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Synthesis, characterization, biological, and molecular docking assessment of

bioactive 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-
imidazol-4-yl) moieties

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Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-020-02144-1

ORIGINAL PAPER

Synthesis, characterization, biological, and molecular

docking assessment of bioactive 1,3‑thiazolidin‑4‑ones fused
with 1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl) moieties
Mohammad Arshad1   · Mohd Shoeb Khan2 · Shahab A. A. Nami3 · Syed Ishraque Ahmad4 · Mohd Kashif5 ·
Ansar Anjum5

Received: 27 June 2020 / Accepted: 2 December 2020

© Iranian Chemical Society 2021

Abstract 
A series of fifteen computationally bioactive 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties
(1–15) were synthetically prepared and assessed for antimicrobial potential against the four strains (two gram-positive and two
gram-negative). The structures were supported by spectroscopic methods like FT-IR, NMR (1H & 13C), mass spectroscopy,
etc. The antimicrobial efficacy of the prepared compounds was achieved by the method of disk diffusion, and the effects
were recorded in terms of zone of inhibition and minimum inhibitory concentration. Dimethyl sulfoxide and ciprofloxacin
were used as negative and positive controls. The results stated that two compounds (7 and 10) were reported to exhibit bet-
ter antimicrobial activity than the standard drug ciprofloxacin, while the other members represented considerable potential.
Molecular docking was also performed to support the in vitro antimicrobial results, to understand the extent of H-bonding
and the binding affinities of the compounds (1–15), with the amino acid residues of the receptor GlcN-6P and, represented
significant H-bonding. An MTT assay was also carried out to see the toxic effects of the prepared compounds and posed that
the compounds were less toxic toward the HepG2 cells.
Graphic abstract

Keywords  1,3-thiazolidin-4-ones · Synthesis · Characterization · Antimicrobial · MTT · Molecular docking

Introduction

Microbial infections are responsible for the deaths of 17

million people worldwide according to the World Health
* Mohammad Arshad Organization [1]. The huge elevation in the incidence of
mohdarshad1985@gmail.com; m.arshad@su.edu.sa antimicrobial resistance is one of the biggest concerns for
Extended author information available on the last page of the article

13
Vol.:(0123456789)
 Journal of the Iranian Chemical Society

the scientific community that has always evoked researchers [47]. Additionally, the compounds with imidazole, a five-
to explore new antimicrobial agents [2, 3]. Medicinal chem- member cyclic nucleus with two nitrogen and three carbon
ists have been focused a lot to study the compounds with atoms, have been studied too much because of their various
heteroatoms because of their tremendous pharmacological properties such as inhibitors of HIV-1 Vpu and host BST-2
applications [4–11]. The derivatives possessing thiazoli- protein interaction [48], antimicrobial [49], antioxidant [49],
dinone nuclei were observed to portray the activities like cytotoxicity [49], inhibitor of c-Met tyrosine kinase [49],
anxiolytic [12], antifungal [13], antiglioma and cytotoxicity anticancer [50], antitumor [51], antitubercular [52], antifun-
[14], anti-Candida [15], anti-HIV [16], antihyperglycemic gal [53], antileishmanial [54], antimalarial [55], antiprolif-
and antidyslipidemic [17], inhibitors of Toxoplasma gondii erative [56], and antidiabetic [57]. The recent study aimed to
[18], antitrypanosomal [19, 20], anti-hepatitis C virus [21], synthesize some bioactive molecules that possess thiazolidi-
anti-proliferative [22], esterase and glucosidase inhibitors none, pyrimidine, and imidazole moieties and believed that
[23], anticancer [24], antimicrobial [25], antioxidant and the fusion of these three biologically active moieties will be
antimicrobial [26], antitubercular [27], antimalarial [28], represented as better antimicrobials.
antidiabetic [29], and anti-Toxoplasma gondii [30]. In our
continuous search for the novel antimicrobial agents, we
recently reported the synthesis, characterization, antimicro- Results and discussion
bial, MTT, and molecular docking assessment of 1,3-thia-
zolidin-4-one derivatives bearing pyrimidine moieties [31]. The structures of 1,3-thiazolidin-4-ones fused with
In one more similar study, we reported the synthesis of 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15) were
thiazolidinone derivatives containing indole and pyridine prepared using ChemDraw Ultra 12.0, and the smiles files
moieties and processed for antimicrobial, MTT and molecu- were copied for the calculations of bioactivity score and
lar docking assessments [32]. The literature reported that physicochemical parameters, which was performed by
the compounds with pyrimidine moieties possess versatile Molinspiration Cheminformatics software (online available
pharmacological applications like anti-tubulin [33], CHK1 software) [58–65]. The results portrayed that the compounds
inhibitor [34], cyclin-dependent kinase 4/6 inhibitors [35], (1–15) were lying under the zone of the active drug as an
cytotoxic [36], non-nucleoside reverse transcriptase inhibi- enzyme inhibitor as well as the GPCR ligand (Table 1). The
tors against HIV-1 [37], anti-inflammatory [38], analgesic bioactivity score of the compounds (4, 10, 13, and 14) was
and antipyretic [39], FAK inhibitors [40], antitubercular reported under the zone of active drug molecule as kinase
[41], antibacterial [42], Janus kinase 3 inhibitors [43], anti- inhibitors, while the remaining compounds were moderately
microbial [44], antioxidant and antimicrobial activities [45], active as kinase inhibitors. All the compounds (1–15) repre-
cyclin-dependent kinase 2 inhibitors [46], and many more sented the moderate active or inactive zone as the ion

Table 1  Bioactivity score for the 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15) and ciprofloxacin
Compounds GPCR ligand Ion channel Kinase inhibitor Nuclear receptor Protease inhibitor Enzyme inhibitor
modulator ligand

1 0.10 − 0.11 − 0.01 − 0.59 − 0.50 0.23

2 0.06 − 0.18 − 0.04 − 0.59 − 0.53 0.18
3 0.09 − 0.13 − 0.03 − 0.59 − 0.52 0.20
4 0.14 − 0.19 0.01 − 0.55 − 0.54 0.16
5 0.06 − 0.21 − 0.04 − 0.57 − 0.52 0.18
6 0.04 − 0.31 − 0.07 − 0.59 − 0.52 0.13
7 0.01 − 0.45 − 0.13 − 0.69 − 0.50 0.05
8 0.01 − 0.32 − 0.06 − 0.45 − 0.56 0.10
9 0.03 − 0.26 − 0.08 − 0.55 − 0.52 0.14
10 0.12 − 0.10 0.01 − 0.48 − 0.48 0.26
11 − 0.02 − 0.24 − 0.12 − 0.62 − 0.56 0.12
12 − 0.02 − 0.26 − 0.07 − 0.56 − 0.56 0.10
13 0.14 − 0.08 0.11 − 0.49 − 0.44 0.23
14 0.04 − 0.19 0.04 − 0.59 − 0.54 0.15
15 0.04 − 0.21 − 0.02 − 0.60 − 0.61 0.11
Ciprofloxacin 0.12 − 0.04 − 0.07 − 0.19 − 0.20 − 0.28

