Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-Assisted One-Pot, Telescopic Approach and Its Interaction with Biomacromolecules

Article abstract of DOI:10.1021/acscombsci.0c00083

In this work, a one-pot, telescopic approach is described for the combinatorial library of thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by base catalyzed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad substrate scope and high functional group tolerance. The synthetic strategy merges well with the thiourea formation followed by base catalyzed ring closure reaction for the thiazolidine-2-imine synthesis in a more modular and straightforward approach. The synthetic procedure reported herein represents a cleaner route toward thiazolidine-2-imines as compared to traditional methodologies. Moreover, the biological significance of combinatorially synthesized thiazolidin-2-imines has been investigated for their use as possible inhibitors for acetyl cholinesterase through molecular docking studies.

Full text of DOI:10.1021/acscombsci.0c00083

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Article
Diversity-Oriented Synthesis of Thiazolidine-2-
imines via Microwave-assisted One-Pot, Telescopic
Approach and its Interaction with Biomacromolecule
Ananya Anubhav Saikia, Ramdas Nishanth Rao, Barnali
Maiti, Musuvathi Motilal Balamurali, and Kaushik Chanda
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.0c00083 • Publication Date (Web): 21 Aug 2020
Downloaded from pubs.acs.org on August 24, 2020
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Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-
assisted One-Pot, Telescopic Approach and its Interaction with
Biomacromolecule
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Ananya Anubhav Saikia,a Ramdas Nishanth Rao,a Barnali Maiti,a Musuvathi Motilal
Balamurali,b* Kaushik Chandaa*
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aDepartment of Chemistry, School of Advanced Sciences, Vellore Institute of Technology,
Vellore-632014, India
bChemistry Division, School of Advanced Sciences, Vellore Institute of Technology,
Chennai-600127, India
Email: chandakaushik1@gmail.com
mmbala@gmail.com
This article is dedicated to Prof Chung Ming Sun for his enormous contribution in diversity
oriented synthesis (DOS)
Abstract:
In this work, a one-pot, telescopic approach is described for the combinatorial library of
thiazolidine-2-imines. The synthetic manipulation proceeds smoothly via the reaction of 2-
aminopyridine/pyrazine/pyrimidine with substituted isothiocyanates followed by the base
catalysed ring closure with 1,2-dibromoethane to obtain thiazolidine-2-imines with broad
substrate scope and high functional group tolerance. The synthetic strategy merges well with
the thiourea formation followed by base catalysed ring closure reaction for the thiazolidine-2-
imine synthesis in a more modular and straightforward approach. The synthetic procedure
reported herein represents a cleaner route towards thiazolidine-2-imines as compared to
traditional methodologies. Moreover, the biological significance of combinatorially
synthesized thiazolidin-2-imines has been investigated as possible inhibitors for acetyl
cholinesterase through molecular docking studies.
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Keywords: Thiazolidine-2-imine, Microwave, Telescopic, Acetylcholinesterase, 1,2-
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dibromoethane, 2-aminopyridine
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Graphical Abstract
Y
130 o
Y
S
10-15
C,
R
R1
min
o C
120
N
N
N
Br
H
H
X
N
Y
N
MW,
K2CO
Y
Br
Y
S
+
R
R1-NCS
NH2
Isothiocyanate
R1= Aromatic
Aliphatic
Not Isolated
DMSO3,
