Preparation of some novel thiazolidinones, imidazolinones, and azetidinone bearing pyridine and pyrimidine moieties with antimicrobial activity

Article abstract of DOI:10.1002/jhet.4009

By aiming to design new antimicrobial agents, we prepared new series of thiazolidin-4-ones(12a–d), imidazolin-4-ones(13a–d), and azetidin-2-ones (14a–d), having pyridine and pyrimidine moieties. Chemical structures of these derivatives were elucidated by

Full text of DOI:10.1002/jhet.4009

Received: 25 November 2019
DOI: 10.1002/jhet.4009
Revised: 10 April 2020
Accepted: 20 April 2020
A R T I C L E
Preparation of some novel thiazolidinones, imidazolinones,
and azetidinone bearing pyridine and pyrimidine moieties
with antimicrobial activity
Rania B. Bakr1,2
| Nadia A. A. Elkanzi3,4
1Department of Pharmaceutical
Abstract
Chemistry, College of Pharmacy, Jouf
University, Sakaka, Kingdom of Saudi
Arabia
By aiming to design new antimicrobial agents, we prepared new series of
thiazolidin-4-ones(12a–d), imidazolin-4-ones(13a–d), and azetidin-2-ones
(14a–d), having pyridine and pyrimidine moieties. Chemical structures of
these derivatives were elucidated by the use of spectral and elemental analyses.
All the new substituted pyridopyrimidines were subjected to in vitro antimi-
crobial testing by estimating the zone of inhibition toward Bacillus subtilis and
Staphylococcus aureus, as examples of bacterial species, in addition to Aspergil-
lus flavus and Candida albicans, as examples of fungal species. The results of
antimicrobial testing detected that all the screened derivatives displayed
antibacterial effect; especially azetidin-2-one derivative, (14c), was the most
active one. Regarding the antifungal potential, only thiazolidinone derivatives,
12a and 12c, and the imidazolinone, 13c, displayed inhibitory activity toward
Aspergillus flavus, while all the tested compounds, 12a–d, 13a–d, and 14a–d,
except 14a, produced inhibitory potential toward Candida albicans. Docking
studies of the most active antimicrobial agents, 12c, 13c, and 14c, within GLN-
6-P, recorded good scores with several binding interactions with the active site.
2Department of Pharmaceutical Organic
Chemistry, Faculty of Pharmacy, Beni-
Suef University, Beni-Suef, Egypt
3Chemistry Department, College of
Science, Jouf University, P.O. Box: 2014,
Sakaka, Saudi Arabia
4Chemistry Department, Faculty of
Science, Aswan University, P.O. Box:
81528, Aswan, Egypt
Correspondence
Rania B. Bakr, Department of
Pharmaceutical Organic Chemistry,
Faculty of Pharmacy, Beni-Suef
University, Beni-Suef 62514, Egypt.
Email: raniabakr@ymail.com;
rbbakr@ju.edu.sa
1 | INTRODUCTION
anticoagulant,[20,21] and antimicrobial.[22–25] For example,
Bis-(substituted tetramide)pyridine derivative, 4, is synthe-
Pyrimidine moiety is still recording a great importance for
medicinal chemists, due to its biological potential as
antiproliferative,[1,2] antihypertensive,[3] hypnotic,[4] anti-
inflammatory,[5–7] and antimicrobial.[8–10] Shaaban et al[11]
prepared new pyrimidine derivative, 1,(Figure 1) which
recorded half potency (12.5 μg/mL) of levoxacin (25 μg/mL)
against P. aeruginosa and P. vulgaris. In addition,
6-phenylthiopyrimidine derivatives, 2a–c, recorded excellent
antifungal effect toward A. flavus and A. niger.[12] In addition,
the pyrimidine derivative, 3, revealed good antifungal activ-
ity, with MIC = 15 μg/mL, compared to fluconazole
(MIC = 10 μg/mL).[13] Pyridine derivatives are the main con-
stituents in many biologically active compounds as
anticancer,[14,15] anti-inflammatory,[16,17] antiallergic,[18,19]
sized and subjected to antimicrobial tests. The results
recorded that compound, 4, exhibited higher inhibitory activ-
ity than ciprofloxacin toward B. subtilis and S. aureus.[26] In
2018, the triazolopyridine compounds, 5 and 6, are docu-
mented to exert the same antibacterial effect toward
B. subtilis as streptomycin with MIC = 25 μg/mL.[27] More-
over,
some
five-membered
heterocycles,
as
thiazolidinones[28,29] and imidazolinones,[30,31] and the four-
membered azetidinones[32] are incorporated in many antimi-
crobial agents. Depending on these facts and on our previous
studies,[33–39] we decided to prepare series of novel
pyridopyrimidine derivatives and evaluate these candidates
for their antimicrobial activity. Our rational based upon com-
bining the pyridine ring with the widely documented
J Heterocyclic Chem. 2020;1–13.
wileyonlinelibrary.com/journal/jhet
© 2020 Wiley Periodicals LLC.
1

2
BAKR AND ELKANZI
O
R
N
FIGURE 1 Chemical structures of
some reported pyrimidines (1-3) and
pyridines (4-6) as antimicrobial agents,
and the designed compounds, (12a–d),
(13a–d), and (14a–d)
H
2a, R = 3CH3
2b, R = 4CH3
2c, R = 4F
N
O
N
O
S
N
O
N
NH
H2N
O
CN
R
SPh
O
(1)
(2a-c)
O
OH
O
O
O
S
HN
N
N
NH
N
N
Cl
N
F
(3)
NH HN
S
O
(4)
N
N
N
N
N
N
N
N
Cl
Cl
(5)
H3CO
(6)
Cl
S
NH
O
X
X
X
O
O
N
N
N
N
N
N
N
N
N
N
N
X
N
X
X
(14a-d)
(13a-d)
(12a-d)
antimicrobial pyrimidine scaffold in one hybrid, is an
attempt to increase the antimicrobial activity of the target
compounds. Furthermore, we thought to make structure
extension by introducing thiazolidinones, imidazolinones,
and/or azetidinones at C-2 of pyrimidine scaffold, aiming at
a synergistic effect and potent anti-microbial activity
(Figure 1).
N-pyridine-2-yl-acrylamide derivatives, 9a–d, were syn-
thesized by reacting the appropriate aldehydes, 7a–d,
with N-(pyridin-2-yl)acetamide, (8), under basic condi-
tions. Coupling these pyridinacrylamides, 9a–d, with
guanidine nitrate followed by condensation with aro-
matic aldehydes, 7a–d, produced benzylidene derivatives,
11a–d. Cyclizing the benzylidene derivatives, 11a–d, with
thioglycolic acid, in the presence of zinc chloride, in diox-
ane for 7-9 hours provided the thiazolidin-4-ones (12a–d)
in 52% to 69% yield. In addition, refluxing the key inter-
mediates, 11a–d, with glycine, in toluene, for 8 to
10 hours produced the target imidazolin-4-one deriva-
tives, 13a–d. Finally, the azetidin-2-ones, 14a–d, were
obtained in high yield by cyclizing benzylidene deriva-
tives, 11a–d, with chloroacetyl chloride, for 2 to 4 hours
2 | DISCUSSION
2.1 | Chemistry
The synthesis of the targets pyridopyrimidine derivatives,
(12a–d), (13a–d), and (14a–d), are explained in Scheme 1.