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Journal of the Iranian Chemical Society

channel modulator, nuclear receptor ligand, and protease (1–15), by reacting (E)-1-(substituted-phenyl-N-{4-(pyridin-
inhibitor. The partition coefficient (milogP) for compounds 2-yl)-6-[1-(pyrimidin-2-yl)-1H-imidazol-4-yl]pyrimidin-
(1–15) was reported in the normal range (− 0.4 to + 5.6), the 2-yl}methanimine (C), with thioglycolic acid, and a pinch
total polar surface area was found less than 160 A, the num- of zinc chloride in dimethyl formamide under reflux [31].
ber of atoms was less than 70, the number of OH-NH was The structures of the 1,3-thiazolidin-4-ones fused with
less than 5, the number of rotatable bonds was less than 10, 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15) were
and the volume was less than 500, as per Lipinski’s rule of confirmed by the help of spectroscopic methods like FT-IR,
1
five. The violations were also observed in terms of molecu- H-NMR, 13C-NMR, and mass spectroscopy. The FTIR
lar weight by some members of the series, while only com- spectra of (2E)-3-(pyridin-2-yl)-1-[1-(pyrimidin-2-yl)-1H-
pound (7) represented violations in terms of molecular imidazol-4-yl]prop-2-en-1-one (A) exhibited the presence
weight and nON (Table  2). The synthesis of the aimed of bands at 1652 cm−1 and 1483 cm−1 due to the C=O and
1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-im- HC=CH functional groups, respectively. While the structure
idazol-4-yl moieties (1–15) was carried out using a four-step of the 4-(pyridin-2-yl)-6-[1-(pyrimidin-2-yl)-1H-imidazol-
protocol, as mentioned in Figure 1. The first step included 4-yl]pyrimidin-2-amine (B) was confirmed by the presence
the synthesis of (2E)-3-(pyridin-2-yl)-1-[1-(pyrimidin-2-yl)- of bands at 3327 cm−1 due to the N ­ H2 functional group and
1H-imidazol-4-yl]prop-2-en-1-one (A), by the condensation the absence of bands for the C=O and HC=CH functional
of  1-(pyrimidin-2-yl)-1H-imidazole-4-carbaldehyde groups, respectively, the FT-IR spectra of the (E)-1-
and  2-acetylpyridine by refluxing in ethanol with 20% (substituted-phenyl-N-{4-(pyridin-2-yl)-6-[1-(pyrimidin-2-
sodium hydroxide [6]. In step 2, the (2E)-3-(pyridin-2-yl)- yl)-1H-imidazol-4-yl]pyrimidin-2-yl}methanimine (C) por-
1-[1-(pyrimidin-2-yl)-1H-imidazol-4-yl]prop-2-en-1-one trayed the presence of a new band at 1617 cm−1 due to
(A) was cyclized to yield 4-(pyridin-2-yl)-6-[1-(pyrimidin- HC=N, in place of bands at 3327 cm−1 due to the N­ H2 group,
2-yl)-1H-imidazol-4-yl]pyrimidin-2-amine (B) by refluxing which recommended the condensation between the pyrimi-
compound A with guanidine hydrochloride in isopropanol dine and substituted aldehydes. The presence of bands in the
[6]. Step 3 dealt with the synthesis of (E)-1-(substituted- FTIR spectra in the range 707–725  cm −1 due to C-S,
phenyl-N-{4-(pyridin-2-yl)-6-[1-(pyrimidin-2-yl)-1H-imi- 1061–1014 cm−1 due to C–N, 1011–1037 cm−1 due to C–N,
dazol-4-yl]pyrimidin-2-yl}methanimine (C), by refluxing 1504–1549  cm −1 due to C=N, 1510–1569 due to
(B) with substituted aromatic carboxaldehyde in ethanol and C=N, 1540–1602 due to C=N, 1583–1685 due to C=N,
glacial acetic acid as catalyst [9]. Finally, step 4 dealt with 1611–1662 due to C=N, 1643–1693 due to C=N, and
the preparation of the compounds 1,3-thiazolidin-4-ones 1710–1742 due to C=O confirmed the formation of 1,3-thi-
fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties azolidin-4-ones fused with

Table 2  Physicochemical S. No. MiLogP1 TPSA2 Natoms3 MW4 NON5 NOHNH6 Nviol7 Nrot8 Vol9
properties for the
1,3-thiazolidin-4-ones fused 1 2.48 102.59 35 478.54 9 0 0 5 402.79
with 1-(pyrimidin-2-yl)-1H-
2 2.92 102.59 36 492.57 9 0 0 5 419.35
imidazol-4-yl moieties (1–15)
and ciprofloxacin 3 3.15 102.59 36 512.99 9 0 1 5 416.33
4 3.11 102.59 36 512.99 9 0 1 5 416.33
5 2.53 111.83 37 508.57 10 0 1 6 428.34
6 2.12 121.06 39 538.59 11 0 2 7 453.88
7 2.11 130.30 41 568.62 12 0 2 8 479.43
8 2.86 111.83 38 522.59 10 0 1 7 445.14
9 2.91 111.83 38 522.59 10 0 1 7 445.14
10 2.00 122.82 36 494.54 10 1 0 5 410.81
11 2.39 148.42 38 523.54 12 0 2 6 426.12
12 2.44 148.42 38 523.54 12 0 2 6 426.12
13 1.31 115.49 35 479.53 10 0 0 5 398.63
14 2.38 102.59 34 484.57 9 0 0 5 393.50
15 1.73 115.73 34 468.50 10 0 0 5 384.36
Ciprofloxacin − 0.701 74.569 24.0 331.347 6 2 0 3 285.46

Partition coefficient (1), total polar surface area (2), number of atoms (3), molecular weight (4), number of
H-bond acceptors (5), number of H-bond donors (6), number of violations (7), number of rotatable bonds
(8), molecular volume (9)

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 Journal of the Iranian Chemical Society

Fig. 1  Schematic diagram for the synthesis of 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15)

1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15). Fur- 4.132–4.194 (q, 2H, C ­ H2), 1.315–1.372 (t, 3H, C­ H3), and
1
ther confirmation was performed by 1H-NMR and 13C- 4.125–4.188 (q, 2H, C­ H2), in the H-NMR spectra, were also
NMR; the presence of singlets at 7.443–7.490 ppm and observed, which further confirmed the synthesis of 1,3-thi-
7.724–7.791 ppm in the 1H-NMR spectra of (2E)-3-(pyridin- azolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-
2-yl)-1-[1-(pyrimidin-2-yl)-1H-imidazol-4-yl]prop-2-en-1- 4-yl moieties (1–15). The structures of the 1,3-thiazolidin-
one (A) recommended its formation. The presence of singlet 4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl
at 5.275 ppm, due to ­NH2, and the absence of singlets at moieties (1–15) were further confirmed by the presence of
7.443–7.490 ppm and 7.724–7.791 ppm in the 1H-NMR peaks around 55.11–55.85  ppm (due to S-CH 2 ) and
spectra of 4-(pyridin-2-yl)-6-[1-(pyrimidin-2-yl)-1H-imida- 170.22–171.55 ppm (due to C=O) in the 13C-NMR spectra.
zol-4-yl]pyrimidin-2-amine (B) confirmed its synthesis. The The additional peaks around 23.06 ppm and 22.66 ppm due
presence of singlet at 8.174 ppm due to HC=N, in place of to ­CH3, 51.74 ppm and 52.71 ppm due to ­CH2, 53.10 ppm,
singlet due to N ­ H 2 in the 1H-NMR spectra of (E)-1- 52.69 ppm, 53.24 ppm, 52.78 ppm, and 52.28 ppm due to
(substituted-phenyl-N-{4-(pyridin-2-yl)-6-[1-(pyrimidin-2- ­O CH 3 further confirmed the structure of compounds;
yl)-1H-imidazol-4-yl]pyrimidin-2-yl}methanimine (C), detailed spectroscopic data are reported in the Experimental
strongly recommended its synthesis. Additionally, the section. 1,3-Thiazolidin-4-ones fused with 1-(pyrimidin-
appearance of the characteristic singlet in 1H-NMR spectra 2-yl)-1H-imidazol-4-yl moieties (1–15) were then screened
around 2.630–2.525 ppm due to the S-CH2 protons strongly for biological potential against the bacterial strains gram-
supported the cyclization of the Schiff bases to the 1,3-thia- positive [S. aureus (ATCC-25923), S. epidermidis (ATCC-
zolidin-4-ones nuclei. Some additional peaks like 2.121 (s, 29887)] and gram-negative [E. coli (ATCC-25922), P. mira-
3H, ­OCH3), 3.709 (s, 3H, ­OCH3), 3.715 (s, 3H, ­OCH3), bilis (ATCC-25933)] employing the disk diffusion protocol
3.791 (s, 3H, C­ H3), 3.717 (s, 3H, O ­ CH3), 3.793 (s, 3H, [66–76]. The antimicrobial effects were calculated in terms
­OCH3), 3.814 (s, 3H, ­OCH3), 1.329–1.398 (t, 3H, ­CH3), of minimum inhibitory concentrations and zone of

