Chem.
2005, 70, 2161.
[15] Y. Brouillette, V. Lisowski, J. Guillon, S. Massip, J. Martinez,
Tetrahedron 2007, 63, 7538.
4 | CONCLUSIONS
[16] A. Alizadeh, E. Sheikhi, Tetrahedron Lett. 2007, 48, 4887.
[17] Y. D. Gong, H. Y. Sohn, M. J. Kurth, J. Org. Chem. 1998, 63, 4854.
We have successfully synthesized a variety of biologically
ꢀ ꢀ ꢀ
[18] N. Trišovic, T. Timic, J. Divljakovic, J. Rogan, D. Poleti, M. M.
active
novel
3-(3-(aryl)prop-2-yn-1-yl)-5,5-diphenyl
ꢀ
ꢀ
ꢀ
Savic, G. Ušcumlic, Monatsh. Chem. 2012, 143, 1451.
[19] J. Marton, J. Enisz, S. Hosztafi, T. Timar, J. Agric. Food Chem.
1993, 41, 148.
imidazolidine-2,4-diones from 5,5-diphenyl-3-(prop-2-yn-
1-yl)imidazolidine-2,4-dione and aryl iodides via
Sonogashira coupling in high to excellent yields. All of

KEIVANLOO ET AL.
11
[20] V. M. Patel, K. R. Desai, Indian J. Chem. 2005, 44B, 1084.
[21] (a) A. Keivanloo, S. Abbaspour, M. Bakherad, B. Notash,
Chem. Select. 2019, 4, 1366. (b) T. Besharati-Seidani, A.
Keivanloo, B. Kaboudin, A. Yoshida, T. Yokomatsu, Tetrahe-
dron 2017, 74, 2350.
[22] A. Keivanloo, S. S. Kazemi, H. Nasr-Isfahani, A. Bamoniri,
Mol. Divers. 2017, 21, 29.
[23] C. A. Lopez, G. G. Trigo, Adv. Heterocycl. Chem. 1985, 38, 177.
[24] P. Kellam, W. S. Dallas, S. P. Ballantine, C. J. Delves, FEMS
Microbiol. Lett. 1995, 134, 165.
[29] S. Sepehri, L. Saghaie, A. Fassihi, Mol. Inform. 2017, 36, 1600060.
[30] G. M. Morris, D. S. Goodsell, R. S. Halliday, R. Huey, W. E. Hart,
R. K. Belew, A. J. Olson, J. Comput. Chem. 1998, 19, 1639.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
[25] H. G. Vinnicombe, J. P. Derrick, Biochem. Biophys. Res.
Commun. 1999, 258, 752.
How to cite this article: Keivanloo A, Lashkari S,
Sepehri S, Bakherad M, Abbaspour S. Synthesis of
hydantoin alkynes through palladium-catalyzed
reaction, antibacterial evaluation, and molecular
docking studies. J Chin Chem Soc. 2021;1–11.
https://doi.org/10.1002/jccs.202000475
[26] N. Borazjani, S. Sepehri, M. Behzadi, A. Jarrahpour, J. A. Rad,
M. Sasanipour, M. Mohkam, Y. Ghasemi, A. R. Akbarizadeh,
C. Digiorgio, J. M. Brunel, Eur. J. Med. Chem. 2019, 179, 389.
[27] M. K. Yun, Y. Wu, Z. Li, Y. Zhao, M. B. Waddell, A. M. Ferreira,
R. E. Lee, D. Bashford, S. W. White, Science 2012, 335, 1110.
[28] S. Abbaspour, A. Keivanloo, M. Bakherad, S. Sepehri, Chem.
Biodivers. 2019, 16, e1800410.