BAKR AND ELKANZI
3
SCHEME 1 Preparation of
thiazolidin-4-ones(12a–d),
imidazolin-4-ones(13a–d) and
azetidin-2-ones(14a–d)
CHO
NH2
N
NH
.HNO3
H2N NH2
N
O
H
O
N
N
CH3
C
N
N
H
X
7a-d
N
H
X
8
X
9a-d
10a-d
S
X
O
N
CH2COOH
SH
CHO
N
N
N
12a-d
ZnCl2 anhydrous
X
7a-d
X
X
CH2COOH
NH2
NH
X
O
N
N
N
N
CH
13a-d
14a-d
N
X
N
N
N
X
Cl
N
O
X
11a-d
ClCOCH2Cl
N
N
11a, X=H
11b, X=OH
11c, X=Cl
N
X
11d, X=N(CH3)2
using dioxane as a solvent. The chemical constitution of
these targets was proved by spectral and elemental
analyses.
signals at 3.22 to 3.61 ppm due to imidazoline CH2 and
singlet signals at 6.23 to 5.97 ppm corresponding to imi-
dazoline CH. Regarding the chemical elucidation of the
target compounds, 14a–d, IR proved the presence of
IR spectrum of compound, 9b, demonstrated the pres-
ence of NH and OH functional groups at 3376 to
1
C O peak at 1670 to 1680 cm−1 and HNMR detected
1
3267 cm−1. Moreover, HNMR of this derivative, 9b, rev-
the appearance of two CH protons of azetidinone ring at
C-3 and C-4 as doublet signals at 4.42 to 5.12 ppm.
ealed the appearance of doublet peak at 7.63 ppm
corresponding to CH, in addition to the presence of a
singlet signal at 12.12 ppm concerned with OH group.
The formation of the benzylidene derivatives, 11a–d, was
elucidated by IR spectra, which confirmed the absence of
2.2 | Antimicrobial evaluation
NH2 peaks of compounds, 10a–d, at 3425 to 3210 cm−1
,
The novel target pyridopyrimidines, 12a–d, 13a–d, and 14a–
d, were subjected to antibacterial activity test against Bacillus
subtilis and Staphylococcus aureus, using ampicillin as a
standard. Moreover, they were also screened for their
in vitro antifungal effect against Aspergillus flavus and Can-
dida albicans, by the use of amphotericin as a standard, by
measuring inhibition zone diameter. It was observed that
3-chloro-4-(4-chlorophenyl)-1-(4-(4-chlorophenyl)-6-pyridin-
2-yl-2,5-dihydropyrimidin-2-yl-2,5-dihydropyrimidin-
2-yl)azetidin-2-one, (14c), exhibited the highest
antibacterial activity followed by 13c and 12c toward Bacil-
lus subtilis and Staphylococcus aureus. Moreover, com-
pounds, 12a, 12d, 13a, 13b, and 14b, demonstrated half the
activity of ampicillin against Bacillus subtilis. Structure
activity relationship of these tested compounds, 12a-d,
in addition, the appearance of azomethine proton at 8.26
1
to 8.75 ppm in HNMR spectra of these derivatives, 11a–
d, also ascertained the structures. The formation of the
pyrimidothiazolidine compounds, 12a–d, was elucidated
by the presence of C O peak, in the range of 1670 to
1679 cm−1, in the IR spectra. 1HNMR charts recorded the
appearance of doublet of doublet peak at 3.27 to
3.46 ppm, indicating CH2 of thiazolidine moiety, in addi-
tion to the appearance of the single signal of
thiazolidinone CH at 5.33 to 5.37 ppm. Furthermore, IR
spectra of the pyrimidoimidazolinones, 13a–d, revealed
the appearance of NH and C O groups in the region,
3410 to 3314 cm−1 and 1682 to1674 cm−1, sequentially. In
addition, 1HNMR demonstrated doublet of doublet

4
BAKR AND ELKANZI
13a–d, and 14a–d, against the two used bacterial species
recorded that the presence of the four-membered azetidin-
2-one ring at C-2 of pyrimidine ring showed higher
antibacterial activity than the presence of the five-
membered ring, thiazolidin-4-one and/or imidazoline-
4-one. This is obvious in compound, 14c, (zone of inhibi-
tion = 20 mm and 17 mm) which exhibited better
antibacterial activity than the five-membered derivatives,
13c (zone of inhibition = 17 mm and 16 mm) and 12C
(zone of inhibition = 15 and 16 mm). In addition, the tar-
get compounds, having electron withdrawing substituent
at para position of both phenyl rings (12c, 13c, and 14c),
revealed higher antibacterial activity (zone of inhibi-
tion = 20-15 mm) than other target compounds incorpo-
rating electron donating substituents (zone of
inhibition = 13-10 mm). Regarding the antifungal poten-
tial, only the thiazolidinone derivative, 12a and 12c, and
the imidazolinone, 13c, recorded antifungal activity
toward Aspergillus flavus, while all the pyridopyrimidines,
12a–d, 13a–d, and 14a–d, except 14a, displayed antifungal
potential against Candida albicans. Furthermore, the
target pyridin-2-yl-2,5-dihydropyrimidin-2-ylthiazolidin-
4-one, (12c) demonstrated more activity against Candida
albicans than the standard drug amphotericin B. From the
data of antifungal activity against Candida albicans, it was
obvious that introducing a five-membered ring, as
thiazolidinone, in compound, 12c, or imidazolinone in
compound, 13c, increased the antifungal activity than
azetidinone moiety as shown by compound, 14c. In addi-
tion, the incorporation of electron withdrawing substituent
at para position of both phenyl rings (12c, 13c, and 14c)
revealed higher antifungal potential than the other tested
derivatives (Table 1).
2.3 | Docking study
To detect the mode of antimicrobial potential of the
newly designed target compounds, we docked the most
active candidates, 12c, 13c, and 14c, into the active site of
glucosamine-6-phosphate synthase enzyme (GlcN-6-P),
using MOE, 2010, Version 8, Chemical Computing Group
Inc. This enzyme is essential for cell wall synthesis by
transporting ammonia to fructose-6-phosphate from
L-glutamine followed by isomerizing the product to
glucosamine-6-phosphate.[40,41] We downloaded X-ray
crystal of GlcN-6-P structure from protein data bank
(PDB: ID 1gdo). Docking was validated by redocking the
co-crystallized ligand with rmsd <2.
The data obtained from docking the most active
pyridopyrimidines, 12c, 13c, and 14c, inside GlcN-6-P,
including hydrogen bondings, energy scores, and the
essential functional groups, are listed in Table 2.
The novel pyridin-2-ylpyrimidin-2-ylthiazolidin-4-one
derivative, (12c), was detected to make two hydrogen
binding interactions, with Gly99 and Ser176, in addition
to performing two arene-arene interactions with Trp74
and His97 (Figure 2).
On
the
other
hand,
pyridin-2-ylpyrimidin-
2-ylimidazolin-4-one, (13c), exhibited four hydrogen bonds
within the active site between: (a) Trp 74 and imidazolin
NH, (b) Gly99 and imidazolin C O, (iii) Gly99 and
TABLE 1
Antimicrobial evaluation of the newly synthesized compounds, 12a–d, 13a–d, 14a–d, ampicillin and amphotericin B.
Bacterial species
Fungi
Compound no.
Bacillus subtilis
26 0.1
Staphylococcus aureus
22 0.09
-
Aspergillus flavus
Candida albicans
-
Ampicillin
-
Amphotericin B
-
15 0.08
19 0.09
11 0.07
11 0.22
21 0.18
11 0.09
12 0.16
12 0.22
16 0.25
12 0.23
0
12a
12b
12c
12d
13a
13b
13c
13d
14a
14b
14c
14d
13 0.60
11 0.14
15 0.20
13 0.11
13 0.09
13 0.13
17 0.21
10 0.24
12 0.11
13 0.22
20 0.62
10 0.07
13 0.06
11 0.21
16 0.11
13 0.21
13 0.22
12 0.18
16 0.26
10 0.08
11 0.24
13 0.22
17 0.07
10 0.18
10 0.15
0
14 0.09
0
0
0
10 0.12
0
0
0
0
0
14 0.21
15 0.15
12 0.12