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Journal of the Iranian Chemical Society

inhibition, (Table 3, Figure 2). The paper disks were applied 120

to the agar plate with the bacterial culture, and the zone of 100

% Area of inhibition/ µg
inhibitions was recorded after incubation of 48 h. On the
80
other hand, serial dilutions were prepared from the stock
S. a
solution to estimate the minimum inhibitory concentrations. 60
S. e
The overall observation revealed that compound-7 and com- 40 E. c
pound-8 were posing better activity than the reference drug P. m
20
ciprofloxacin, while other members of the series were having
considerable antimicrobial effects. The 1,3-thiazolidin- 0
4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moi-
eties (1–15) were assessed for percent viability of the cells Treated Compounds
against HepG2 cells by MTT assay. Results revealed that the
percent viability was dependent on the concentration and Fig. 2  Percent area of inhibition/microgram for the 1,3-thiazolidin-
further observed that the viability of the cells decreased with 4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–
15) and ciprofloxacin
increasing concentrations of the treated compounds [77, 78].
The compounds (1–15) were found to be less toxic toward
HepG2 cells, and the percent viability of the cells ranged GLY473, ASP474, ALA496, and ASN522 (Table 4 and
from 90 to 94% @3.125 µM, 82 to 88% @6.25 µM, 78 to Figure 4).
83% @12.5 µM, 73 to 77% @25 µM, 70 to 74% @50 µM,
and 65 to 72% @100 µM (Figure 3). Molecular docking was
also carried out to estimate the binding affinities of 1,3-thi- Experimental
azolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-imidazol-
4-yl moieties (1–15), using AutoDockTools 1.5.6, 1,3-Thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-
AutoDock-Vina, and PyMOL, against the receptor Glc-N-6P 1H-imidazol-4-yl moieties (1–15) were structurally
(2VF5) [79–81]. The binding affinities were observed in the designed on ChemDraw Ultra12.0 to record the drug-
range -7.8 to -6.4 kcal/mole, with root-mean-square density likeness properties using Molinspiration Cheminformatics
of 0 to 29.761 (l. b) and 0 to 32.154 (u. b). The residues of software. 1-(Pyrimidin-2-yl)-1H-imidazole-4-carbalde-
GlcN-6P that were observed to be involved in H-bonding hyde, 2-acetylpyridine, ethanol, NaOH, guanidine hydro-
were TYR248, SER303, THR312, SER316, SER401, chloride, isopropanol, substituted carboxaldehyde, glacial

Table 3  Zone of inhibitions/ S. No. Effect of compounds on microorganism

minimum inhibitory
concentrations (MICs) for the Gram-positive Gram-negative
1,3-thiazolidin-4-ones fused
with 1-(pyrimidin-2-yl)-1H- S. aureus S. epidermidis E. coli P. mirabilis
imidazol-4-yl moieties (1–15) Zone of inhibition (mm) Zone of inhibition Zone of inhibition Zone of inhibition
and ciprofloxacin /MIC (µg/ml) (mm)/MIC (µg/ml) (mm)/MIC (µg/ml) (mm)/MIC (µg/ml)

1 16.10 ± 0.22/6.25 16.14 ± 0.24/3.12 17.16 ± 0.24/6.25 16.50 ± 0.20/12.5

2 16.22 ± 0.16/6.25 17.32 ± 0.20/3.12 17.20 ± 0.30/6.25 16.24 ± 0.02/12.5
3 17.10 ± 0.14/6.25 16.20 ± 0.12/3.12 17.12 ± 0.20/6.25 16.30 ± 0.22/12.5
4 16.18 ± 0.20/6.25 17.24 ± 0.20/3.12 17.10 ± 0.24/6.25 16.10 ± 0.10/12.5
5 19.14 ± 0.22/6.25 18.28 ± 0.10/3.12 19.26 ± 0.18/6.25 18.04 ± 0.08/12.5
6 17.20 ± 0.14/6.25 17.82 ± 0.24/3.12 18.48 ± 0.22/6.25 18.16 ± 0.10/12.5
7 21.58 ± 0.20/6.25 23.12 ± 0.24/3.12 24.10 ± 0.14/6.25 22.80 ± 0.20/12.5
8 18.24 ± 0.22/6.25 18.250 ± 0.20/3.12 19.08 ± 0.20/6.25 18.26 ± 0.20/12.5
9 19.12 ± 0.20/6.25 18.14 ± 0.16/3.12 18.70 ± 0.18/6.25 18.30 ± 0.10/12.5
10 21.90 ± 0.24/6.25 23.20 ± 0.22/3.12 23.95 ± 0.26/6.25 22.80 ± 0.10/12.5
11 15.12 ± 0.22/6.25 15.30 ± 0.26/3.12 16.28 ± 0.12/6.25 15.24 ± 0.18/12.5
12 15.10 ± 0.14/6.25 15.28 ± 0.20/3.12 16.32 ± 0.15/6.25 16.54 ± 0.10/12.5
13 16.10 ± 0.30/6.25 16.28 ± 0.22/3.12 16.36 ± 0.24/6.25 15.44 ± 0.10/12.5
14 15.20 ± 0.04/6.25 15.40 ± 0.26/3.12 16.50 ± 0.20/6.25 15.44 ± 0.22/12.5
15 15.10 ± 0.16/6.25 15.48 ± 0.32/3.12 16.30 ± 0.20/6.25 16.60 ± 0.22/12.5
Cipro 21.44 ± 0.24/6.25 22.94 ± 0.42/3.12 23.82 ± 0.46/6.25 22.64 ± 0.30/12.5

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Fig. 3  Percent viability of the 120

HepG2 cells for the 1,3-thi-
azolidin-4-ones fused with
1-(pyrimidin-2-yl)-1H-imida- 100

% Viability of cells
zol-4-yl moieties (1–15) and
ciprofloxacin
80 3.125
6.25
60
12.5
40
25

20 50
100
0
(µmol/ L)
Treated Compounds

Table 4  Molecular docking S. No. Binding affinity Binding with residues of GlcN-6P Distance from best mode for
findings for the 1,3-thiazolidin- (Kcal/mole) nine modes of binding
4-ones fused with 1-(pyrimidin-
2-yl)-1H-imidazol-4-yl moieties Rmsd (l. b) Rmsd (u. b)
(1–15) and ciprofloxacin
1 − 7.6 to − 6.9 THR 312, SER 316 0 to 23.524 0 to 26.703
2 − 7.6 to − 7.1 TYR 248 0 to 27.871 0 to 30.603
3 − 7.8 to − 7.1 SER 316 0 to 1.521 0 to 6.580
4 − 7.2 to − 6.8 ASP 474 0 to 27.172 0 to 29.781
5 − 7.4 to − 6.8 SER 316 0 to 23.677 0 to 25.938
6 − 7.3 to − 6.4 SER 316, ASN 522 0 to 29.761 0 to 32.154
7 − 7.3 to − 6.5 SER 316, GLY 473 0 to 27.855 0 to 30.317
8 − 7.5 to − 6.9 SER 316, GLY 473 0 to 29.096 0 to 31.443
9 − 7.6 to − 6.9 SER 316 0 to 22.543 0 to 25.221
10 − 7.4 to − 6.8 SER 303, SER 401 0 to 28.031 0 to 29.826
11 − 7.4 to − 6.9 ALA 496 (Two Bonds) 0 to 27.315 0 to 29.998
12 − 7.5 to − 6.9 SER 316 0 to 4.131 0 to 7.279
13 NA NO BONDING 0 to 13.969 0 to 16.574
14 − 7.5 to − 6.7 SER 316 0 to 3.375 0 to 7.966
15 − 7.5 to − 6.8 SER 316 (Two Bonds) 0 to 2.034 0 to 6.410