MW
DMSO,
4-5min
R
N
N
X=CH/N
Y=CH/N
X=YN
R1
Imine Bridged Thiazolidine
Evaluation of
Potential AChE
Inhibitor
Synthesis &
Characterization
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Introduction
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The efficiency of low molecular weight molecules pharmaceutical agents is always an
inevitable to focus in drug discovery, as a low molecular weight compounds form fewer
metabolites after Phase-1 and Phase-II reactions of metabolism in pharmacokinetics.1,2 The
appealing simplicity of microwave-assisted reactions3,4 and telescopic approaches5,6 has
enabled the synthetic chemistry community to build low molecular weight architectures as
pharmacophores in a single step without isolating intermediates. Thiazolidines are a class of
privileged 5-membered, saturated, heterocyclic molecules with a thioether group and an
amine group in the 1- and 3-positions and belong to the family of marine macrolides with
promising biological properties. The first thiazolidine ring containing sponge macrolide,
latrunculin A (A), isolated from the Red Sea collection of Latrunculia magnifier was found to
allosterically inhibit polymerization of G-actin.7-9 Molecules with thiazolidine moieties are
being investigated for anti-proliferative activity (B),10,11 anti-convulsant nature (C),12 and
anti-tubercular activity (D) as depicted in Figure 1.13 Recently, Shehzadi et al. demonstrated
thiazolidin-2-imines as potent acetylcholinesterase inhibitors.14 Moreover, it is well known
the importance of sulphur heterocycles in the field of medicinal chemistry and organic
synthesis.15
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S
O
O
O
F
N
O
N
N
S
O
O
O
N
S
OH
O
N
O
OH
H
O
HN
O
O
S
(D)
Anti-tubercular agent
(C)
Anti-convulsant agent
(B)
Anti-cancer agent
A
Latrunculins A (
)
Figure 1. Biologically active thiazolidine moieties
Because of their wide-ranging bioactivities in pharmacological and biological investigations,
the synthesis of thiazolidine derivatives is a challenging task. In literature, most of the
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synthetic efforts were focussed on thiazolidinones16,17 and carboxylic acids.18,19 In spite of
their pharmaceutical value, a comprehensive literature survey suggests that very few reports
are available for the synthesis of 1,3-thizolidin-2-imines without any additional functionality
like acid and ketone groups. In 2001, Alper et al. for the first time reported the Pd catalyzed
regioselective ring-expansion reaction of 2-vinylthiiranes with heterocumulenes to form 1,3-
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thiazolidine 2-imine derivatives in refluxing THF solution (Scheme 1A).20
Previous Work
A
)
R1
Pd2(dba)3.CHCl3
dppp ligand
R1N
C NR1
N
R
R
S
NR1
S
THF, 5Psi, N2
20-48 h
2-Vinylthiiranes Carbodimides
1,3-thiazolidine-2-imine
B
)
O
S
IPA, 82 oC
3-4 h
NHAr1
S
ArN
N
Ar1
+ ArHN
NHR1
O
R1N
O
O
1,3-thiazolidine-2-imine
Maleic acid
derivatives
Thioureas
R1
S
C
)
Ts
N
R2
ZnBr2, CH2Cl2
N
R2 NCS
+
N
R1
Ts
Isothiocyanate
Aziridines
Ar
1,3-thiazolidine-2-imine
D
)
R1
N
S
R2
CuOTf, Pybox
Toluene, rt,
R2 NCS
N
Ph
N
Ph
Imine
H
Ar
Alkyne
12 h
R1
1,3-thiazolidine-2-imine
Isothiocyanate
R3
E
)
CuOTf, ZnCl2
S
O
R2-NH2
+
R3
+
R4-NCS
+
R4
DMF,60 oC, 4Å MS
N
R1
N
R1
16 h
R2
Isothiocyanate
Aldehyde Amine
Alkyne
1,3-thiazolidine-2-imine
Present Work
Y
Br
Y
Y
Y
S
Br
MW, 120oC
X
Y
S
MW
R
R
R1-NCS
+
R
R1
N
N
N
DMSO, 4min
K2CO3, DMSO
130oC, 10 min
N
N
N
N
NH2
R1
H
H
Isothiocyanate
R1= Aromatic/Aliphatic
X=CH/N
Y=CH/N
X=YN
Not Isolated
1,3-thiazolidine-2-imine
2-Aminopyridine/pyrazine/pyrimidine
Scheme 1. Different synthetic approaches to 1,3-thiazolidine-2-imines.