BAKR AND ELKANZI
5
TABLE 2
Docking results of compounds, 12c, 13c, and 14c, inside GLN-6-P enzyme (PDB: 1gdo)
Compound no.
Affinity Kcal/mol
No. of hydrogen bonds
Distance (Å) from main residue
Functional group
12c
−16.89
2
Ser176
Gly99
2.50
2.13
Thiazolidinone CO
Pyrimidine N
13c
14c
−15.76
−13.06
4
2
Trp74
Gly99
Cys1
2.15
2.89
3.02
2.99
Imidazolinone NH
Imidazolinone CO
Imidazolinone CO
Imidazolinone NH
Trp74
Cys1
Gly99
2.10
2.38
Azetidinone CO
Pyrimidine N
FIGURE 2 3D and 2D binding modes of the pyridopyrimidinthiazolidin-4-one (12c) inside GLN-6-P enzyme
imidazolin C O, (iv) Trp 74 and imidazolin NH, and
(v) Cys1 and imidazolin C O (Figure 3).
MS-5988 spectrometer (Palo Alto, CA) at 70 electron volt.
Elemental analyses were measured at Cairo University in
Micro-analytical Center, Egypt. Elemental and IR analyses
results in addition to molecular formula of all the newly
constructed compounds are shown in Table 3.
Furthermore,
pyridin-2-yl-2-yl-pyrimidin-
2-ylazetidin-2-one, (14c), demonstrated two hydrogen
bindings, through Cys1 and Gly99 amino acids, and one
arene-arene interaction, with Trp74 (Figure 4).
N-(pyridin-2-yl)acetamide (8).[42] To a solution of
2-aminopyridine (10 mmol) and triethylamine (10 mmol)
in chloroform (20 mL), acetyl chloride (10 mmol) was
added, dropwise, with stirring at 5ꢀC. The mixture was
stirred at room temperature for 2 hours. The reaction
mixture was poured on ice cold water, and the organic
layer was isolated and dried over sodium sulfate, then the
chloroform was evaporated, and the product was crystal-
lized by ethyl acetate/ hexane (1:10).
3 | MATERIALS AND METHODS
3.1 | Chemistry
3.1.1 | General methods
All the chemicals used during this study were brought from
Sigma-Aldrich, Kingdom of Saudi Arabia. Silica gel, pre-
coated with F254Merck plates, was utilized (Darmstadt, Ger-
many) to detect the reaction progress. Gallenkamp electro
melting point apparatus (Weiss-Gallenkamp, Loughbor-
ough, UK) was used to record melting points and are not
accurate. Bruker-Vector 22 Fourier transform spectropho-
tometer (Billerica, MA) was used to record IR spectra. The
1H NMR and 13C NMR spectra were obtained with a
VarianMercuryVXR-300 NMR spectrometer (Palo Alto, CA).
Charts of mass had been measured on a Hewlett Packard
General synthesis of compounds9a–d. A mixture of dif-
ferent aromatic aldehydes, 7a–d, (0.01 mol) and
4
3
5
O
H
2
2
5
C
6
1
N
N
3
1
H
4
6
X

6
BAKR AND ELKANZI
FIGURE 3 3D and 2D binding modes of the pyridopyrimidinimidazolin-4-one (13c) inside GLN-6-P enzyme
FIGURE 4 3D and 2D binding modes of the pyridopyrimidinazetidin-2-one (14c) inside GLN-6-P enzyme
N-(pyridin-2-yl)acetamide, 8, (0.01 mol) in the presence
of sodium hydroxide (0.02 mol) was grounded in mortar,
with pestle, till the fine powder was obtained, which
detected by TLC. The solid product formed was poured in
cold water followed by acidification by dilute
hydrochloric acid till the pH value reached 5 to 6, then
the mixture was stirred for 30 minutes and solid was fil-
tered, dried, and recrystallized from ethanol to produce,
9a–d.
5H), 7.31 (d, J = 8.05 Hz, H-2\, 6\, 2H), 7.54 (d,
J = 8.32 Hz, H-4, 1H), 7.63 (d, J = 15.62 Hz, CH, 1H),
8.12 (d, J = 8.32 Hz, H-6, 1H), 10.83 (s, NH, 1H), 12.12 (s,
OH, exchanged with D2O, 1H); 13C NMR (DMSO-d6):
110.21 (C-3), 114.32 (C-5), 115.60 (C-3\, 5\), 121.54
(O C C H), 128.11 (C-2\, 6\), 128.84 (C-4\), 133.46 (C-
1\), 137.01 (C-4), 142.54 ( C H), 148.66 (C-5), 161.22 (C-
2), 162.89 (C O); EI-MS m/z (% rel. Abund.): 240.
[M+, 20].
3-Phenyl-N-pyridin-2-yl-acrylamide (9a).[43] Solid:
3-(4-Chlorophenyl)-N-pyridin-2-yl-acrylamide (9c).[44]
Solid: Yield: 68%; M.p.: 152ꢀC-154ꢀC; 1H NMR (δ, DMSO-
d6): 6.69-6.80 (m, H-5, 3, CH C O, 3H), 7.20-7.23 (m, H-
2\, 6\, 3\, 5\, 4H), 7.51 (d, J = 8.52 Hz, H-4, 1H), 7.61 (d,
J = 15.19 Hz, CH, 1H), 8.14 (d, J = 8.15 Hz, H-6, 1H),
10.15 (s, NH, exchanged with D2O, 1H); 13C NMR
(DMSO-d6): 108.97 (C-3), 111.22 (C-5), 117.43
(O C C H), 127.82 (C-2\, 6\), 128.53 (C-3\, 5\), 133.11
(C-4\), 133.78 (C-1\), 137.98 (C-4), 142.05 ( C H), 148.43
(C-5), 161.74 (C-2), 162.71 (C O); EI-MS m/z (% rel.
Abund.): 258 [M+, 19].
1
Yield: 67%; M.p.: 115ꢀC-117ꢀC; H NMR (δ, DMSO-d6):
6.69-6.77 (m, H-3, 5 and CH C O, 3H), 7.18-7.20 (m, H-
3\, 4\, 5\, 3H), 7.33 (d, J = 8.21 Hz, H-2\, 6\, 2H), 7.51-7.59
(m, H-4, 6, 2H), 7.62 (d, J = 15.57 Hz, CH, 1H), 10.54
(s, NH, exchanged with D2O, 1H); 13C NMR (DMSO-d6):
110.43 (C-3), 114.55 (C-5), 121.78 (O C C H), 127.32
(C-2\, 6\), 128.51 (C-4\), 128.97 (C-3\, 5\), 133.54 (C-1\),
137.21 (C-4), 142.21 ( C H), 148.52 (C-5), 161.22 (C-2),
162.21 (C O); EI-MS m/z (% rel. Abund.): 224 [M+, 25].
3-(4-Hydroxyphenyl)-N-pyridin-2-yl-acrylamide
1
(9b).[43,44] Solid: Yield: 67%; M.p.: 130ꢀC-132ꢀC; H NMR
3-(4-Dimethylaminophenyl)-N-pyridin-2-yl-acrylamide
(δ, DMSO-d6): 6.67-6.81 (m, H-5, 3, CH C O, H-3\, 5\,
(9d).[45] Solid: Yield: 72%; M.p.: 166ꢀC-168ꢀC; H NMR
1