acetic acid, thioglycolic acid, dimethyl formamide anhy- the MTT assay. Molecular docking was performed by the
drous zinc chloride, silica gel aluminum sheets, MTT, Muel- help of AutoDockTools 1.5.6, AutoDock-Vina, and PyMOL.
ler–Hinton agar, Petri plates, required solvents, and reagents
were bought from HIMEDIA, Sigma-Aldrich, and Merck,
Germany. Elemental analysis was recorded on a Heraeus
Vario EL III analyzer, and to record, melting point, Melt Computational screening
temp, was used. To record mass spectra, Micromass Quat-
tro II triple quadrupole mass spectrometer was used, FT-IR Primarily, the structures of 1,3-thiazolidin-4-ones fused with
spectra were taken on a PerkinElmer model 1600 FT-IR 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15) were
RX1, and 1H-NMR/13C-NMR were recorded on a Bruker designed on ChemDraw Ultra12.0 and converted to a smiles
Avance 300 MHz spectrometer. The ultraviolet laminar flow format that was copied and pasted on the Molinspiration
cabinet was used to carry out antimicrobial analysis, and Cheminformatics software to find out the bioactivity score
ELISA (enzyme-linked immunosorbent assay) was used for and physicochemical properties as mentioned [58–65].

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Journal of the Iranian Chemical Society

Fig. 4  Molecular-docked images for the most active compounds (7 & 10) of the series with the receptor GlcN-6P

Chemistry pyrimidin‑2‑amine (B) 4-(Pyridin-2-yl)-6-[1-(pyrimidin-

2-yl)-1H-imidazol-4-yl]pyrimidin-2-amine (10 mmol) was
The procedure for the synthesis of (2E)‑3‑(pyridin‑2‑yl)‑1‑ added to guanidine hydrochloride (10 mmol) in a round-
[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]prop‑2‑en‑1‑one bottom flask possessing isopropanol (50 ml) [6]. The result-
(A) 1-(Pyrimidin-2-yl)-1H-imidazole-4-carbaldehyde ant compound (B) was observed as a precipitate which was
(10 mmol) and 2-acetylpyridine (10 mmol) were mixed in filtered and dried under vacuum.
a round-bottom flask containing ethanol (50 ml) with 10%
NaOH and set on refluxing at room temperature for 24 h [6]. The procedure for the synthesis of (E)‑1‑(substituted‑
The precipitate was observed, which was filtered and dried phenyl‑N‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑im‑
under vacuum. idazol‑4‑yl]pyrimidin‑2‑yl}methanimine (C) 4-(Pyri-
din-2-yl)-6-[1-(pyrimidin-2-yl)-1H-imidazol-4-yl]pyrimi-
Th e p ro ce d u re fo r t h e s y nt h e s i s o f 4 ‑ ( py r i ‑ din-2-amine (10  mmol) and substituted carboxaldehyde
din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H ‑imidazol‑4‑yl] (10 mmol) were mixed in ethanol (50 ml) in a round-bottom

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 Journal of the Iranian Chemical Society

