Synthesis of novel 2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile derivatives by new spiro[indoline-3,4′-[1,3]dithiine]?Cu(NO3)2 supported on Fe3O4?gly?CE MNPs as efficient catalyst and evaluation of biological activity

Article abstract of DOI:10.1016/j.bioorg.2020.103751

New spiro[indoline-3,4′-[1,3]dithiine]?Cu(NO₃)₂ supported on Fe₃O₄?gly?CE magnetic nanoparticle were synthesized and used as efficient and recyclable catalyst in the synthesis of 2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile derivatives. The structure of magnetic nanoparticles were confirmed using energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), scanning electron microscopy (SEM), vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA), infrared spectroscopy (FT-IR) and inductively coupled plasma optical emission spectroscopy (ICP-OES). Subsequently, antibacterial and antifungal activities in terms of inhibition zone diameter, minimum inhibitory concentration, minimum bactericidal concentration and antioxidant activity against the DPPH free radical of the derivatives were investigated. The results revealed acceptable biological effects of the synthetic derivatives and a significant relationship between their structure and biological activity were observed.

Full text of DOI:10.1016/j.bioorg.2020.103751

Bioorganic Chemistry 98 (2020) 103751
Contents lists available at ScienceDirect
Bioorganic Chemistry
journal homepage: www.elsevier.com/locate/bioorg
Synthesis of novel 2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile
derivatives by new spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO ) supported
3
2
on Fe O @gly@CE MNPs as efficient catalyst and evaluation of biological
3
4
activity
⁎
Mohammadreza Moghaddam-Manesh, Enayatollah Sheikhhosseini , Dadkhoda Ghazanfari,
Mohammadreza Akhgar
Department of Chemistry, Kerman Branch, Islamic Azad University, Kerman, Iran
A R T I C L E I N F O
A B S T R A C T
Keywords:
New spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
3
)
2
supported on Fe
3
O @gly@CE magnetic nanoparticle were
4
Magnetic nanoparticle
synthesized and used as efficient and recyclable catalyst in the synthesis of 2-oxospiro[indoline-3,4′-[1,3]di-
thiine]-5′-carbonitrile derivatives. The structure of magnetic nanoparticles were confirmed using energy-dis-
persive X-ray spectroscopy (EDX), X-ray diffraction (XRD), scanning electron microscopy (SEM), vibrating
sample magnetometer (VSM), thermogravimetric analysis (TGA), infrared spectroscopy (FT-IR) and inductively
coupled plasma optical emission spectroscopy (ICP‐OES). Subsequently, antibacterial and antifungal activities in
terms of inhibition zone diameter, minimum inhibitory concentration, minimum bactericidal concentration and
antioxidant activity against the DPPH free radical of the derivatives were investigated. The results revealed
acceptable biological effects of the synthetic derivatives and a significant relationship between their structure
and biological activity were observed.
2
-Oxospiro[indoline-3,4′-[1,3]dithiine]
Antimicrobial activity
Antioxidant activity
1
. Introduction
inhibitors have been recently synthesized [11]. Jessica et al. synthe-
sized compounds containing l,3-dithiin and suppressed them as the
The use of nanoparticles has recently received much attention due
glycineamide ribonucleotide formyltransferase inhibitor, which pre-
vents DNA synthesis and also may prevent tumor growth [27]. In ad-
dition, biological Activity of 5-Alkylthio-1,3-dithianes against insects
have been reports [28].
to their unique properties [1]. These compounds are used in various
fields such as chemistry, biology, physics, etc. [2–5]. One of the ap-
plications of these compounds in chemistry is as catalysts. Nano-
particles can be used as magnetic cores for catalyst synthesis. In this
According to our previous studies, 1,3-dithiin have a high ability to
inhibit bacterial strains. Also, these compounds exhibit good oxidative
effects [29–31].
regard, Fe
3
4
O nanoparticles are mainly used as magnetic cores for the
preparation of magneto nano catalysts. The most important advantages
of these catalysts include environmental friendliness, recyclability and
easy separation after reaction. Because of their magnetism, these cat-
alysts can be separated using a magnet and reused after washing
Several methods have been reported for the synthesis of l,3-dithiin
derivatives, the best of which is the use of carbonyl compounds, espe-
cially aldehydes, and propane-1,3-dithiol with various catalysts
[32–36]. However, the use of other starting materials has also been
reported for the synthesis of l,3-dithiin derivatives. As an example, the
use of arylidenemalononitriles and active methylene compounds with
carbon disulfide has been reported as starting materials in the synthesis
of l,3-dithiin derivatives [29,37].
[
6–13]. Spiroheterocycles have critical bioactive components, and their
synthesis has been prominent [14–21]. The l,3-dithiin is an organo-
sulfur compound with biological properties. The derivative 2-vinyl-4H-
1
,3-dithiine has antithrombotic activity, and found in garlic [22–24].
Biological activities such as antimicrobial and antifungal activities
of compounds containing dithiane have been reported [25,26].