BAKR AND ELKANZI
7
TABLE 3
Data of elemental analyses, mass, molecular formula, percentage yield, and melting points of all the constructed compounds
Elem. analyses calculated (Found)
Molecular
Compound formula
M.
wt.
IR: ν (cm−1
)
C
H
N
9a
9b
C14H12N2O
C14H12N2O2
224.26 1654 (C O), 3044 (
C
C
H), 3267 (N H)
H), 3376-3267
74.98 (75.11) 5.39 (5.21) 12.49 (12.70)
69.99 (70.21) 5.03 (5.12) 11.66 (11.70)
240.26 1651 (C O), 3029 (
(N H and O H)
9c
C14H11ClN2O
258.71 IR: ν (cm−1), 1654 (C O), 3041 (
C
H),
65.00 (65.23) 4.29 (4.00) 10.83 (11.13)
3374 (N H)
9d
C16H17N3O
C15H14N4
267.33 1657 (C O), 3039 (
C
H), 3325 (N H)
71.89 (71.55) 6.41 (6.02) 15.72 (15.99)
71.98 (71.56) 5.64 (5.50) 22.38 (22.14)
67.65 (67.78) 5.30 (5.55) 21.04 (21.34)
63.27 (63.55) 4.60 (5.00) 19.68 (20.03)
69.60 (69.79) 6.53 (6.68) 23.87 (24.00)
78.08 (78.28) 5.36 (5.20) 16.56 (16.44)
71.34 (71.30) 4.90 (4.66) 15.13 (15.00)
10a
10b
10c
10d
11a
11b
250.31 3047 (
266.31 3047 (
284.75 3121 (
293.37 3145 (
338.42 3119 (
C
C
C
C
C
H), 3319, 3267 (NH2)
H), 3425-3210 (NH2 and OH)
H), 3410-3244 (NH2)
C15H14N4O
C15H13ClN4
C17H19N5
H), 3343-3256 (NH2)
C22H18N4
H), 2943 (CH aliphatic)
C22H18N4O2
370.41 3424-3261 (2OH), 3119 (
aliphatic)
C H), 2943 (CH
11c
11d
12a
C22H16Cl2N4
C26H28N6:
407.31 3078 (
424.55 3097 (
412.52 3108 (
C
C
C
H aromatic), 2939 (CH aliphatic)
H aromatic), 2934 (CH aliphatic)
H aromatic), 2939 (CH aliphatic),
64.88 (64.55) 3.96 (4.05) 13.76 (14.05)
73.56 (73.33) 6.65 (6.50) 19.79 (19.54)
69.88 (69.50) 4.89 (5.10) 13.58 (13.29)
C24H20N4OS
1671 (C O)
12b
12c
12d
13a
13b
13c
13d
14a
14b
14c
14d
C24H20N4O3S
C24H18Cl2N4OS
C28H30N6OS
C24H21N5O
444.52 3421-3263 (2OH), 3119 (
C
H aromatic),
64.85 (65.20) 4.54 (4.86) 12.60 (12.20)
59.88 (59.60) 3.77 (3.98) 11.64 (11.42)
67.44 (67.50) 6.06 (6.20) 16.85 (16.72)
72.89 (73.00) 5.35 (5.60) 17.71 (17.66)
67.44 (67.24) 4.95 (5.00) 16.38 (16.45)
62.08 (62.00) 4.12 (4.28) 15.08 (15.32)
69.83 (70.00) 6.49 (6.32) 20.36 (20.50)
69.48 (69.58) 4.62 (4.55) 13.50 (13.78)
64.50 (64.57) 4.29 (4.39) 12.54 (12.70)
59.58 (60.00) 3.54 (3.77) 11.58 (11.50)
67.12 (67.10) 5.83 (5.60) 16.77 (16.95)
2943 (CH aliphatic), 1679 (C O)
481.41 3072 (
C
H aromatic), 2940 (CH aliphatic),
1670 (C O)
498.65 3082 (
C
H aromatic), 2892 (CH aliphatic),
1677 (C O)
395.64 3314 (N H), 3123 (
C H aromatic), 2944
(C H aliphatic), 1674 (C O)
C24H21N5O3
C24H19Cl2N5O
C28H31N7O
427.47 3410-3259 (N H and O H), 3087 (
2922 (C H aliphatic), 1677 (C O)
C H),
464.36 3326 (N H), 3073 (
aliphatic), 1682 (C O)
481.61 3321 (NH), 3087 ( H), 2899 (CH
aliphatic), 1679 (C O)
414.90 3121 ( H), 2896 (CH aliphatic), 1674
(C O)
446.12 3425-3277 (2O H), 3110 (
2897 (C H aliphatic), 1670 (C O)
C H), 2944 (C H
C
C24H19ClN4O
C24H19ClN4O3
C24H17Cl3N4O
C28H29ClN6O
C
C
H aromatic),
483.79 3091 (
C
H), 2926 (C H aliphatic), 1678
H), 2891 (C H aliphatic), 1680
(C O)
501.04 3088 (
C
(C O)
(δ, DMSO-d6): 2.83 (s, 2CH3, 6H), 6.72-6.84 (m, H-5,
3, CH C O, 3H), 7.05 (m, H-3\, 5\, 2H), 7.16 (d,
J = 8.36 Hz, H-2\, 6\, 2H), 7.49 (d, H, J = 8.71 Hz, −4,
1H); 13C NMR (DMSO-d6): 45.66 (2CH3), 108.99 (C-3),
111.34 (C-5), 117.10 (O C C H), 119.43 (C-3\, 5\),
126.54 (C-2\, 6\), 133.65 (C-4\), 127.62 (C-1\), 138.54 (C-4),
143.95 ( C H), 150.67 (C-5), 161.68 (C-2), 162.21
(C O); EI-MS m/z (% rel. Abund.): 267 [M+, 31].
1H), 7.61 (d, J = 15.69 Hz,
CH, 1H), 8.17 (d,
J = 8.42 Hz, H-6, 1H), 10.44 (s, NH, exchanged with D2O,

8
BAKR AND ELKANZI
227ꢀC-228ꢀC; 1H NMR (δ, DMSO-d6): 1.55 (s, H-5\, 2H), 2.74
(s, 2CH3, 6H), 4.32 (s, C-2\, 1H), 5.69 (s, NH2, exchanged with
D2O, 2H), 6.92 (d, J = 8.45 Hz, H-2\\, H-6\\, 2H), 7.54-7.61 (m,
H-3\\, H-5\\, H-5, 3H), 7.84-8.21 (m, H-3,H-4, 2H), 8.86 (d,
J = 7.21 Hz, H-6, 1H); 13C NMR (DMSO-d6): 34.99 (C-5),
48.76 (2CH3), 88.95 (C-2\), 114.56 (C-3\\, 5\), 124.92 (C-3),
126.22 (C-5), 128.73 (C-2\\, 6\\), 131.03 (C-4\\),135.67 (C-4),
149.99 (C-1\\), 159.05(C-6), 159.21 (C-2), 164.32 (C-4\), 164.77
(C-6\); EI-MS m/z (% rel. Abund.): 293 [M+, 17].
3.2 | Preparation of compounds 10a–d
NH2
2
1
3
N
N
2
4
6
3
1
3
4
4
5
2
1
5
N
6
X
3.3 | Synthesis of compounds, 11a–d
5
6
X
A mixture of 9a–d (0.01 mol) and guanidine nitrate
(0.01 mol) in the presence of 50% NaOH solution (0.02 mol)
was heated under reflux in 20 mL ethanol for 8 to 10 hours.
The mixture was cooled to room temperature, and the sepa-
rated solid was filtered, washed with ethanol, and dried to
afford the corresponding derivatives, 10a–d.
4
5
3
6
2
1
4-Phenyl-6-pyridin-2-yl-2,5-dihydropyrimidin-2-ylamine
CH
1
(10a). Solid: Yield: 82%; M.p.: 198ꢀC-200ꢀC; H NMR (δ,
N
DMSO-d6): 1.73 (s, H-5\, 2H), 4.65 (s, H-2\, 1H), 5.20 (s,
NH2, exchanged with D2O, 2H), 7.44-7.52 (m, H-3\\, 4\\, 5\\,
3H), 7.56-7.61 (m, H-2\\, 6\\, H-3, 3H), 8.21-8.24 (m, H-4,
5, 2H), 8.70 (d, J = 7.99 Hz, H-6, 1H); 13C NMR (DMSO-d6):
34.67 (C-5\), 88.98 (C-2\), 124.12 (C-3), 126.98 (C-5), 128.07
(C-3\\, 5\\), 129.97 (C-2\\, 6\\), 131.24 (C-4\), 136.45 (C-4),
137.24 (C-1\\), 150.56 (C-6), 159.87 (C-2), 164.43 (C-4\),
164.87 (C-6\); EI-MS m/z (% rel. Abund.): 250 [M+, 29].
4-(2-amino-6-pyridin-2-yl-2,5-dihydropyrimidin-4-yl)
phenol (10b). Solid: Yield: 77%; M.p.: 202ꢀC-204ꢀC; 1H
NMR (δ, DMSO-d6): 1.66 (s, H-5\, 2H), 4.54 (s, H-2\, 1H),
5.56 (s, NH2, D2O exchangeable, 2H), 6.88 (d, J = 8.21 Hz,
H-2\\, 6\\, 2H), 7.15-7.22 (m, H-3\\, 5\\, H-5,3H), 7.79-8.34
(m, H-3, 4, 2H), 8.89 (d, J = 8.28 Hz, H-6, 1H), 10.22 (s, OH,
exchanged with D2O, 1H); 13C NMR (DMSO-d6): 35.21 (C-5\),
89.12 (C-2\), 116.24 (C-3\\, 5\\), 124.25 (C-3), 126.87 (C-5),
128.34 (C-2\\, 6\\), 130.62 (C-4\\), 136.32 (C-4), 150.33 (C-1\\),
150.32 (C-6), 159.05 (C-2), 164.32 (C-4\), 164.77 (C-6\); EI-MS
m/z (% rel. Abund.): 266 [M+, 19].
2
1
3
N
N
6
4
6
3
6
5
2
4
5
1
5
4
1
N
X
2
3
A mixture of 10a–d (0.01 mol) and the substituted benzalde-
hydes, 7a–d, (0.01 mol) in the presence of catalytic amount
of glacial acetic acid was heated under reflux in methanol
(15 mL) for 6 to 8 hours. The solid formed was cooled and
poured into chilled water. The separated solid was filtered
out, dried, and crystallized by ethanol to give 11a–d.
Benzylidene-(4-phenyl-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-yl)amine (11a). Solid: Yield: 70%; M.
p.: 247ꢀC-249ꢀC; 1H NMR (δ, DMSO-d6): 1.43 (s, H-5\, 2H),
4.61 (s, H-2\, 1H), 7.32-7.37 (m, H-3\\, 4\\, 5\\, H-3\\\, 4\\\, 5\\\,
6H), 7.64-7.68 (m, H-2\\, 6\\, H-2\\\, 6\\\, H-5, 5H), 7.99-8.12
(m, H-3, 4, 2H), 8.26 (s, N CH, 1H), 8.89 (d, J = 8.32 Hz,
H-6, 1H); 13C NMR (DMSO-d6): 34.72 (C-5\), 90.65 (C-2\),
124.83 (C-3), 126.34 (C-5), 128.32 (C-3\\, 5\\), 128.61 (C-3\\\,
5\\\), 129.76 (C-2\\, 6\\), 129.94 (C-2\\\, 6\\\), 130.88 (C-4\\),
130.89 (C-4\\\), 136.52 (C-4), 137.22 (C-1\\), 137.56 (C-1\\\),
150.56 (C-6), 159.33 (C-2), 163.22 (HC N), 164.64 (C-4\),
164.99 (C-6\); EI-MS m/z (% rel. Abund.): 338 [M+, 21].
4-[2-(4-Hydroxybenzylidene-amino)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-4-yl]phenol (11b). Solid: Yield: 72%;
4-(4-Chlorophenyl)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-ylamine (10c). Solid: Yield: 63%; M.
1
p.: 208ꢀC-210ꢀC; H NMR (δ, DMSO-d6): 2.11 (s, H-5\,
2H), 4.33 (s, H2\, 1H), 5.70 (s, NH2, exchanged with D2O,
2H), 7.24 (d, J = 8.11 Hz, H-2\\, 6\\, 2H), 7.51-7.64 (m, H-
3\\, 5\\, H-5, 3H), 7.80-8.26 (m, H-3, 4, 2H), 8.87 (d,
J = 7.87 Hz, H-6, 1H); 13C NMR (DMSO-d6): 35.20 (C-5\),
89.19 (C-2\), 124.89 (C-3), 126.87 (C-5), 128.34 (C-2\\, 6\\),
130.51 (C-4\\), 135.67 (C-4), 136.32 (C-3\\, 5\\), 149.99 (C-
1\\), 151.05 (C-6), 159.21 (C-2), 164.32 (C-4\), 164.77 (C-
6\); EI-MS m/z (% rel. Abund.): 284 [M+, 26].
M.p.: 239ꢀC-241ꢀC; H NMR (δ, DMSO-d6): 1.45 (s, H-5\,
1
2H), 4.60 (s, H-2\, 1H), 6.74-6.77 (m, H-3\\, 5\\, H-3\\\, 5\\,
4H), 7.61-7.65 (m, H-2\\, 6\\, H-2\\\, 6\\\, H-5, 5H),
8.01-8.10 (m, H-3, 4, 2H), 8.34 (s, N CH, 1H), 8.89 (d,
4-(4-Dimethylaminophenyl)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-ylamine (10d). Solid: Yield: 58%; M.p.:

BAKR AND ELKANZI
9
J = 8.62 Hz, H-6, 1H), 12.12 (s, OH, exchanged with D2O,
1H), 12.23 (s, 1H, OH, D2O exchangeable); 13C NMR
(DMSO-d6): 34.71 (C-5\), 92.23 (C-2\), 115.76 (C-3\\, 5\\),
115.87 (C-3\\\, 5\\\), 124.43 (C-3), 126.23 (C-5), 129.23 (C-
2\\, 6\\), 129.27 (C-2\\\, 6\\\), 130.56 (C-1\\), 130.69 (C-1\\\),
136.22 (C-4), 154.65 (C-6), 159.21 (C-2), 159.63 (C-4\\),
159.88 (C-4\\), 163.23 (HC N), 164.23 (C-4\), 164.6 (C-6\);
EI-MS m/z (% rel. Abund.): 370 [M+, 46].
was refluxed for 7 to 9 hours in 20 mL 1,4-dioxane. The
progress of the reaction was monitored by TLC (toluene:
ethyl acetate, 3:1). After completion, reaction mass was
dumped in ice cold water. The product was separated,
washed with water, and recrystallized from ethanol to
give, 12a–d.
2-Phenyl-3-(4-phenyl-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-yl)thiazolidin-4-one (12a). Solid:
1
(4-Chlorobenzylidene)-[4-(4-chlorophenyl)-6-pyridin-2-yl-
2,5-dihydropyrimidin-4-yl]amine (11c). Solid: Yield: 60%; M.
Yield: 52%; M.p.: 278ꢀC-280ꢀC; H NMR (δ, DMSO-d6):
1.42 (s, H-5\, 2H), 3.34, 3.46 (dd, J1 = 16.8 Hz,
J2 = 9.3 Hz, thiazolidinone CH2, 2H), 5.30 (s, H-2\, 1H),
5.35 (s, thiazolidinone CH, 1H), 7.12-7.18 (m, H-2\\, 3\\, 4\
\, 5\\, 6\\, 5H), 7.31-7.37 (m, H-3\\\, 4\\\, 5\\\, 3H), 7.61-7.64
(m, H-2\\\, 6\\\, H-5, 3H), 8.00-8.12 (m, H-3, 4, 2H), 8.89
(d, J = 7.99 Hz, H-6, 1H); 13C NMR (DMSO-d6): 34.89 (C-
5\), 36.74 (thiazolidin C-5), 49.83 (thiazolidino C-2), 84.25
(C-2\), 124.14 (C-3), 126.25 (C-5), 127.25 (C-3\\, 5\\),
128.06 (C-3\\\, 5\\\), 128.68 (C-2\\, 6\\), 128.93 (C-2\\\, 6\\\),
129.12 (C-4\\), 130.98 (C-4\\\), 136.42 (C-4), 137.45 (C-1\\),
137.98 (C-1\\\), 150.12 (C-6), 159.22 (C-2), 164.54 (C-4\),
164.73 (C-6\), 170.22 (C O); EI-MS m/z (% rel. Abund.):
412 [M+, 39].
1
p.: 243ꢀC-244ꢀC; H NMR (δ, DMSO-d6): 1.44 (s, H-5\, 2H),
4.66 (s, H-2\, 1H), 7.31-7.34 (m, H-3\\, 5\\, H-3\\\, 5\\, 4H),
7.58-7.61 (m, H-2\\, 6\\, H-2\\\, 6\\\, 4H), 7.67 (m, H-5, 1H),
8.02-8.08 (m, H-3, 4, 2H), 8.75 (s, N CH, 1H), 8.87 (d,
J = 8.19 Hz, H-6, 1H); 13C NMR (DMSO-d6): 34.73 (C-5\),
93.01 (C-2\), 124.34 (C-3), 126.21 (C-5), 129.13 (C-2\\, 6\\),
129.18 (C-2\\\, 6\\\), 130.78 (C-1\\), 131.22 (C-1\\\), 135.41 (C-3\,
5\\), 135.62 (C-3\\, 5\\\), 136.21 (C-4), 136.32 (C-4\\), 136.77 (C-
4\\\), 150.45 (C-6), 159.01 (C-2), 163.42 (HC N), 164.12 (C-4\),
164.32 (C-6\); EI-MS m/z (% rel. Abund.): 407 [M+, 39].
(4-Dimethylaminobenzylidene)-
[4-(4-dimethylaminophenyl)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-4-yl]amine (11d). Solid: Yield: 69%;
2-(4-Hydroxyphenyl)-3-[4-(4-hydroxyphenyl)-6-pyridin-
1
M.p.: 276ꢀC-277ꢀC; H NMR (δ, DMSO-d6): 1.46 (s, H-5,
2-yl-2,5-dihydropyrimidin-2-yl]thiazolidin-4-one
(12b).
2H), 2.84 (s, 4CH3, 12H), 4.81 (s, H-2\, 1H), 6.67-6.73 (m,
H-3\\, 5\\, H-3\\\, 5\\\, 4H), 7.41-7.45 (m, H-2\, 6\\, H-2\\\, 6\\
\, 4H), 7.68 (m, H-5, 1H), 8.14-8.23 (m, H-3, 4, 2H), 8.45 (s,
N CH, 1H), 8.90 (d, J = 8.76 Hz, H-6, 1H); 13C NMR
(DMSO-d6): 34.62 (C-5\), 44.38 (4CH3), 94.12 (C-2\), 113.26
(C-4\\), 113.92 (C-4\\\), 124.30 (C-3), 126.11 (C-5), 126.82
(C-1\\), 126.95 (C-1\\\), 129.97 (C-2\, 6\\), 130.14 (C-2\\, 6\\\),
136.21 (C-3\, 5\\), 136.32 (C-3\\, 5\\\), 136.98 (C-4), 150.23
(C-6), 159.82 (C-2), 163.52 (HC N), 164.42 (C-4\), 164.63
(C-6\); EI-MS m/z (% rel. Abund.): 424 [M+, 29].
Solid: Yield: 52%; M.p.: 261ꢀC-263ꢀC; 1H NMR (δ,
DMSO-d6): 1.46 (s, H-5\, 2H), 3.30, 3.44 (dd,
J1 = 16.23 Hz, J2 = 8.67 Hz, thiazolidinone CH2, 2H),
5.30 (s, H-2\, 1H), 5.33 (s, thiazolidinone CH, 1H),
6.64-6.77 (m, H-3\\, H-5\\, H-3\\\, 5 \\\, 4H), 6.92 (d,
J = 8.52 Hz, H-2\\\, 6 \\\, 2H), 7.52-7.56 (m, H-2\\, 6
,
\\
H-5, 3H), 8.05-8.12 (m, H-3, 4, 2H), 8.92 (d,
J = 7.54 Hz, H-6, 1H), 12.30 (s, OH, exchanged with
D2O, 1H), 12.47 (s, OH, D2O exchangeable, 1H); 13C
NMR (DMSO-d6): 34.68 (C-5\), 36.84 (thiazolidin C-5),
49.76 (thiazolidin C-2), 84.34 (C-2\), 115.74 (C-3\\, 5\\),
115.82 (C-3\\\, 5\\), 124.40 (C-3), 126.48 (C-5), 129.97
(C-2\\, 6\\), 130.12 (C-2\\\, 6\\\), 130.52 (C-1\), 130.87
(C-1\\\), 136.30 (C-4), 150.1 (C-6), 155.03 (C-2), 159.21
(C-4\\), 159.85 (C-4\\\), 164.21 (C-4\), 164.82 (C-6\),
170.09 (C O); EI-MS m/z (% rel. Abund.): 444 [M
+, 50].
3.4 | Synthesis of compound 12a–d
A mixture of compounds, 11a–d (0.01 mol), thioglycolic
acid (0.02 mol), and pinch of anhydrous zinc chloride,
2-(4-Chlorophenyl)-3-[4-(4-chlorophenyl)-6-pyridin-
2
3
S
2-yl-2,5-dihydropyrimidin-2-yl]thiazolidin-4-one
(12c).
4
Solid: Yield: 52%; M.p.: 273ꢀC-274ꢀC; 1H NMR (δ,
DMSO-d6): 1.45 (s, H−5 \, 2H), 3.27, 3.40 (dd,
J1 = 15.89 Hz, J2 = 7.57 Hz, thiazolidinone CH2, 2H),
5.31 (s, H-2\, 1H), 5.37 (s, thiazolidinone CH, 1H),
6.63-6.52 (m, H-3\\, 5 \\, H-3\\\, 5 \\\, 4H), 6.92-7.23 (m,
H-2\\, 6 \\, H-2\\\, H-6\\\, 2H),7.65 (m, H-5, 1H),
8.03-8.09 (m, H-3,H-4, 2H), 8.90 (d, J = 7.89 Hz, H-6,
1H); 13C NMR (DMSO-d6): 34.81 (C-5), 36.92
(thiazolidin C-5), 48.51 (thiazolidin C-2), 87.01 (C-2\),
124.09 (C-3), 128.36 (C-5), 129.20 (C-2\\, 6\\), 129.52
1
1
X
O
N
5
5
2
6
3
N
1
N
6
3
6
6
4
2
5
4
5
4
1
N
2
X
3