flask [9]. Few drops of glacial acetic acid were added to the (Ar–C), 126.30 (Ar–C), 127.77 (Ar–C), 128.31 (Ar–C),
mixture and set on refluxing. The final product was obtained 128.95 (Ar–C), 129.34 (Ar–C), 130.17 (Ar–C), 131.22 (Ar–
as a precipitate which was filtered and dried under vacuum. C), 132.06 (Ar–C), 170.66 (C=O); ESI–MS (m/z) ­[M+ + 1]:
493.15 (493.18).
The procedure for  the  synthesis of  1,3‑thiazoli‑
din‑4‑ones fused with  1‑(pyrimidin‑2‑yl)‑1H‑imida‑ 2‑(4‑ Chlorophenyl‑3‑{4‑(pyri‑
zol‑4‑yl moieties (1–15) (E)-1-(substituted-phenyl-N- din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]
{4-(pyridin-2-yl)-6-[1-(pyrimidin-2-yl)-1H-imidazol-4-yl] pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 87;
pyrimidin-2-yl}methanimine (10 mmol) and thioglycolic gray-colored crystal; m. p: 198–200 °C; Anal. Calc. for
acid (10 mmol) were mixed in a round-bottom flask hav- ­C25H17ClN8OS: C 58.53, H, 3.34, N, 21.84; (Found) C
ing dimethylformamide (50 ml). A pinch of anhydrous zinc 58.55, H, 3.35, N, 21.86; FT-IR (­ cm−1): 721 (C–S), 1027
chloride was added to the mixture as a catalyst [31]. Com- (C–N), 1040 (C–N), 1530 (C=N), 1562 (C=N), 1602
pounds (1–15) were obtained as a precipitate which was fil- (C=N), 1625 (C=N), 1661 (C=N), 1690 (C=N), 1721
tered and dried under vacuum. (C=O), 2953 (CH-Ar); 1H-NMR (DMSO-d6) (ppm): 2.604
(s, 2H, S-CH2), 6.883–6.920 (d, 1H, Ar–H), 6.967–7.005 (d,
2‑Phenyl‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrimidin‑2‑y 1H, Ar–H), 7.055–7.082 (d, 1H, Ar–H), 7.124–7.153 (d, 1H,
l)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thiazoli‑ Ar–H), 7.217–7.255 (m, 4H, Ar–H), 7.288 (s, 1H, Ar–H),
din‑4‑one  %Yield: 82; gray-colored crystal; m. p: 192– 7.329 (s, 1H, Ar–H), 7.363 (s, 1H, Ar–H), 7.417–7.454 (m,
194 °C; Anal. Calc. for ­C25H18N8OS: C 62.75, H, 3.79, N, 3H, Ar–H); 13C-NMR (DMSO-d6) (ppm): 55.34 (S-CH2),
23.42; (Found) C 62.78, H, 3.75, N, 23.45; FT-IR ­(cm−1): 118.34 (Ar–C), 118.94 (Ar–C), 119.55 (Ar–C), 120.10 (Ar–
713 (C–S), 1022 (C–N), 1045 (C–N), 1521 (C=N), 1556 C), 120.92 (Ar–C), 121.22 (Ar–C), 122.17 (Ar–C), 122.85
(C=N), 1598 (C=N), 1618 (C=N), 1651 (C=N), 1688 (Ar–C), 123.09 (Ar–C), 123.66 (Ar–C), 124.25 (Ar–C),
(C=N), 1728(C=O), 2973 (CH-Ar); 1H-NMR (DMSO-d6) 125.27 (Ar–C), 126.00 (Ar–C), 126.85 (Ar–C), 127.31 (Ar–
(ppm): 2.615 (s, 2H, S-CH2), 7.070–7.122 (m, 5H, Ar–H), C), 128.18 (Ar–C), 128.90 (Ar–C), 129.37 (Ar–C), 130.41
7.198–7.240 (m, 4H, Ar–H), 7.305 (s, 1H, Ar–H), 7.359 (Ar–C), 131.27 (Ar–C), 132.07 (Ar–C), 132.64 (Ar–C),
(s, 1H, Ar–H), 7.410 (s, 1H, Ar–H), 7.651–7.703 (m, 3H, 170.96 (C=O); ESI–MS (m/z) ­[M+ + 1]: 514.09 (514.11).
Ar–H); 13C-NMR (DMSO-d6) (ppm): 55.27 (S-CH 2),
121.22 (Ar–C), 122.08 (Ar–C), 122.87 (Ar–C), 123.14 (Ar– 2‑(2‑ Chlorophenyl‑3‑{4‑(pyri‑
C), 123.65 (Ar–C), 123.99 (Ar–C), 124.29 (Ar–C), 124.81 din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]
(Ar–C), 125.10 (Ar–C), 125.68 (Ar–C), 126.30 (Ar–C), pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 85;
127.84 (Ar–C), 128.23 (Ar–C), 129.44 (Ar–C), 130.18 (Ar– gray-colored crystal; m. p: 196–198 °C; Anal. Calc. for
C), 131.85 (Ar–C), 132.20 (Ar–C), 132.90 (Ar–C), 133.15 ­C25H17ClN8OS: C 58.53, H, 3.34, N, 21.84; (Found) C
(Ar–C), 133.82 (Ar–C), 134.07 (Ar–C), 134.85 (Ar–C), 58.52, H, 3.36, N, 21.85; FT-IR (­ cm−1): 722 (C–S), 1018
170.75 (C=O); ESI–MS (m/z) ­[M+ + 1]: 479.14 (479.17). (C–N), 1042 (C–N), 1509 (C=N), 1527 (C=N), 1568
(C=N), 1600 (C=N), 1630 (C=N), 1671 (C=N), 1742
2‑(4‑Methylphenyl‑3‑{4‑(pyri‑ (C=O), 2978 (CH-Ar); 1H-NMR (DMSO-d6) (ppm): 2.596
din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl] (s, 2H, S-CH2), 6.997–7.039 (m, 4H, Ar–H), 7.088–7.142
pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 83; (m, 4H, Ar–H), 7.210 (s, 1H, Ar–H), 7.243 (s, 1H, Ar–H),
gray-colored crystal; m. p: 184–186 °C; Anal. Calc. for 7.319 (s, 1H, Ar–H), 7.355–7.391 (m, 3H, Ar–H); 13C-NMR
­C26H20N8OS: C 63.40, H, 4.09, N, 22.75; (Found) C 63.42, (DMSO-d6) (ppm): 55.39 (S-CH2), 117.33 (Ar–C), 118.29
H, 4.11, N, 22.73; FT-IR (­ cm−1): 709 (C–S), 1011 (C–N), (Ar–C), 119.40 (Ar–C), 120.14 (Ar–C), 121.88 (Ar–C),
1037 (C–N), 1511 (C=N), 1532 (C=N), 1575 (C=N), 1609 122.42 (Ar–C), 122.89 (Ar–C), 123.17 (Ar–C), 124.07 (Ar–
(C=N), 1638 (C=N), 1677 (C=N), 1735 (C=O), 2948 (CH- C), 124.91 (Ar–C), 125.27 (Ar–C), 125.95 (Ar–C), 126.26
Ar); 1H-NMR (DMSO-d6) (ppm): 2.121 (s, 3H, C ­ H3), 2.525 (Ar–C), 127.13 (Ar–C), 128.40 (Ar–C), 129.00 (Ar–C),
(s, 2H, S-CH2), 7.105–7.133 (d, 1H, Ar–H), 7.181–7.235 (d, 129.58 (Ar–C), 130.06 (Ar–C), 131.33 (Ar–C), 131.95 (Ar–
1H, Ar–H), 7.267–7.300 (d, 1H, Ar–H), 7.347–7.374 (d, 1H, C), 132.49 (Ar–C), 133.57 (Ar–C), 170.81 (C=O); ESI–MS
Ar–H), 7.407–7.453 (m, 4H, Ar–H), 7.487 (s, 1H, Ar–H), (m/z) ­[M+ + 1]: 514.09 (514.11).
7.518 (s, 1H, Ar–H), 7.547 (s, 1H, Ar–H), 7.593–7.634 (m,
3H, Ar–H); 13C-NMR (DMSO-d6) (ppm): 24.88 ­(CH3), 2‑(4‑Methoxyphenyl‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrim
55.55 (S-CH2), 117.31 (Ar–C), 118.10 (Ar–C), 118.83 (Ar– idin‑2‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thi‑
C), 119.09 (Ar–C), 119.73 (Ar–C), 120.50 (Ar–C), 121.25 azolidin‑4‑one  %Yield: 81; gray-colored crystal; m. p:
(Ar–C), 121.85 (Ar–C), 122.33 (Ar–C), 122.90 (Ar–C), 190–192 °C; Anal. Calc. for C ­ 26H20N8O2S: C 61.41, H,
123.55 (Ar–C), 124.10 (Ar–C), 124.69 (Ar–C), 125.30 3.96, N, 22.03; (Found) C 61.40, H, 3.94, N, 22.00; FT-IR

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Journal of the Iranian Chemical Society