Multi-ring compounds containing a l,3-dithiin ring with the prop-
erty of histone deacetylase and DNA topoisomerase II-Targeted
Regarding the importance of 1,3-dithiane, spiro compounds and
magnetic nanocatalysts, novel 6′-amino-2′-(tetrahydro pyrimidin-
5(2H)-ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile
⁎
Corresponding author.
E-mail address: sheikhhosseini@iauk.ac.ir (E. Sheikhhosseini).
https://doi.org/10.1016/j.bioorg.2020.103751
Received 2 January 2020; Received in revised form 4 February 2020; Accepted 9 March 2020
0045-2068/ © 2020 Elsevier Inc. All rights reserved.

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
were synthesized and by using it spiro[indoline-3,4′-[1,3]dithiine]@Cu
same temperature. The black precipitates were removed by magnet and
(
NO
3
)
2
supported on Fe
3
O @gly@CE magnetic nanoparticle were
4
washed several times with water and ethanol and dried at ambient
synthesized and was used as a magnetic nanocatalysts in the synthesis
of 2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile derivatives .
The biological properties of these compounds such as antibacterial and
antifungal properties as well as their antioxidant activity were in-
vestigated.
temperature [39]. With the sonication, 1g of the prepared Fe
3
O @gly
4
was disperse in toluene (100 mL), then 8 mmol 6′-amino-2-oxo-2′-
(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)spiro[indoline-3,4′-
[1,3]dithiine]-5′-carbonitrile (7a) was added under N atmosphere and
2
stirred at reflux temperature for 12 h. The precipitates were removed
with a magnet and dried over room temperature after several times
rinses with ethanol. 1 g of nanoparticles of the previous step were
dispersed in 100 mL EtOH under ultrasound conditions and 1.93 g Cu
The novelty in this work is the synthesis of new magnetic nano-
complexes and their application is in the synthesis of new bioactive
derivatives of 1,3-dithiane. The importance of these nanoparticles as
catalysts is their easy separability after reaction and reuse compared to
previously reported catalysts [29].
(NO
3
)
2
·3H O added to the mixture, then stirred and refluxed for 12 h
2
under N
2
atmosphere. The Fe
3
O
4
@gly@thiophen@Cu(NO
3
) with the
2
magnet were separated and after several times washing with water and
ethanol were dried at ambient temperature.
2
. Experimental section
2.1. General
2.5. Synthesis of products 7a-f in MNPs‑catalyzed condition
All chemicals and solvents were procured from Merck and Sigma-
A mixture of 1 mmol (0.066 g) malononitrile and 1 mmol isatine
derivatives in 2 mL acetonitrile was stirred at room temperature for
30 min. In the other container, 1 mmol barbituric acid derivatives,
3 mmol (0.2284 g) carbon disulphide and MNPs (10 mg) in 2 mL of
acetonitrile was stirred at room temperature for 30 min. Then, the
mixtures were added together and stirred at room temperature for
4.5–6.5 h. After completion of the reaction (monitoring with TLC n-
hexane/ethyl acetate), 10 mL acetonitrile was added to the mixture and
the catalyst was separated by an external magnet and washed with
EtOH and water, then the precipitates were separated and the pur-
ification was done by recrystal in acetonitrile.
Aldrich with high-grade quality and used without further purification.
Antibiotics were purchased from Sigma-Aldrich. Melting points were
recorded on a Kruss type KSP1 N melting point meter and uncorrected.
Monitoring progress of the reactions and the purity of the products
were affected by TLC and all yields refer to isolated products. A scan-
ning electron microscope (SEM) was applied to observe the surface
morphology of nanoparticles using a Hitachi S4160 instrument. The X-
ray diffraction (XRD) analysis was conducted by using a Bruker D8 X-
ray diffractometer with Cu-Kα radiation (λ = 1.5418 Å) in the range of
1
0–70° and the scanning rate of 1.5°/min. The IR spectra of the pro-
ducts were recorded on a Bruker Tensor 27 FT-IR spectrometer using
6′-amino-2-oxo-2′-(2,4,6-trioxotetrahydropyrimidin-5(2H)-ylidene)
spiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7a)
−
1
1
13
KBr disks with absorption in cm . The H and C NMR spectra of
DMSO-d solutions were recorded on a Bruker FT-NMR Ultra Shield-
−1
6
Light yellow powder; M.p. 210–212 °C; IR (KBr, cm ): 3144, 3011
1
4
00 spectrometer (250 and 75 MHz, resp.). Elemental analyses were
(NH , NH), 2255 (CN), 1667 (CO), 1581 (C]C). H NMR (250 MHz,
2
performed for C, H, N, and S on a Thermo Finnigan Flash EA micro-
analyzer. The concentration of bacterial and fungal suspensions was
determined by using Jenway 6405 UV–V is spectrophotometer.