10
BAKR AND ELKANZI
(C-2\\\, 6\\\), 130.21 (C-1\), 130.76 (C-1\\\), 132.69 (C-3\
\, 5\\), 135.12 (C-3\\\, 5\\\), 136.58 (C-4), 136.91 (C-4\\),
136.99 (C-4\\\), 150.31 (C-6), 159.81 (C-2), 164.55 (C-
4\), 164.64 (C-6\), 169.14 (C O); EI-MS m/z (% rel.
Abund.): 481 [M+, 63].
8.06-8.13 (m, H-3, 4, 2H), 8.93 (d, J = 7.69 Hz, H-6, 1H),
10.34 (s, NH, 1H); 13C NMR (DMSO-d6): 34.99 (C-5\), 54.21
(imidazolidin C-5), 60.84 (imidazolidin C-2), 82.55 (C-2\),
124.25 (C-3), 126.09 (C-5), 127.34 (C-3\\, 5\\), 128.06 (C-3\\\,
5\\\), 128.31 (C-2\, 6\\), 128.62 (C-2\\, 6\\\), 129.32 (C-4\),
130.22 (C-4\\\), 136.88 (C-1\\), 137.33 (C-1\\\), 150.25 (C-6),
159.41 (C-2), 164.33 (C-4\), 164.62 (C-6\), 170.08 (C O); EI-
MS m/z (% rel. Abund.): 395 [M+, 67].
2-(4-Dimethylaminophenyl)-
3-[4-(4-dimethylaminophenyl)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-yl]thiazolidin-4-one (12d). Solid:
Yield: 50%; M.p.: 273ꢀC-274ꢀC; 1H NMR (δ, DMSO-
d6): 1.48 (s, H-5\, 2H), 2.87 (s, 4 CH3, 12H), 3.29, 3.44
(dd, J1 = 15.34 Hz, J2 = 7.54 Hz, thiazolidinone CH2,
2H), 5.35 (s, H-2\, 1H), 5.34 (s, thiazolidinone CH,
2-(4-Hydroxyphenyl)-3-[4-(4-hydroxyphenyl)-6-pyridin-
2-yl-2,5-dihydropyrimidin-2-yl]imidazolin-4-one
(13b).
1
Solid: Yield: 69%; M.p.: 210ꢀC-211ꢀC; H NMR (δ, DMSO-
d6): 1.43 (s, H-5\, 2H), 3.36, 3.61 (dd, J1 = 16.22 Hz,
J2 = 8.22 Hz, imidazoline CH2, 2H), 5.36 (s, H-2\, 1H), 5.97
(s, imidazoline CH, 1H), 6.61-6.69 (m, H-3\\, H-5\\, H-3\\\, 5\
\, 4H), 6.89-7.53 (m, H-2\\, 6\\, 2H), 7.53 (m, H-2\\\, 6 \\\, H-5,
3H), 8.09-8.18 (m, H-3, 4, 2H), 8.84 (d, J = 8.59 Hz, H-6,
1H), 10.76 (s, NH, 1H), 12.52 (s, OH, D2O exchangeable,
1H), 12.63 (s, OH, D2O exchangeable, 1H); 13C NMR
(DMSO-d6): 34.70 (C-5\), 52.52 (imidazolidin C-5), 61.22
(imidazolidin C-2), 82.22 (C-2\), 115.53 C-3\\, 5\\), 116.78 (C-
3\\\, 5\\\), 124.22 (C-3), 126.33 (C-5), 129.91 (C-2\\, 6\\), 130.09
(C-2\\\, 6\\\), 130.44 (C-1\\), 130.77 (C-1\\\), 136.11 (C-4),
150.21 (C-6), 155.42 (C-2), 159.77 (C-4\\), 164.20 (C-4\\\),
164.98 (C-4\), 164.99 (C-6\), 170.33 (C O); EI-MS m/z (%
rel. Abund.): 427 [M+, 47].
1H), 6.50-6.72 (m, H-3\\, 5\\, H-3\\\
, , 4H),
5\\\
6.98-7.38 (m, H-2\, 6\\, H-2\\\, 6\\\, 4H), 7.99-8.12 (m,
H-5, 1H), 8.15-8.24 (m, H-3, 4, 2H), 8.92 (d,
J = 8.22 Hz, H-6, 1H); 13C NMR (DMSO-d6): 34.50 (C-
5\), 36.59 (thiazolidin C-5), 44.02 (4CH3), 49.72
(thiazolidin C-2), 82.97 (C-2\), 113.32 (C-4\\), 113.64
(C-4\\\), 124.23 (C-3), 126.98 (C-5), 127.06 (C-1\\),
127.53 (C-1\\\), 129.88 (C-2\\, 6\\), 129.93 (C-2\\\, 6\\\),
136.41 (C-3\\, 5\\), 142.01 (C-3\\\, 5\\\), 146.27 (C-4),
150.22 (C-6), 159.12 (C-2), 164.52 (C-4\), 164.62 (C-
6\), 170.61 (C O); EI-MS m/z (% rel. Abund.):
498 [M+, 29].
2-(4-Chlorophenyl)-3-[4-(4-chlorophenyl)-6-pyridin-
2-yl-2,5-dihydropyrimidin-2-yl] imidazolin-4-one (13c).
Solid: Yield: 64%; M.p.: 225ꢀC-226ꢀC; 1H NMR (δ, DMSO-
d6): 1.42 (s, H-5\, 2H), 3.29, 3.44 (dd, J1 = 14.23 Hz,
J2 = 8.71 Hz, imidazoline CH2, 2H), 5.29 (s, H-2\, 1H), 5.99
(s, imidazoline CH, 1H), 6.61 (d, J = 7.75 Hz, H-3\\, 5\\, 2H),
6.73 (d, J = 7.99 Hz, H-3\\\, 5\\\, 2H), 7.02 (d, J = 7.75 Hz, H-
2\\, 6\\, 2H), 7.55 (d, J = 7.99 Hz, H-2\\\, 6\\\, 2H), 7.69 (m,
H-5, 1H), 8.08-8.11 (m, H-3, 4, 2H), 8.99 (d, J = 8.23 Hz,
H-6, 1H), 10.65 (s, 1H, NH); 13C NMR (DMSO-d6): 34.87 (C-
5), 53.66 (imidazolidin C-5), 60.11 (imidazolidin C-2), 82.55
(C-2\), 124.32 (C-3), 126.55 (C-5), 128.74 (C-2\\, 6\\), 129.51
(C-2\\\, 6\\\), 129.99 (C-1\), 130.31 (C-1\\\), 132.88 (C-3\\, 5\\),
135.89 (C-3\\\, 5\\\), 135.21 (C-4), 136.44 (C-4\\), 136.52 (C-4\\
\), 150.81 (C-6), 159.22 (C-2), 164.26 (C-4\), 164.61 (C-6\),
169.20 (C O); EI-MS m/z (% rel. Abund.): 464 [M+, 81].
2-(4-Dimethylaminophenyl)-
3.5 | Synthesis of compound 13a–d
3
2
NH
4
1
X
O
N
5
2
6
3
N
N
1
6
3
6
4
1
2
5
4
5
4
N
1
2
5
X
3
A mixture of derivatives, 11a–d (0.01 mol) and glycine
(0.01 mol), was refluxed in 20 mL toluene for 8 to 10 hours,
and the reaction mixture was cooled, and then the sepa-
rated solid was filtered out, dried, and crystallized by etha-
nol/DMF to afford the corresponding, 13a–d.
2-Phenyl-3-(4-phenyl-6-pyridin-2-yl-2,5-dihydropyrimidin-
2-yl-2,5-dihydropyrimidin-2-yl)imidazolin-4-one (13a). Solid:
Yield: 59%; M.p.: 190ꢀC-191ꢀC; 1H NMR (δ, DMSO-d6): 1.48
(s, H−5 \, 2H), 3.24, 3.39 (dd, J1 = 15.5 Hz, J2 = 7.62 Hz, imi-
dazoline CH2, 2H), 5.44 (s, H-2\, 1H), 6.09 (s, imidazoline
CH, 1H), 7.09-7.12 (m, 2\\,3\\, 4\\, 5\\, 6\\, 5H), 7.26-7.29 (m,
3H, H-3\\\, 4\\\, 5\\\), 7.54-7.56 (m, H-2\\\, 6\\\, H-5, 3H),
3-[4-(4-dimethylaminophenyl)-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-yl]imidazolin-4-one (13d). Solid:
1
Yield: 60%; M.p.: 274ꢀC-275ꢀC; H NMR (δ, DMSO-d6):
1.48 (s, H−5\, 2H), 2.89 (s, 4 CH3, 12H), 3.22, 3.48 (dd,
J1 = 15.99 Hz, J2 = 9.43 Hz, imidazoline CH2, 2H), 5.33 (s,
H-2\, 1H), 6.23 (s, imidazoline CH, 1H), 6.52 (d, J = 8.43 Hz,
2H, H-3\\, 5\\, 2H), 6.79 (d, J = 8.25 Hz, H-3\\\, 5\\\, 2H), 6.96
(d, J = 8.43 Hz, H-2\\, 6\\, 2H), 7.31 (d, J = 8.25 Hz, H-2\\\, 6\\
\, 2H), 8.03-8.15 (m, H-5, 1H), 8.15-8.24 (m, H-3, 4, 2H), 8.92
(d, J = 8.22 Hz, H-6, 1H), 10.73 (s, 1H, NH); 13C NMR
(DMSO-d6): 34.15 (C-5\), 45.21 (4CH3), 51.65 (imidazolidin C-