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Subsequently, in 2014, Pankova et al. reported the synthesis of thiazolidines via regioselective
addition of unsymmetrical thioureas to maleic acid derivatives (Scheme 1B).21 The same year
Stoltz and his group reported the (3+2) cycloaddition of N-sulfonyl-2-substituted aziridines
with isothiocyantes for the synthesis of thiazolidine 2-imines using ZnBr2 as a lewis acid
catalyst (Scheme1C).22 In 2015, Dethe et al. reported the Cu catalysed, enantioselective
synthesis of thiazolidine-2-imines from imines, acetylenes and isothiocyanates (Scheme
1D).23 Recently, Shehzadi et al. demonstrated the four component synthesis of thiazolidin-2-
imines via a Cu(I)/Zn(II) dual catalyst from aldehydes, primary amines, alkynes and
isothiocyanates (Scheme 1E).14
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Despite the significant progress made in thiazolidine annulation, methodologies developed
so far, they have encompassed disadvantages such as uses of costly Pd, Cu, and Zn catalysts,
use of toxic bulky phosphine ligands, the need of high temperatures, long reaction times, and
tedious separations of homogeneous catalysts from the final product. These drawbacks
significantly restrict the use of thiazolidin-2-imines in pharmacological studies. These
shortcomings could be addressed using an efficient transition metal free microwave assisted
telescopic approach.
In continuation of our efforts to explore the potential application of synthesized bioactive
compounds in our laboratory,24-28 herein, we report a one-pot, telescopic approach for the
synthesis of thiazolidin-2-imine and its derivatives using microwave irradiation. The
telescopic approach shows a wide range of functional group tolerance, and the validity of the
methodology
has
been
investigated
using
various
substituted
2-
aminopyridine/pyrazine/pyrimidine and isothiocyanates, resulting in excellent yields. To the
best of our knowledge, a one-pot, telescopic approach for the synthesis of thiazolidin-2-imine
and its derivatives using microwave irradiation has not been witnessed earlier. Finally, we
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have investigated the role of thiazolidin-2-imine derivatives as inhibitors for acetyl
cholinesterase through molecular docking studies.
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Results and Discussion
We commenced our investigation using a model reaction of 2-amino pyridine 1{1} with
phenyl isothiocynate 2{1} to obtain the thiourea 3{1,1} which could be used as a precursor
for the thiazolidine-2-imine synthesis as depicted in Scheme 2. For this reaction, we have
investigated the key factors and optimized reaction conditions as depicted in Table 1.
NCS
S
Solvent
Base
N
NH2
N
N
N
H
{1,1}
H
1
2
3
{1}
{1}
Scheme 2. Synthesis of thiourea intermediate 3{1,1}.
Treatment of 1{1} with phenyl isothiocyanate 2{1} in neat condition at room temperature did
not yield any thiourea product 3{1,1}(Table 1, entry 1), however on increasing the
o
temperature at 100 C, the yield of product 3{1,1} increased up to 40% (Table 1, entry 2).
Subsequently, to further increase the yield of thiourea formation, we carried out the reaction
in refluxing EtOH solution using Et3N, and K2CO3 as bases respectively yielded product
formation up to 60% (Table 1, entries 3,4). Next, we turned our attention of using polar
aprotic solvents such as DMF and CH3CN to increase the yield of thiourea intermediate
3{1,1} up to 70% (Table 1, entries 5,6).
Table 1. Optimization of Reaction Conditionsa
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Yield(%)d
0
Entry
Base
-
Temperature
rt
Time
4h
Solvent
Neat
1
2
100 o
C
Neat
EtOH
EtOH
-
4h
4h
4h
40
50
60
Et3Nb
K2CO3
3
4
reflux
reflux
b
b
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130 o
C
K2CO3
-
5
6
DMF
4h
4h
60
70
CH3CN
reflux
130oC
7
8
DMSO
DMSO
-
4h
80
92
MW.c 120 o
C
-
4 min
reaction was performed using {1} (1 mmol), {1} (1 mmol), bBase (1 mmol)
cMicrowave reactions were carried out in Microwave Model No. CATA R (Catalyst systems,
Pune) using power 280 watt, d Yield of the isolated product.
a
1
2
o
Further screening of the reaction condition using DMSO as a solvent at 130 C for 4 hr
yielded the best output (Table 1, entry 7). To shorten the time, irradiation of the same
o
reaction mixture under microwaves at 120 C for 4 min afforded the compound 3{1,1} in
nearly quantitative yield (Table 1, entry 8).