DMSO-d ) δ: 6.72 (1H, d, J = 7.47 Hz, H-Ar), 6.83 (1H, t, J = 7.18 Hz,
6
H-Ar), 6.94 (2H, s, NH ), 7.11 (1H, t, J = 7.62 Hz, H-Ar), 7.29 (1H, d,
2
1
3
J = 7.12 Hz, H-Ar), 9.16 (2H, s, NH), 10.32 (1H, s, NH). C NMR
(
75 MHz, DMSO-d
6
) δ: 52.4, 82.0, 109.3, 113.8, 121.6, 123.9, 128.8,
2
.2. Synthesis of products 7a-f in base‑catalyzed conditions
131.8, 142.9, 151.9, 164.3, 177.1. Anal. Calcd for C H N O S : C,
1
6 9 5 4 2
4
8.11; H, 2.27; N, 17.53; S, 16.06. Found: C, 48.15; H, 2.26; N, 17.56; S,
16.02.
6′-amino-2′-(4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)-2-
A mixture of 1 mmol malononitrile (0.066 g) and 1 mmol isatine
derivatives was added to 2 mL of acetonitrile and stirred at ambient
temperature for 0.5 h. In another container, add 1 mmol of barbituric
acid derivatives, 3 mmol carbon disulfide (0.2284 g) and 2 mmol
triethylamine (0.2024 g) to 2 mL of acetonitrile and was stirred at
ambient temperature for 1 h. Then add the mixtures together and was
stirred at ambient temperature for 5–9 h. After completion of the re-
action (monitoring with TLC hexane/ethyl acetate), the precipitates
were separated and the purification was done by recrystal in acetoni-
trile.
oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7b)
−1
Light cream powder; M.p. 215–216 °C; IR (KBr, cm ): 3400 and
1
3154 (NH, NH ), 2194 (CN), 1722 (CO), 1587 (C]C). H NMR
2
(250 MHz, DMSO-d ) δ: 6.69–6.94 (4H, m, 2H-Ar and NH ), 7.13 (1H, t,
6
2
J = 7.50 Hz, H-Ar), 7.28 (1H, d, J = 7.0 Hz, H-Ar), 10.39 (1H, s, NH),
1
3
10.64 (2H, s, 2NH). C NMR (75 MHz, DMSO-d ) δ: 52.1, 90.4, 109.3,
6
113.6, 118.6, 123.6, 128.0, 129.1, 131.0, 135.5, 142.6, 160.8, 162.1,
173.7, 178.5, 179.1. Anal. Calcd for C H N O S : C, 46.25; H, 2.18; N,
16 9 5 3 3
1
6.86; S, 23.16. Found: C, 46.22; H, 2.20; N, 16.88 0.53; S, 23.17.
2
.3. Computational studies
6′-amino-5-chloro-2-oxo-2′-(2,4,6-trioxotetrahydropyrimidin-5(2H)-
ylidene)spiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7c)
−1
By using Gaussian 09 program package at 298.15 K and 1 atm,
Light cream powder; M.p. 212–213 °C; IR (KBr, cm ): 3370, 3170
1
geometrie of 7a were optimized at the B3LYP level of theory in con-
(NH
2
, NH), 2257 (CN), 1702, 1683 (CO), 1585 (C]C). H NMR
**
junction with 6-311++G basis set and no molecular symmetry con-
straint was considered [38].
(250 MHz, DMSO-d
NH ), 7.17 (1H, d, J = 8.25 Hz, H-Ar), 7.29 (1H, s, H-Ar), 9.29 (s, 2H,
NH), 10.42 (1H, s, NH). C NMR (75 MHz, DMSO-d
110.7, 113.6, 123.9, 125.3, 125.8, 127.9, 128.7, 133.7, 141.6, 141.9,
6
) δ: 6.75 (1H, d, J = 8.0 Hz, H-Ar), 6.91 (2H, s,
2
1
3
6
) δ: 52.6, 81.8,
2
.4. Synthesis of spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
3
2
) supported
on Fe @gly@CE magnetic nanoparticles
3
O
4
151.9, 164.2, 176.8. Anal. Calcd for C16
H
8
5
ClN O
4 2
S
: C, 44.29; H, 1.86;
N, 16.14; S, 14.78. Found: C, 44.33; H, 1.85; N, 16.12; S, 14.77.
6′-amino-5-chloro-2′-(4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-
ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7d)
FeCl ·4H O (1.988 g) and FeCl ·6H O (5.406 g) were dissolved in
2
2
3
2
8
0 mL of water and stirred at 1000 rpm under N
2
atmosphere.
−1
Temperature was slowly increased to 70 °C under and stirred at the
same temperature for 30 min, 30 mL of 25% ammonia solution was
added to the reaction mixture and stirred for 30 min at the same tem-
perature. 4 mL aqueous solution (0.3 g/mL) of glycine was added and
the temperature was slowly raised to 90 °C, and stirred for 60 min at
Light cream powder; M.p. 224–226 °C; IR (KBr, cm ): 3220, 3174
1
(NH
2
, NH), 2194 (CN), 1729, 1656 (CO), 1501 (C]C). H NMR
(250 MHz, DMSO-d
Ar), 7.05 (2H, s, NH
NH), 10.85 (1H, s, NH). C NMR (75 MHz, DMSO-d
6
) δ: 6.73 (1H, d, J = 8.25 Hz, H-Ar), 6.94 1H, s, H-
2
), 7.12 (1H, d, J = 8.0 Hz, H-Ar), 10.37 (s, 2H,
1
3
6
) δ: 48.4, 89.7,
2

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
1
1
1
10.7, 118.5, 123.6, 125.8, 127.9, 137.6, 141.6, 160.3, 161.0, 162.2,
78.8, 178.9. Anal. Calcd for C16 ClN : C, 42.71; H, 1.79; N,
5.57; S, 21.38. Found: C, 42.76; H, 1.78; N, 15.57; S, 21.35.