BAKR AND ELKANZI
11
2), 59.56 (imidazolidin C-5), 83.81 (C-2\), 113.11 (C-4\\), 113.56
(C-4\\\), 124.09 (C-3), 126.76 (C-5), 126.32 (C-1\\), 127.87 (C-1\\
\), 129.95 (C-2\\, 6\\), 129.99 (C-2\\\, 6\\\), 132.23 (C-3\\, 5\\),
132.87 (C-3\\\, 5\\\), 147.58 (C-4), 150.44 (C-6), 159.05 (C-2),
164.35 (C-4\), 164.67 (C-6\), 170.52 (C O); EI-MS m/z (% rel.
Abund.): 481 [M+, 29].
J = 8.79 Hz, H-3\\\, 5\\\, 2H), 6.86 (d, J = 8.45 Hz, H-2\\,
6\\, 2H), 7.51-7.58 (m, H-2\\\, 6\\\, H-5, 3H), 8.13-8.20 (m,
H-3, 4, 2H), 8.84 (d, J = 8.86 Hz, H-6, 1H), 12.50 (s, OH,
D2O exchangeable, 1H), 12.69 (s, OH, D2O exchangeable,
1H); 13C NMR (DMSO-d6): 34.76 (C-5\), 54.02 (azetidin
C-4), 62.36 (azetidin C-3), 86.23 (C-2\), 115.52 (C-3\\, 5\),
116.01 (C-3\\\, 5\\), 124.02 (C-3), 126.33 (C-5), 129.77 (C-2\
\, 6\\), 130.03 (C-2\\\, 6\\\), 130.61 (C-1\), 130.74 (C-1\\\),
136.41 (C-4), 150.54 (C-6), 155.22 (C-2), 159.52 (C-4\\),
159.63 (C-4\\\), 164.01 (C-4\), 164.35 (C-6\), 164.95 (C O);
EI-MS m/z (% rel. Abund.): 446 [M+, 47].
3.6 | Synthesis of compound 14a–d
Cl
2
3
3-Chloro-4-(4-chlorophenyl)-1-(4-(4-chlorophenyl)-
6-pyridin-2-yl-2,5-dihydropyrimidin-2-yl-
1
4
O
X
2,5-dihydropyrimidin-2-yl)azetidin-2-one (14c). Solid:
1
Yield: 59%; M.p.: 195ꢀC-196ꢀC; H NMR (δ, DMSO-d6):
N
5
1.46 (s, H-5\, 2H), 4.80 (d, J = 8.52 Hz, azetidine CH-4,
1H), 5.16 (d, J = 8.52 Hz, azetidine CH-3, 1H), 5.44 (s, H-
2\, 1H), 6.64 (d, J = 7.89 Hz, H-3\\, 5\\, 2H), 6.78 (d,
J = 7.89 Hz, H-2\\, 6\\, 2H), 7.04 (d, J = 8.43 Hz, H-3\\\, 5\
\\, 2H), 7.79 (d, J = 8.43 Hz, H-2\\\, 6\\\, 2H), 7.82 (m, H-5,
1H), 8.09-8.16 (m, H-3, 4, 2H), 9.03 (d, J = 8.89 Hz, H-6,
1H); 13C NMR (DMSO-d6): 34.59 (C-5\), 54.66 (azetidin
C-4), 62.33 (azetidin C-3), 87.33 (C-2\), 124.11 (C-3),
126.32 (C-5), 128.66 (C-2\\, 6\\), 129.71 (C-2\\\, 6\\\),
129.86 (C-1\\), 130.44 (C-1\\\), 130.98 (C-3\\, 5\\), 132.97
(C-3\\\, 5\\\), 135.44 (C-4), 135.77 (C-4\\), 136.13 (C-4\\\),
136.44, 150.66 (C-6), 159.41 (C-2), 146.09 (C-4\), 164.12
(C-6\), 164.98 (C O); EI-MS m/z (% rel. Abund.): 483 [M
+, 62].
6
2
3
4
1
N
6
N
2
5
3
6
1
3
2
4
5
5
4
1
N
6
X
To a stirred solution of 11a–d (0.01 mol) in 1,4-dioxane
(20 mL), chloroacetyl chloride (0.01 mol) was added,
drop by drop, at 0ꢀC to 5ꢀC in the presence of
triethylamine (0.01 mol) as catalyst for 2 to 4 hours. The
product formed was then cooled and poured on to
crushed ice with constant stirring. The solid obtained was
recrystallized from ethanol/DMF to give, 14a–d.
3-Chloro-4-(4-dimethylaminophenyl)-1-(4-(4-dimethy
laminophenyl)-6-pyridin-2-yl-2,5-dihydropyrimidin-2-yl-
2,5-dihydropyrimidin-2-yl)azetidin-2-one (14d). Solid:
3-Chloro-4-phenyl-1-(4-phenyl-6-pyridin-2-yl-2,-
5-dihydropyrimidin-2-yl-2,5-dihydropyrimidin-2-yl)
azetidin-2-one (14a). Solid: Yield: 59%; M.p.: 270ꢀC-
272ꢀC; H NMR (δ, DMSO-d6): 1.49 (s, H-5, 2H), 4.42 (d,
1
Yield: 59%; M.p.: 195ꢀC-196ꢀC; H NMR (δ, DMSO-d6):
1.45 (s, H-5\, 2H), 2.86 (s, 4 CH3, 12H), 4.83 (d,
J = 8.44 Hz, azetidine CH-4, 1H), 5.16 (d, J = 8.44 Hz,
azetidine CH-3, 1H), 5.33 (s, H-2\, 1H), 6.51-6.72 (m, H-3\
\, 5\\, H-3\\\, 5\\\, 4H), 6.93-7.27 (m, H-2\, 6\\, H-2\\\, 6\\\,
4H), 8.02-8.14 (m, H-5, 1H), 8.19-8.22 (m, H-3, 4, 2H),
8.88 (d, J = 8.11 Hz, H-6, 1H); 13C NMR (DMSO-d6):
34.19 (C-5\), 54.39 (azetidin C-4), 61.11 (azetidin C-3),
87.22 (C-2\), 112.14 (C-4\\), 113.87 (C-4\\\), 124.11 (C-3),
126.45 (C-5), 126.78 (C-1\\), 127.25 (C-1\\\), 129.82 (C-2\\,
6\\), 129.90 (C-2\\\, 6\\\), 136.82 (C-3\\, 5\\), 142.08 (C-3\\\,
5\\\), 146.29 (C-4), 150.42 (C-6), 159.92 (C-2), 164.21 (C-
4\), 164.49 (C-6\), 164.72 (C O); EI-MS m/z (% rel.
Abund.): 500 [M+, 29].
1
J = 7.98 Hz, azetidine CH-4, 1H), 5.19 (d, J = 7.98 Hz,
azetidine CH-3, 1H), 5.25 (s, H-2\, 1H), 7.06-7.10 (m, H-2\
\, 3\\, 4\\, 5\\, 6\\, 5H), 7.28-7.32 (m, phenyl H-3\\\, 4\\\, 5\\
\, 3H), 7.62-7.65 (m, H-2\\\, 6\\\, H-5, 3H), 7.99-8.11 (m,
H-3, 4, 2H), 8.91 (d, J = 8.43 Hz, H-6, 1H); 13C NMR
(DMSO-d6): 34.75 (C-5\), 54.33 (azetidin C-4), 62.10
(azetidin C-3), 86.99 (C-2\), 124.36 (C-3), 126.55 (C-5),
128.02 (C-3\\, 5\\), 128.32 (C-3\\\, 5\\\), 128.56 (C-2\, 6\\),
129.88 (C-2\\, 6\\\), 131.25 (C-4\), 136.58 (C-4\\\), 137.89
(C-1\\), 137.52 (C-1\\\), 150.89 (C-6), 159.31 (C-2), 164.21
(C-4\), 164.47 (C-6\), 164.88 (C O); EI-MS m/z (% rel.
Abund.): 414 [M+, 67].
3-Chloro-4-(4-hydroxyphenyl)-1-(4-(4-hydroxyphenyl)-
6-pyridin-2-yl-2,5-dihydropyrimidin-2-yl-
2,5-dihydropyrimidin-2-yl)azetidin-2-one (14b). Solid:
3.7 | Antimicrobial evaluation
1
Yield: 64%; M.p.: 279ꢀC-280ꢀC; H NMR (δ, DMSO-d6):
1.44 (s, H−5\, 2H), 4.82 (d, J = 8.65 Hz, azetidine CH-4,
1H), 5.12 (d, J = 8.65 Hz, azetidine CH-3, 1H), 5.29 (s, H-
2\, 1H), 6.59 (d, J = 8.45 Hz, H-3\\, 5 \\, 2H), 6.66 (d,
All novel substituted pyridopyrimidines were assessed for
in vitro antimicrobial testing, toward Bacillus subtilis and
Staphylococcus aureus as examples of bacterial species, in