­(cm−1): 718 (C–S), 1025 (C–N), 1039 (C–N), 1513 (C=N), 55.33 (S-CH2), 118.25 (Ar–C), 118.87 (Ar–C), 119.20 (Ar–
1544 (C=N), 1575 (C=N), 1605 (C=N), 1634 (C=N), 1665 C), 120.41 (Ar–C), 121.55 (Ar–C), 122.45 (Ar–C), 123.29
(C=N), 1730 (C=O), 2958 (CH-Ar); 1H-NMR (DMSO-d6) (Ar–C), 123.85 (Ar–C), 124.50 (Ar–C), 125. 22 (Ar–C),
(ppm): 2.605 (s, 2H, S-CH2), 3.715 (s, 3H, ­OCH3), 6.802– 126.14 (Ar–C), 127.35 (Ar–C), 128.44 (Ar–C), 129.10 (Ar–
6.831 (d, 1H, Ar–H), 6.910–6.935 (d, 1H, Ar–H), 6.977– C), 129.80 (Ar–C), 130.21 (Ar–C), 130.79 (Ar–C), 131.44
7.007 (d, 1H, Ar–H), 7.089–7.137 (m, 4H, Ar–H), 7.211 (Ar–C), 132.24 (Ar–C), 132.85 (Ar–C), 133.40 (Ar–C),
(s, 1H, Ar–H), 7.330 (s, 1H, Ar–H), 7.375 (s, 1H, Ar–H), 134.09 (Ar–C), 170.57 (C=O); ESI–MS (m/z) ­[M+ + 1]:
7.428–7.463 (m, 3H, Ar–H); 13C-NMR (DMSO-d6) (ppm): 569.17 (569.20).
52.28 ­(OCH3), 55.77 (S-CH2), 120.14 (Ar–C), 120.84 (Ar–
C), 121.32 (Ar–C), 121.92 (Ar–C), 122.25 (Ar–C), 123.07 2‑(2‑Ethox yphenyl‑3‑{4‑(pyri‑
(Ar–C), 123.77 (Ar–C), 124.05 (Ar–C), 124.90 (Ar–C), din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]
125.28 (Ar–C), 125.97 (Ar–C), 126.41 (Ar–C), 127.08 (Ar– pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 90;
C), 127.85 (Ar–C), 128.26 (Ar–C), 129.51 (Ar–C), 129.95 gray-colored crystal; m. p: 196–198 °C; Anal. Calc. for
(Ar–C), 130.23 (Ar–C), 130.79 (Ar–C), 131.40 (Ar–C), ­C27H22N8O2S: C 62.06, H, 4.24, N, 21.44; (Found) C 62.04,
132.51 (Ar–C), 133.16 (Ar–C), 171.43 (C=O); ESI–MS H, 4.22, N, 21.45; FT-IR (­ cm−1): 725 (C–S), 1015 (C–N),
(m/z) ­[M+ + 1]: 509.15 (509.17). 1042 (C–N), 1515 (C=N), 1550 (C=N), 1591 (C=N), 1622
(C=N), 1662 (C=N), 1693 (C=N), 1733 (C=O), 2930 (CH-
2‑(3,4‑Dimethoxyphenyl‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyr Ar); 1H-NMR (DMSO-d6) (ppm): 1.329–1.398 (t, 3H, C ­ H3),
imidin‑2‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thi‑ 2.627 (s, 2H, S-CH2), 4.132–4.194 (q, 3H, ­CH2), 6.870–
azolidin‑4‑one  %Yield: 78; gray-colored crystal; m. p: 6.914 (m, 4H, Ar–H), 6.951–6.993 (m, 4H, Ar–H), 7.115
195–197 °C; Anal. Calc. for C ­ 27H22N8O3S: C 60.21, H, (s, 1H, Ar–H), 7.218 (s, 1H, Ar–H), 7.285 (s, 1H, Ar–H),
4.12, N, 20.81; (Found) C 60.23, H, 4.14, N, 20.82; FT-IR 7.353–7.391 (m, 3H, Ar–H); 13C-NMR (DMSO-d6) (ppm):
­(cm−1): 715 (C–S), 1017 (C–N), 1047 (C–N), 1525 (C=N), 22.66 ­(CH3), 53.10 ­(CH2), 54.88 (S-CH2), 120.05 (Ar–C),
1565 (C=N), 1590 (C=N), 1620 (C=N), 1653 (C=N), 1686 120.85 (Ar–C), 121.25 (Ar–C), 121.89 (Ar–C), 122.10 (Ar–
(C=N), 1717 (C=O), 2967 (CH-Ar); 1H-NMR (DMSO-d6) C), 122.79 (Ar–C), 123.27 (Ar–C), 123.90 (Ar–C), 124.55
(ppm): 2.630 (s, 2H, S-CH2), 3.709 (s, 3H, ­OCH3), 3.791 (Ar–C), 124.99 (Ar–C), 125.55 (Ar–C), 126.33 (Ar–C),
(s, 3H, ­OCH3), 6.844 (s, 1H, Ar–H), 6.901–6.933 (d, 1H, 127.24 (Ar–C), 128.21 (Ar–C), 128.93 (Ar–C), 129.18 (Ar–
Ar–H), 7.146–7.173 (d, 1H, Ar–H), 7.277–7.319 (m, 4H, C), 130.14 (Ar–C), 131.25 (Ar–C), 131.88 (Ar–C), 132.34
Ar–H), 7.366 (s, 1H, Ar–H), 7.379 (s, 1H, Ar–H), 7.390 (s, (Ar–C), 132.79 (Ar–C), 133.27 (Ar–C), 171.53 (C=O); ESI–
1H, Ar–H), 7.477–7.518 (m, 3H, Ar–H); 13C-NMR (DMSO- MS (m/z) ­[M+ + 1]: 523.16 (523.15).
d6) (ppm): 51.94 ­(OCH3), 52.78 ­(OCH3), 55.45 (S-CH2),
116.28 (Ar–C), 117.31 (Ar–C), 117.90 (Ar–C), 118.25 (Ar– 2‑(4‑Ethox yphenyl‑3‑{4‑(pyri‑
C), 119.49 (Ar–C), 119.98 (Ar–C), 120.21 (Ar–C), 120.84 din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]
(Ar–C), 121.52 (Ar–C), 122.10 (Ar–C), 122.78 (Ar–C), pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 88;
123.57 (Ar–C), 124.11 (Ar–C), 125.20 (Ar–C), 126.35 (Ar– gray-colored crystal; m. p: 206–208 °C; Anal. Calc. for
C), 127.42 (Ar–C), 128.17 (Ar–C), 128.92 (Ar–C), 129.50 ­C27H22N8O2S: C 62.06, H, 4.24, N, 21.44; (Found) C 62.07,
(Ar–C), 130.09 (Ar–C), 131.42 (Ar–C), 132.41 (Ar–C), H, 4.25, N, 21.46; FT-IR (­ cm−1): 723 (C–S), 1019 (C–N),
171.34 (C=O); ESI–MS (m/z) ­[M+ + 1]: 539.16 (539.13). 1050 (C–N), 1517 (C=N), 1536 (C=N), 1568 (C=N), 1589
(C=N), 1611 (C=N), 1643 (C=N), 1725 (C=O), 2935
2–(3,4,5‑Triimethoxyphenyl‑3‑{4‑(pyridin‑2‑yl) (CH-Ar); 1H-NMR (DMSO-d6) (ppm): 1.315–1.372 (t,
‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl]pyrimi‑ 3H, ­CH3), 2.544 (s, 2H, S-CH2), 4.125–4.188 (q, 3H, C
­ H2),
din‑2‑yl}‑1,3‑thiazolidin‑4‑one  %Yield: 92; gray-colored 7.091–7.112 (d, 1H, Ar–H), 7.157–7.186 (d, 1H, Ar–H),
crystal; m. p: 203–205 °C; Anal. Calc. for ­C28H24N8O4S: 7.220–7.247 (d, 1H, Ar–H), 7.288–7.314 (d, 1H, Ar–H),
C 59.14, H, 4.25, N, 19.71; (Found) C 59.16, H, 4.24, N, 7.355–7.393 (m, 4H, Ar–H), 7.410 (s, 1H, Ar–H), 7.488
19.70; FT-IR (­ cm−1): 711 (C–S), 1014 (C–N), 1049 (C–N), (s, 1H, Ar–H), 7.535 (s, 1H, Ar–H), 7.572–7.614 (m, 3H,
1510 (C=N), 1540 (C=N), 1583 (C=N), 1622 (C=N), 1650 Ar–H); 13C-NMR (DMSO-d6) (ppm): 23.06 ­(CH3), 52.71
(C=N), 1691 (C=N), 1715 (C=O), 2970 (CH-Ar); 1H-NMR ­(CH2), 54.90 (S-CH 2), 119.41 (Ar–C), 120.10 (Ar–C),
(DMSO-d6) (ppm): 2.591 (s, 2H, S-CH2), 3.717 (s, 3H, 120.85 (Ar–C), 121.07 (Ar–C), 121.85 (Ar–C), 122.44 (Ar–
­OCH3), 3.793 (s, 3H, O ­ CH3), 3.814 (s, 3H, O
­ CH3), 6.958 C), 123.31 (Ar–C), 124.15 (Ar–C), 124.81 (Ar–C), 125.23
(s, 1H, Ar–H), 6.991 (s, 1H, Ar–H), 7.207–7.246 (m, 4H, (Ar–C), 125.85 (Ar–C), 126.18, 126.82 (Ar–C), 127.50 (Ar–
Ar–H), 7.288 (s, 1H, Ar–H), 7.314 (s, 1H, Ar–H), 7.359 (s, C), 127.95 (Ar–C), 128.22 (Ar–C), 129.10 (Ar–C), 129.87
1H, Ar–H), 7.423–7.466 (m, 3H, Ar–H); 13C-NMR (DMSO- (Ar–C), 130.25 (Ar–C), 131.42 (Ar–C), 132.02 (Ar–C),
d6) (ppm): 51.74 ­(OCH3), 52.69 ­(OCH3), 53.24 ­(OCH3),

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 Journal of the Iranian Chemical Society