′-amino-5-bromo-2-oxo-2′-(2,4,6-trioxotetrahydropyrimidin-5(2H)-
3. Results and discussion
H
8
5
O
S
3 3
3.1. Catalyst synthesis
6
ylidene)spiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7e)
In this study, we first synthesized 6′-amino-2′-(tetrahydropyrimidin-
5(2H)-ylidene)-2-oxospiro [indoline-3,4′-[1,3]dithiine]-5′-carbonitrile
by using isatine, malononitrile, barbituric acid, carbon disulfide and
triethylamine as catalysts. Then in the foure step, spiro[indoline-3,4′-
−
1
Dark cream .powder M.p. 219–220 °C; IR (KBr, cm ): 3246, 3013
1
(
NH
2
, NH), 2260 (CN), 1701 (CO), 1595 (C]C). H NMR (250 MHz,
DMSO-d
6
) δ: 6.71 (1H, d, J = 8.25 Hz, H-Ar), 6.90 (2H, s, NH
2
), 7.30
(
(
1H, d, J = 7.0 Hz, H-Ar), 7.14 (1H, s, H-Ar), 9.28 (s, 2H, NH), 10.51
[1,3]dithiine]@Cu(NO
were synthesized.
3
)
2
supported on Fe
3
O
4
@gly@CE nanoparticles
·6H O and glycine
1
3
1H, s, NH). C NMR (75 MHz, DMSO-d ) δ: 52.5, 81.8, 111.3, 113.0,
6
1
1
1
13.6, 121.7, 126.6, 131.6, 134.1, 142.3, 151.9, 161.2, 164.3, 164.4,
76.7. Anal. Calcd for C16 BrN : C, 40.18; H, 1.69; N, 14.64; S,
3.41. Found: C, 40.13; H, 1.68; N, 14.66; S, 13.43.
′-amino-5-bromo-2′-(4,6-dioxo-2-thioxotetrahydropyrimidin-5(2H)-
In the first step by using FeCl
2
·4H O, and FeCl
2
3
2
H
8
5
O
S
4 2
Fe
from the reaction of Fe
chloroethane, Fe @gly@CE were synthesized. From the reaction of
Fe @gly@CE with 6′-amino-2′-(tetrahydropyrimidin-5(2H)-ylidene)
−2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile, spiro[indo-
line-3,4′-[1,3]dithiine supported on Fe @gly@CE in the third step
were synthesized. Finally, from the reaction of synthesized nano-
particles in previous step with Cu(NO , the desired magnetic nano-
particle, spiro[indoline-3,4′-[1,3]dithiine]@ Cu(NO supported on
3
O
4
coated with glycine were synthesized [37]. In the second step
O
3 4
@gly magnetic nanoparticles with 1,2-di-
6
O
3 4
ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile (7f)
O
3 4
−
1
Light pink powder; M.p. 225–226 °C; IR (KBr, cm ): 3273, 3164
1
(
NH
2
, NH), 2194 (CN), 1729, 1657 (CO) 1501 (C]C). H NMR
3 4
O
(
250 MHz, DMSO-d
6
) δ: 6.69 (1H, d, J = 8.0 Hz, H-Ar), 7.05 (3H, br s,
NH
2
and H-Ar), 7.26 (1H, d, J = 8.0 Hz, H-Ar), 10.38 (s, H, NH), 10.83
3 2
)
1
3
(
2H, br s, 2NH). C NMR (75 MHz, DMSO-d
6
) δ: 56.4, 89.7, 109.3,
)
3 2
1
1
1
11.3, 113.6, 118.5, 126.3, 130.8, 131.9, 137.9, 142.0, 160.3, 161.0,
Fe
3
O @gly@ CE were synthesized. Next, we performed quantum me-
4
62.2, 178.8. Anal. Calcd for C16
H
8
BrN
5
O
S
3 3
: C, 38.87; H, 1.63; N,
chanical studies to determine a metal binding site into an organic
compound and form stable complex. The optimized structure of the 6′-
amino-2′-(tetrahydropyrimidin-5(2H)-ylidene)-2-oxospiro[indoline-
4.17; S, 19.46. Found: C, 38.84; H, 1.63; N, 14.20; S, 19.43.
3
,4′-[1,3]dithiine]-5′-carbonitrile were shown in Fig. 1.
2.6. Antimicrobial activity
The structural of the spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
)
3 2
supported on Fe
3
O @gly@CE magnetic nanoparticles were confirmed
4
The in vitro inhibitory activities of all the newly synthesized com-
using energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction
pounds and antibiotics were evaluated against 17 standard pathogenic
bacteria including gram-negative strains Acinetobacter baumannii
(
XRD), scanning electron microscopy (SEM), Vibrating Sample
Magnetometer (VSM), thermogravimetric analysis (TGA), infrared
spectroscopy (FT-IR) and inductively coupled plasma optical emission
spectroscopy (ICP‐OES).