12
BAKR AND ELKANZI
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addition to Aspergillus flavus and Candida albicans as
examples of fungal species, by measuring zone of inhibi-
tion applying Hammer et al procedure.[46]
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3.8 | Docking study
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Molecular operational environment was the program for
choice to make the docking study. Glucosamine-
6-phosphate synthase (GlcN-6-P) was obtained from pro-
tein knowledge bank (PDB: ID 1gdo). The antimicrobial
agents, 12c, 13c, and 14c, had been docked in the site of
GlcN-6-P as documented.[37] Hydrogen bond interactions
and binding energy scores are listed in Table 2.
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4 | CONCLUSION
New pyridopyrimidine compounds, linked with thiazolidin-
4-ones(12a–d),imidazolin-4-ones(13a–d),
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azetidin-
2-ones(14a–d), were synthesized by reacting the
pyridopyrimidine key intermediate, 11a–d, with thioglycolic
acid, glycine, and/or chloroacetyl chloride, respectively. All
substituted pyridopyrimidines, 12a–d, 13a–d, and 14a–d,
were assessed for their in vitro antimicrobial activity against
Bacillus subtilis and Staphylococcus aureus as examples of bac-
terial species, in addition to Aspergillus flavus and Candida
albicans as examples of fungal species. It was clear that the
azetidine-2-one derivative, 14c, was the most active derivative
toward all the tested bacteria, followed by both, 13c and 12c.
On the other hand, compounds, 12a, 12c, and 13c, recorded
antifungal activity toward Aspergillus flavus, while all the
tested compounds demonstrated antifungal potential against
Candida albicans, except compound, 14a. To predict the
mode of effect of these candidates, molecular docking was
carried out on the most potential derivatives, 12c, 13c, and
14c, within GLN-6-P active site. This study explained the good
fitting of these tested derivatives with the active site.
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ORCID
Rania B. Bakr https://orcid.org/0000-0001-6564-1712
Nadia A. A. Elkanzi https://orcid.org/0000-0002-1687-
1834
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How to cite this article: Bakr RB, Elkanzi NAA.
Preparation of some novel thiazolidinones,
imidazolinones, and azetidinone bearing pyridine
and pyrimidine moieties with antimicrobial
activity. J Heterocyclic Chem. 2020;1–13. https://
doi.org/10.1002/jhet.4009