132.84 (Ar–C), 133.35 (Ar–C), 170.89 (C=O); ESI–MS (C=N), 1651 (C=N), 1688 (C=N), 1720 (C=O), 2938 (CH-
(m/z) ­[M+ + 1]: 523.16 (523.15). Ar); 1H-NMR (DMSO-d6) (ppm): 2.593 (s, 2H, S-CH2),
7.092–7.120 (d, 1H, Ar–H), 7.168–7.200 (d, 1H, Ar–H),
2‑(4‑Hydroxyphenyl‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrim 7.235–7.262 (d, 1H, Ar–H), 7.304–7.332 (d, 1H, Ar–H),
idin‑2‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thi‑ 7.377–7.405 (m, 4H, Ar–H), 7.483 (s, 1H, Ar–H), 7.512
azolidin‑4‑one  %Yield: 86; gray-colored crystal; m. p: (s, 1H, Ar–H), 7.555 (s, 1H, Ar–H), 7.594–7.633 (m, 3H,
200–202 °C; Anal. Calc. for C ­ 25H18N8O2S: C 60.72, H, Ar–H); 13C-NMR (DMSO-d6) (ppm): 55.37 (S-CH 2),
3.67, N, 22.66; (Found) C 60.70, H, 3.68, N, 22.68; FT-IR 117.15 (Ar–C), 117.70 (Ar–C), 118.22 (Ar–C), 118.89 (Ar–
­(cm−1): 719 (C–S), 1026 (C–N), 1043 (C–N), 1519 (C=N), C), 119.27 (Ar–C), 120.34 (Ar–C), 121.44 (Ar–C), 121.97
1544 (C=N), 1585 (C=N), 1616 (C=N), 1642 (C=N), 1682 (Ar–C), 122.14 (Ar–C), 122.90 (Ar–C), 123.25 (Ar–C),
(C=N), 1710 (C=O), 2943 (CH-Ar); 1H-NMR (DMSO-d6) 124.17 (Ar–C), 124.87 (Ar–C), 125.29 (Ar–C), 125.97 (Ar–
(ppm): 2.555 (s, 2H, S-CH2), 6.953–6.987 (d, 1H, Ar–H), C), 126.41 (Ar–C), 127.07 (Ar–C), 127.85 (Ar–C), 128.19
7.093–7.118 (d, 1H, Ar–H), 7.185–7.219 (d, 1H, Ar–H), (Ar–C), 129.39 (Ar–C), 130.56 (Ar–C), 131.58 (Ar–C),
7.275–7.307 (d, 1H, Ar–H), 7.367–7.408 (m, 4H, Ar–H), 171.45 (C=O); ESI–MS (m/z) ­[M+ + 1]: 524.12 (524.14).
7.474 (s, 1H, Ar–H), 7.507 (s, 1H, Ar–H), 7.551 (s, 1H,
Ar–H), 7.795–7.637 (m, 3H, Ar–H), 9.879 (s, 1H, OH); 13C- 2‑(Pyrdin‑2‑yl)‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrimidin‑
NMR (DMSO-d6) (ppm): 55.67 (S-CH2), 120.14 (Ar–C), 2‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thiazoli‑
120.84 (Ar–C), 121.19 (Ar–C), 121.77 (Ar–C), 122.30 (Ar– din‑4‑one  %Yield: 88; light black-colored crystal; m. p:
C), 122.89 (Ar–C), 123.25 (Ar–C), 123.91 (Ar–C), 124.24 227–229  °C; Anal. Calc. for ­C24H17N9OS: C 60.11, H,
(Ar–C), 125.51 (Ar–C), 126.09 (Ar–C), 126.85(Ar–C), 3.57, N, 26.29; (Found) C 60.12, H, 3.58, N, 26.30; FT-IR
127.22 (Ar–C), 127.90 (Ar–C), 128.41 (Ar–C), 129.10 (Ar– ­(cm−1): 724 (C–S), 1028 (C–N), 1061 (C–N), 1504 (C=N),
C), 129.81 (Ar–C), 130.34 (Ar–C), 131.27(Ar–C), 131.85 1537 (C=N), 1574 (C=N), 1605 (C=N), 1637 (C=N), 1671
(Ar–C), 132.19 (Ar–C), 132.99 (Ar–C), 171.27 (C=O); ESI– (C=N), 1731 (C=O), 2979 (CH-Ar); 1H-NMR (DMSO-d6)
MS (m/z) ­[M+ + 1]: 495.13 (495.15). (ppm): 2.585 (s, 2H, S-CH2), 6.844–6.883 (m, 4H, Ar–H),
6.934–6.979 (m, 4H, Ar–H), 7.090 (s, 1H, Ar–H), 7.114
2 ‑ ( 2 ‑ N i t r o p h e n y l ‑ 3 ‑ { 4 ‑ ( p y r i ‑ (s, 1H, Ar–H), 7.197 (s, 1H, Ar–H), 7.224–7.263 (m, 3H,
din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl] Ar–H); 13C-NMR (DMSO-d6) (ppm): 54.77 (S-CH 2),
pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 85; 113.11 (Ar–C), 113.85 (Ar–C), 114.26 (Ar–C), 114.77 (Ar–
yellow-colored crystal; m. p: 209–211 °C; Anal. Calc. for C), 115.27 (Ar–C), 115.79 (Ar–C), 116.28 (Ar–C), 116.95
­C25H17N9O3S: C 57.35, H, 3.27, N, 24.08; (Found) C 57.37, (Ar–C), 117.51 (Ar–C), 118.33 (Ar–C), 119.58 (Ar–C),
H, 3.28, N, 24.10; FT-IR (­ cm−1): 712 (C–S), 1020 (C–N), 120.24 (Ar–C), 121.49 (Ar–C), 122.38 (Ar–C), 123.70 (Ar–
1053 (C–N), 1512 (C=N), 1546 (C=N), 1579 (C=N), 1608 C), 124.70 (Ar–C), 125.67 (Ar–C), 127.51 (Ar–C), 128.11
(C=N), 1638 (C=N), 1678 (C=N), 1714 (C=O), 2940 (CH- (Ar–C), 128.95 (Ar–C), 129.31 (Ar–C), 130.27 (Ar–C),
Ar); 1H-NMR (DMSO-d6) (ppm): 2.609 (s, 2H, S-CH2), 170.22 (C=O); ESI–MS (m/z) ­[M+ + 1]: 480.13 (480.12).
6.971–7.013 (m, 4H, Ar–H), 7.150–7.194 (m, 4H, Ar–H),
7.233 (s, 1H, Ar–H), 7.279 (s, 1H, Ar–H), 7.317 (s, 1H, 2‑(Thiophen‑2‑yl)‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrimidin
Ar–H), 7.385–7.427 (m, 3H, Ar–H); 13C-NMR (DMSO- ‑2‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thiazoli‑
d6) (ppm): 55.85 (S-CH2), 115.12 (Ar–C), 116.20 (Ar–C), din‑4‑one  %Yield: 80; light black-colored crystal; m. p:
116.77 (Ar–C), 117.50 (Ar–C), 118.07 (Ar–C), 118.88 (Ar– 183–185 °C; Anal. Calc. for C ­ 23H16N8OS2: C 57.01, H,
C), 119.50 (Ar–C), 120.05 (Ar–C), 120.66 (Ar–C), 121.14 3.33, N, 23.12; (Found) C 57.02, H, 3.35, N, 23.10; FT-IR
(Ar–C), 121.71 (Ar–C), 122.44 (Ar–C), 123.19 (Ar–C), ­(cm−1): 728 (C–S), 1012 (C–N), 1055 (C–N), 1506 (C=N),
123.99 (Ar–C), 124.57 (Ar–C), 125.49 (Ar–C), 126.11 1539 (C=N), 1574 (C=N), 1608 (C=N), 1637 (C=N), 1677
(Ar–C), 126.83 (Ar–C), 127.57 (Ar–C), 128.14 (Ar–C), (C=N), 1734 (C=O), 2971 (CH-Ar); 1H-NMR (DMSO-d6)
128.95 (Ar–C), 130.06 (Ar–C), 171.32 (C=O); ESI–MS (ppm): 2.575 (s, 2H, S-CH2), 7.018–7.055 (m, 3H, Ar–H),
(m/z) ­[M+ + 1]: 524.12 (524.14). 7.105–7.148 (m, 4H, Ar–H), 7.188 (s, 1H, Ar–H), 7.215
(s, 1H, Ar–H), 7.250 (s, 1H, Ar–H), 7.295–7.337 (m, 3H,
2 ‑ ( 4 ‑ N i t r o p h e n y l ‑ 3 ‑ { 4 ‑ ( p y r i ‑ Ar–H); 13C-NMR (DMSO-d6) (ppm): 55.60 (S-CH 2),
din‑2‑yl)‑6‑[1‑(pyrimidin‑2‑yl)‑1H‑imidazol‑4‑yl] 112.89 (Ar–C), 113.42 (Ar–C), 113.98 (Ar–C), 114.40 (Ar–
pyrimidin‑2‑yl}‑1,3‑thiazolidin‑4‑one %Yield: 77; C), 115.11 (Ar–C), 116.00 (Ar–C), 117.25 (Ar–C), 117.82
yellow-colored crystal; m. p: 205–207 °C; Anal. Calc. for (Ar–C), 118.43 (Ar–C), 119.22 (Ar–C), 119.85 (Ar–C),
­C25H17N9O3S: C 57.35, H, 3.27, N, 24.08; (Found) C 57.33, 120.41 (Ar–C), 121.01 (Ar–C), 121.70 (Ar–C), 122.55 (Ar–
H, 3.26, N, 24.09; FT-IR (­ cm−1): 707 (C–S), 1023 (C–N), C), 123.33 (Ar–C), 123.88 (Ar–C), 124.57 (Ar–C), 125.55
1055 (C–N), 1527 (C=N), 1551 (C=N), 1582 (C=N), 1618