(
PTCC 1855), Pseudomonas aeruginosa (PTCC 1310), Klebsiella pneu-
moniae (PTCC 1290), Escherichia coli (PTCC 1399), Shigella dysen-
teriae (PTCC 1188), Proteus mirabilis (PTCC 1776), Salmonella enterica
subsp. enterica (PTCC 1709), Yersinia enterocolitica (PTCC 1151) and
gram-positive strains Streptomyces fradiae (PTCC 1121) Streptococcus
pyogenes (PTCC1447), Streptococcus agalactiae (PTCC 1768),
Streptococcus equinus (PTCC 1445), Staphylococcus aureus (PTCC
In EDX spectrum (Fig. 2) the elements include Fe, O, C, N, S, and Cu
were observed which represents the elements of the raw materials were
present in the synthesized magnetic nanoparticles.
According to the X-pert high score software, standard crystalline
cubic spinel X-ray spectra of Fe
3
O nanoparticles in positions of 2θ
4
1
1
189), Staphylococcus epidermidis (PTCC 1435), Bacillus cereus (PTCC
665), Bacillus thuringiensis subsp. kurstaki (PTCC 1494),
angles at 30.4, 35.7, 43.4, 53.9, 57.3 and 61.1 [41–43] in XRD pattern
of spiro[indoline-3,4′-[1,3]dithiine]@ Cu(NO
gly@CE that were observed (Fig. 3).
3
)
2
supported on Fe
3
4
O @
Rhodococcus equi (PTCC 1633) and fungi including Aspergillus fumi-
gatus (PTCC 5009), Candida albicans (PTCC5027) and Fusarium oxy-
sporum (PTCC 5115) which were prepared from the Persian type cul-
ture collection. Antimicrobial properties including broth microdilution
and time-kill susceptibility were tested according to the Clinical and
Laboratory Standards Institute (CLSI) guidelines M07-A9, M26-A, M02-
A11, M44-A and M27-A2 [29,40].
Based on SEM images of synthesized magnetic nanoparticles, the
size of the compounds was in the range of nano scale and the mor-
phology and surface structure has uniform (Fig. 4).
Vibrating sample magnetometer (VSM) measurements for Fe
3
4
O @
−1
gly has been reported 65.2 emu g
[39]. For synthesized magnetic
−1
nanoparticles VSM was obtained 15.9 emu g . The difference and
decrease in VSM value indicates the formation of the desired structure
All the tests were repeated three times, and the results were ex-
pressed as the average of three independent experiments.
(
Fig. 5).
2.7. Antioxidant activity
The antioxidant effect of the synthesized compounds on the DPPH
radical was evaluated according to previous reported methods [29,40].
Accordingly, 1 mL of various concentrations of the test compounds (25,
5
0, 75, and 100 μg/mL) in methanol was added to 4 mL of 0.004% (w/
v) methanol solution of DPPH. After a 30 min incubation period at
room temperature, the absorbance was read against blank at 517 nm.
The percent of inhibition (I %) of free radical production from DPPH
was calculated by the following equation:
%
of scavengin = (A control
A sample) / (A control) × 100
A control: all the reagents expect the test compound;
A sample: absorbance of the test compound;
Fig. 1. Optimized structure of the 6′-amino-2′-(tetrahydropyrimidin-5(2H)-yli-
The tests were carried out in triplicate, and their average was re-
dene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile.
ported.
3

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
Fig. 2. EDX spectrum of spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
3
)
2
sup-
ported on Fe
3
4
O @gly@CE.
Fig. 5. VSM curve of spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
on Fe @gly@CE.
3
) supported
2
O
3 4
Fig. 6. TGA analysis spectrum of spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
supported on Fe @gly@CE.
)
3 2
O
3 4
Peaks of the target groups were observed at all steps of synthesis.
For example in the FT-IR spectrum of the final product: stretching vi-
−1
−1
bration of CueN appeared in regions 450 cm , the peak at 570 cm
can be attributed to stretching vibration of FeeO. CeS stretching vi-
Fig. 3. XRD patterns of a: Fe
3
O
4
; b: spiro[indoline-3,4′-[1,3]dithiine]@Cu
−1
brations appeared in regions 810 cm . Stretching vibrations peaks in
(
NO supported on Fe @gly@CE.
3
)
2
3
O
4
−1
−1
−1
the region 1100 cm , 1630 cm and 2100 cm due to CeO, nitrile
group and carbonyls group, respectively. CeH stretching vibration of
−1
the alkaline chain in the region of 2893 cm
and broad bond at
−1
3
433 cm
for the amine group has appeared.
Inductively coupled plasma optical emission spectroscopy
(
ICP‐OES) to determine the amount of Cu loaded on magnetic nano-
−1
particle was performed and 1.32 mmol.g
was found.
Based on the calculations obtained on 6′-amino-2′-(tetra-
hydropyrimidin-5(2H)-ylidene)-2-oxospiro
[indoline-3,4′-[1,3]di-
Fig. 4. SEM images of a: Fe
1,3]dithiine] supported on Fe
thiine]@Cu(NO supported on Fe
3
O
4
@gly
@ gly@CE; d: spiro[indoline-3,4′-[1,3]di-
@gly@CE.
;
b: Fe
3
O
4
@gly@CE; c: spiro[indoline-3,4′-
thiine]-5′-carbonitrile, the best position in terms of spatial position and
atomic charge, Fig. 8 was suggested for the magnetic nanoparticles.
[
3 4
O
3
)
2
O
3 4
3
.2. Synthesis of 6′-amino-2′- tetrahydropyrimidin-5(2H)-ylidene)-2-
oxospiro [indoline-3,4′-[1,3]dithiine]-5′-carbonitrile derivatives
In thermogravimetric analysis (TGA) of synthesized magnetic na-
noparticles (Fig. 6), the small amount of weight loss up to 100° C were
related to the evaporation of the water trapped on the surface of na-
noparticle. Weight loss up to 450° C, was related to organic compounds
and weight loss observed at 450° C to 550° C were related to decom-
position of the complex. Reduce the weight in the TGA curve proved the
structure of the synthesized desired product.
By using isatine derivatives, malononitrile, barbituric acid deriva-
tives and carbon disulfide as a starting material, new derivatives of 6′-
amino-2′- tetrahydropyrimidin-5(2H)-ylidene)-2- oxospiro [indoline-
3,4′-[1,3]dithiine]-5′-carbonitrile with two different conditions (base
condition vs acid condition) were synthesized (Scheme 1).
The use of triethylene amine in base conditions and spiro[indoline-
3,4′-[1,3]dithiine]@Cu(NO
3
)
2
supported on Fe
3
4
O @gly@CE (MNPs) as
The FT-IR spectrum steps of the synthesized magnetic nanoparticles
were illustrated in Fig. 7.
acid catalysts was another conditions to synthesize new derivatives. In
the MNPs-catalyzed condition, the reactions were optimized for
4

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
Scheme 1. Multicomponent synthesis of 6′-amino-2′-(tetrahydropyrimidin-
5
(2H)-ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile deriva-
tives (7a-f).
Table 1
Optimization catalyst amount.
Entry
Product
MNPs (mg)
Time (h)
Yield (%)
1
2
3
4
5
6
7a
7a
7a
7a
7a
7a
0
7
0
5
7
41
65
85
92
90
10
15
20
25
6.5
5.5
5.5
5.5
Table 2
Multicomponent
synthesis
6′-amino-2′-(4,4-dimethyl-2,6-dioxocyclohex-
ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile 7a-f derivatives
under two different conditions.
Entry
R
X
T (°C)
Base-catalyzed
MNPs-catalyzed
Time (h)
Yield (%)
Time (h)
Yield (%)
7a
7b
7c
7d
7e
7f
H
O
S
r
r
r
r
r
r
t
t
t
t
t
t
9
89
92
81
78
74
70
6.5
5
92
93
87
84
86
85
H
8.5
7
Cl
Cl
Br
Br
O
S
4.5
4.5
6
7
O
S
8.5
8
Fig. 7. FT‐IR spectra a: Fe
3
O
4
@gly
;
b: Fe
@ gly@CE; d: spiro[indoline-3,4′-[1,3]di-
@gly@CE.
3
O
4
@gly@CE; c: spiro[indoline-3,4′-
5.5
[
1,3]dithiine] supported on Fe
3 4
O
thiine]@Cu(NO
3
)
2
supported on Fe
3 4
O
reactivity of starting materials such as isatine derivatives.
The chemical structures of derivatives 7a–f was confirmed based on
1
13
H NMR, C NMR, FT IR spectra and elemental analyses. For example
−
1
in derivative 7a, amine groups exhibited bands near 3144, 3011 cm
1
and 6.87, 9.15, 10.39, 10.64 ppm based on FT IR and H NMR, re-
−1
spectively. Nitrile exhibited bands near 2255 cm and 82.0 ppm based
1
3
on FT IR and C NMR, respectively, also carbonyl groups exhibited
−1
bands near 1667 cm and 162.2, 173.7, 178.5, 179.1 ppm based on FT
1
3
IR and C NMR, respectively. The proposed mechanism is presented in
Scheme 2.
From the reaction of isatine with malononitrile, 3a (2-(2-oxoindolin-
3
-ylidene) malononitrile) was formed. In the presence of the base cat-
alyst, carbon disulfide and barbituric acid formulated 8a that was in
equilibrium with the 6a.
From the Michael addition reaction of 3a (2-(2-oxoindolin-3-yli-
dene)malononitrile) with 6a, intermediate 9a was formed, which led to
the creation of 10a by intramolecular hydrogen shifts. By the nucleo-
philic sulfur attack on the cyanide group, intermediate 11a was created
and eventually with hydrogen shift, 7a (6′-amino-2-oxo-2′-(2,4,6-
trioxotetrahydropyrimidin-5(2H)-ylidene)spiro [indoline-3,4′-[1,3]di-
thiine]-5′-carbonitrile) was formed.