13
Journal of the Iranian Chemical Society

(Ar–C), 126.70 (Ar–C), 127.78 (Ar–C), 128.51 (Ar–C), Molecular docking

170.97 (C=O); ESI–MS (m/z) ­[M+ + 1]: 485.09 (485.12).
The molecular docking studies were performed using Auto-
2‑(Furan‑2‑yl)‑3‑{4‑(pyridin‑2‑yl)‑6‑[1‑(pyrimidin‑2 DockTools 1.5.6, AutoDock-Vina, and PyMOL software to
‑yl)‑1H‑imidazol‑4‑yl]pyrimidin‑2‑yl}‑1,3‑thiazoli‑ estimate the binding affinity and the H-bonding between the
din‑4‑one  %Yield: 84; light black-colored crystal; m. p: 1,3-thiazolidin-4-ones fused with 1-(pyrimidin-2-yl)-1H-im-
188–190 °C; Anal. Calc. for C ­ 23H16N8O2S: C 58.97, H, idazol-4-yl moieties (1–15) and the receptor GlcN-6P (PDB:
3.44, N, 23.92; (Found) C 58.95, H, 3.46, N, 23.90; FT-IR 2VF5). The smiles for the ligands (1–15) were generated
­(cm−1): 716 (C–S), 1029 (C–N), 1058 (C–N), 1515 (C=N), by ChemDraw Ultra 12.0 and used to translate these smiles
1549 (C=N), 1584 (C=N), 1607 (C=N), 1636 (C=N), 1675 to PDB files using online smiles translator. Now, the PDBs
(C=N), 1737 (C=O), 2983 (CH-Ar); 1H-NMR (DMSO-d6) of the receptor and ligands were converted to PDBQTs by
(ppm): 2.600 (s, 2H, S-CH2), 6.990–7.033 (m, 3H, Ar–H), AutoDockTools 1.5.6 which was utilized for docking by
7.088–7.125 (m, 4H, Ar–H), 7.190 (s, 1H, Ar–H), 7.227 AutoDock-Vina, and the final docked images were gener-
(s, 1H, Ar–H), 7.263 (s, 1H, Ar–H), 7.305–7.345 (m, 3H, ated using PyMOL [79–81].
Ar–H); 13C-NMR (DMSO-d6) (ppm): 55.11 (S-CH 2),
115.19 (Ar–C), 115.99 (Ar–C), 116.43 (Ar–C), 117.21 (Ar–
C), 117.85 (Ar–C), 118.15 (Ar–C), 119.22 (Ar–C), 120.11 Conclusion
(Ar–C), 120.88 (Ar–C), 121.44 (Ar–C), 122.28 (Ar–C),
123.33 (Ar–C), 124.02 (Ar–C), 124.81 (Ar–C), 125.26 (Ar– Fifteen computationally bioactive 1,3-thiazolidin-4-ones
C), 126.16 (Ar–C), 126.91 (Ar–C), 127.55 (Ar–C), 128.14 fused with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moie-
(Ar–C), 129.10 (Ar–C), 129.75 (Ar–C), 130.42 (Ar–C), ties were prepared and screened for antimicrobial, percent
171.11 (C=O); ESI–MS (m/z) ­[M+ + 1]: 469.12 (469.14). viability, and molecular docking. The structures were sup-
ported by FT-IR, NMR (1H & 13C), and mass spectroscopy,
and two compounds of the series (7 and10) exhibited bet-
Antimicrobial screening ter zone of inhibition than the standard drug ciprofloxacin,
while the other members possessed considerable activity.
Antimicrobial assessment of 1,3-thiazolidin-4-ones fused In silico molecular docking was also carried out that exhib-
with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15) ited interaction between the ligands and receptor (GlcN-6P).
was achieved against Gram-positive [S. aureus (ATCC- Therefore, it was observed that 1,3-thiazolidin-4-ones fused
25923), S. epidermidis (ATCC-29887)] and Gram-nega- with 1-(pyrimidin-2-yl)-1H-imidazol-4-yl moieties (1–15)
tive [E. coli (ATCC-25922), P. mirabilis (ATCC-25933)] represented very good binding affinities and H-bonding. The
by the disk diffusion procedure [66–76]. Paper disks percent viability of the cells portrayed that the compounds
(6 mm) were prepared and dipped into the stock solution were less toxic toward HepG2 cells.
of each compound (1 mg + 100 ml DMSO) and poured
onto agar plates having bacterial strains to record the zone Acknowledgements  Dr. Mohammad Arshad is highly thankful to
of inhibition. Serial dilutions (3.125, 6.25, 12.5, 50, 100, Dr. Feras Al-Marshad, The Dean College of Medicine, Al-Dawadmi,
Shaqra University Kingdom of Saudi Arabia, for his kind support to
200, and 400 µg/ml) were prepared from the stock solu- accomplish this study.
tions to find out the minimum inhibitory concentration
(MIC). Compliance with ethical standards 

Conflict of interest  The authors have no conflicts of interest.

Percent viability of the cell assessment

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Journal of the Iranian Chemical Society

Affiliations

Mohammad Arshad1   · Mohd Shoeb Khan2 · Shahab A. A. Nami3 · Syed Ishraque Ahmad4 · Mohd Kashif5 ·

Ansar Anjum5

1 4
Department of Basic Sciences, College of Medicine, Shaqra Department of Chemistry, Zakir Hussain Delhi College,
University, Al‑Dawadmi 11911, Kingdom of Saudi Arabia University of Delhi, New Delhi 110002, India
2 5
Interdisciplinary Nanotechnology Centre, Aligarh Muslim Department of Applied Sciences, Galgotia’s College
University, Aligarh, India of Engineering and Technology, Greater Noida,
3 Uttar Pradesh 201306, India
Department of Kulliyat, Faculty of Unani Medicine, Aligarh
Muslim University, Aligarh, India

13

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