Fig. 8. Suggested structure for spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
supported on Fe @gly@CE.
)
3 2
O
3 4
magneto nanoparticles amount (Table 1).
After synthesized of the derivatives, catalyst was separated by a
magnet (Fig. 9) and washed several times with ethanol and water and
used again after drying. The recovery results for the magnetic nano-
particles as a catalyst indicate that they can be reused efficiently up to
six times (Fig. 10).
The optimization results showed that the best yield was 20 mg of the
catalyst. According to the results presented in Table 2, the products
synthesized with MNPs had a shorter reaction time and higher yields,
and there was no significant relationship between the yields and
5

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
Table 3
Antibacterial activities of derivatives 7a-f against gram-negative strains.
Bacteria Products Antibiotics
7
a
7b
7c
7d
7e
7f
a
b
1
1
1
1
1
855
310
290
399
188
IZD
9.19
128
–
–
–
–
–
–
–
–
–
10.71
8
–
–
–
–
9.80
–
–
–
–
–
–
19.74
32
MIC
–
256
512
–
MBC 256
16
–
32
IZD
12.13
64
20.48 9.63
14.93
128
256
15.42
256
512
25.87
0.25
0.5
MIC
32
64
128
–
–
MBC 128
64
–
IZD
16.64
128
13.84
128
256
–
18.53 21.42
MIC
–
–
0.25
0.5
4
8
MBC 256
–
–
IZD
20.11 14.28 12.43 9.01
15.26 13.92 22.95 23.12
MIC
8
128
256
8
256
512
8
64
8
8
MBC 16
16
16
128
16
–
16
IZD
14.12 12.28 11.41 10.96 12.98 10.16
20.74
0.063
0.126
MIC
32
128
256
16
32
16
32
32
64
128
256
–
Scheme 2. Proposed mechanism for the synthesis of 6′-amino-2′-(tetra-
hydropyrimidin-5(2H)-ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-car-
bonitrile derivatives.
MBC 64
–
1776
IZD
18.42 11.16 16.54 10.21 12.38 9.48
31.61 21.41
MIC
32
128
256
8
32
64
128
256
512
0.5
1
0.5
1
MBC 64
16
1024
1
1
709
151
IZD
17.40 11.48 11.18 10.68 15.25 10.96 23.71 28.74
MIC
64
512
32
64
256
512
128
256
11.28
256
512
512
2
4
4
4
MBC 128
1024
1024
IZD
14.31 9.63
12.57 9.90
–
–
–
19.21 23.16
MIC
32
256
512
32
64
128
256
8
4
8
MBC 64
32
IZD values reported as mm; MIC and MBC values reported as μg/mL, a:
Cefazolin; b: Gentamicin.
Table 4
Antibacterial activities of derivatives 7a-f against gram-positive strains.
Bacteria
Products
Antibiotics
7
a
7b
7c
7d
7e
7f
a
b
1
1
1
1
1
121
447
768
445
189
IZD
15.22
128
–
–
–
12.34
32
–
–
–
–
–
–
–
–
–
–
–
–
10.43 9.87
21.64 21.46
MIC
64
64
128
–
16
16
8
Fig. 9. Capability of separating the catalyst using a magnet.
MBC 256
64
128
24.86
32
16
IZD
27.09 11.41 25.17
20.49 14.63
MIC
64
64
128
–
32
–
8
2
4
–
–
–
MBC 128
64
64
–
16
IZD
19.02
256
10.22
512
1024
17.83
64
12.51
512
1024
14.95
64
–
34.35
MIC
–
–
4
8
MBC 512
–
–
IZD
16.48
128
–
–
20.71 19.25
MIC
–
–
32
64
1
4
MBC 256
–
128
128
–
IZD
19.47 10.68 12.33 10.61 12.21 9.80
21.58 20.85
MIC
8
32
64
–
64
128
256
64
32
64
8
1
2
MBC 16
128
128
16
Fig. 10. Reusability of magnetic nanoparticle in synthesis 7a.
1435
IZD
13.52
256
13.46 11.26 14.53 10.26 23.89 27.12
MIC
–
256
32
64
–
512
512
1
4
–
–
–
–
–
–
–
–
–
2
MBC 512
–
512
1024
1024
2
Inductively coupled plasma optical emission spectroscopy
1
1
1
665
494
633
IZD
13.18
512
–
14.76
256
12.07 10.21
23.78
(
ICP‐OES) of the nanocatalyst after 6 re-use was performed and it was
MIC
–
–
128
256
11.39
16
512
0.5
−
1
found to be 1.32 mmol.g
.
MBC 1024
–
512
–
1024
4
IZD
12.83
32
–
12.17
512
–
–
–
–
–
–
–
25.23
MIC
–
–
1
3
.2. Biological evaluation
.2.1. Antibacterial activity
MBC 64
–
1024
–
32
2
IZD
14.96 10.18 12.52
–
12.18
16
21.05
3
MIC
16
64
32
64
–
2
4
MBC 32
128
–
32
All the tested synthesized compounds had antibacterial properties
and were generally effective on 7–17 against gram-negative and gram-
positive standard strain. Best effects based on the MIC (minimum in-
hibitory concentration) and MBC (minimum bactericidal concentration)
value was related to 7c. This derivative had an effect on 17 bacteria
with MIC at 8–512 μg/mL. Derivatives 7a, 7e, 7d, 7b and 7f, respec-
tively, had the following rankings based on the MIC and MBC value in
antibacterial effects. The results were reported in Tables 3 and 4.
Antibacterial activity was generally dependent on the barbituric
acid derivative and ultimately on the isatin derivative.
IZD values reported as mm; MIC and MBC values reported as μg/mL, a:
Cefazolin; b: Gentamicin.
Derivatives contains barbituric acid had the highest effect than
derivatives contains thiobarbituric acid and the order of effect of the
isatin derivatives was chlorine, hydrogen and bromine. So as can be
seen in the Table 3 and Table 4 derivative 7c has the highest effect with
barbituric acid and chlorine in its structure.
6

M. Moghaddam-Manesh, et al.
Bioorganic Chemistry 98 (2020) 103751
Table 5
Tolnaftate and Terbinafine drugs. For example, Tolnaftate had no effect
Antifungal activities of derivatives 7a-f.
on 5009, 5027, and 5115 but 7c had the MIC value of 8–16 µg.
Fungi
Products
Antibiotics
a
3
.2.3. Antioxidant activity
7
a
7b
7c
7d
7e
7f
b
Antioxidant results showed that the synthetic compounds 7a-f had
inhibitory effects greater than 50% in 20 μg/mL. The IC50 for these
compounds was 11.60–17.24. The most inhibitory effect was on deri-
vatives 7f, 7b, 7e, 7a, 7d and 7c, respectively, and the IC50 was obtained
3.94 μg/mL for ascorbic acid (Table 6).
5
5
5
009
027
115
IZD
36.81 23.27 27.17 21.84 28.42 18.65 28.04
–
–
–
–
–
–
–
–
–
MIC
8
64
128
–
8
128
256
–
32
128
256
–
32
MFC 16
16
11.45
8
64
64
IZD
9.68
64
9.74
64
34.51
32
MIC
–
–
–
The proposed mechanisms for the DPPH free radical stability by 7a-f
are presented in the Scheme 3.
MFC 128
–
16
–
128
–
64
IZD
28.24 19.17 22.23 21.87 24.18 13.42 24.15
MIC
64
64
16
32
32
64
32
64
64
32
64
MFC 128
128
128
4. Conclusion
IZD values reported as mm; MIC and MFC values reported as μg/mL, a:
Terbinafine; b: Tolnaftate.
We synthesized new 6′-amino-2′-(tetrahydropyrimidin-5(2H)-yli-
dene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-5′-carbonitrile
deriva-
tives using acidic and base conditions. We used triethylene amine in
base condition. Moreover, we used a novel spiro[indoline-3,4′-[1,3]
Table 6
Antioxidant activities of derivatives 7a-f.
Compounds
dithiine]@Cu(NO
3
)
2
supported on Fe
3
O @gly@CE as MNPs catalyst in
4
Scavenging concentrationsa
IC50a
acid condition, and the results showed higher yields and less time than
base condition. In addition, the catalyst was recyclable and, due to its
magnetism, was easily separated by the magnet at the end of the re-
5
10
15
20
action. Spiro[indoline-3,4′-[1,3]dithiine]@Cu(NO
3
)
2
supported on
7
7
7
7
7
7
a
b
c
d
e
f
45
47
48
52
15.42
12.50
17.24
16.52
15.04
11.60
3.94
47
53
55
62
Fe
3
O @gly@CE is in the nanoscale range and has uniform morphology
4
28
32
41
57
without any agglomeration in its structure. In the study of antibacterial
effects, all the synthetic derivatives were effective on standard and
resistant strain bacteria. Moreover, there existed a relationship between
the structure of the compounds and their antibacterial properties. The
antibacterial properties of the derivatives were firstly bound to the
barbituric acid derivative ring and ultimately dependent on the isatine
derivatives. In general, derivatives containing barbituric acid have a
better effect than those containing thiobarbituric acid. In addition,
derivatives containing chlorine, hydrogen, and bromine at carbon 5 of
isatine have an order of antibacterial properties. Antifungal study re-
sults showed that the antifungal effects of the derivatives were similar
to their antibacterial effects and depended on the structure of the de-
rivatives. However, Derivative 7c with barbituric acid and chlorine in
its structure had the highest antibacterial and antifungal effects,
whereas Derivative 7f had the highest antioxidant effect. Based on the
results, there was a crossover relationship between the structure and
antioxidant properties of the derivatives.
38
41
46
52
46
47
49
53
45
48
63
69
Ascorbic acid
87.5
92.25
97.08
98.98
a
μg/mL.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Acknowledgments
The authors are grateful to Islamic Azad University (Kerman
Branch).
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tetrahydropyrimidin-5(2H)-ylidene)-2-oxospiro[indoline-3,4′-[1,3]dithiine]-
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