With the optimized conditions in hand, we next examined the formation of five-membered
thiazolidine 2-imine frameworks which could be achieved via base catalysed nucleophillic
attack of C=S bond on 1,2-dihaloethane followed by intramolecular ring closure reaction as
depicted in Scheme 3.
X
X
N
S
S
S
X=Cl, Br
+
N
N
Solvent
Reaction
Conditions
N
N
N
N
N
N
H
H
3
4
4'
{1,1}
{1,1}
{1,1}
Scheme 3. Two different modes of thiazolidine-2-imine ring formation.
When the compound 3{1,1} was treated with 1,2-dichloroethane in the presence of a Et3N as
base in DMSO at 130 oC for 5 h, it did not yield the cyclised product 4{1,1}or 4´{1,1} (Table
2, entry1). Further screening of various bases like piperidine, K2CO3 and NaOH also did not
yield the cyclised product (Table 2, entries 2, 3, and 4). Subsequently, irradiating the reaction
o
mixture under microwave in the presence of K2CO3 as the base at 130 C for 15 min in
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DMSO failed to obtain any product (Table 2, entry 5). Realizing that Cl is not a good leaving
group for this cyclisation, we further proceeded to use 1,2-dibromoethane as the electrophile
for this cyclization. Treatment of compound 3{1,1} with 1,2-dibromoethane in the presence
of Et3N as a base in DMSO at 130 °C led to the formation of 4{1,1}or 4´{1,1} in 50 % yield
(Table 2, entry 6) whereas the use of other bases such as piperidine, NaOH, and K2CO3 did
not increase the yield of cyclised product substantially (Table 2, entries 7, 8, and 9). To our
delight, a 95% yield of product 4{1,1}or 4´{1,1} was achieved in the presence of K2CO3 as
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o
the base in DMSO at 130 C under microwave irradiation for 10 min (Table 2, entry 10),
established the supremacy of microwaves in this ring closure reaction. Unfortunately, the
reaction did not proceed at all in the absence of base (Table 2, entry 11). The use of 1,2-
diiodoethane as the electrophile in the heterocyclisation reaction did not make any significant
changes in the outcome of the reaction (Table 2, entry 12).
Table 2. Optimization of Heterocyclisation Reaction Conditions.a
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Br
Br
S
S
N
S
+
5
6
Solvent, Base
reaction conditions
N
N
N
H
N
N
N
N
N
H
7
8
9
3
4{
4'
{1,1}
{1,1}
1,1}
Exclusively
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Yield(%)c
Entry
Solvent
DMSO
DMSO
DMSO
Base
Et3N
Nucleophile
Temperature
Time
5h
130 oC
130 oC
130 oC
Cl
Cl
1
2
3
0
0
0
Cl
Cl
Piperidine
K2CO3
5h
Cl
Cl
5h
130 oC
Cl
Cl
4
DMSO
NaOH
5h
0
Cl
Cl
MWb, 130 oC
130 oC
K2CO3
Et3N
5
6
DMSO
DMSO
15 min
5h
0
Br
Br
50
Br
Br
7
8
DMSO
DMSO
Piperidine
NaOH
130 oC
130 oC
5h
5h
50
52
Br
Br
130 oC
Br
Br
K2CO3
9
DMSO
5h
60
MWb, 130 oC
MWb, 130 oC
MWb, 130 oC
Br
Br
K2CO3
No base
K2CO3
10
11
DMSO
DMSO
DMSO
10 min
10 min
10 min
95
0
Br
Br
I
12
89
I
a
b
3{
reaction was performed using 1,1} (1 mmol),
1,2-dihaloethane (
1 mmol), Base (1 mmol) Microwave
reactions were carried out in Microwave Model No. CATA R (Catalyst systems, Pune) using power 280 watt,
c Yield of the isolated product.
However to ascertain whether the compound 4{1,1} is formed over 4´{1,1}, computational
methods were employed to optimize the geometry by following density functional theory
using B3LYP hybrid functional and 6-311G++** basis set in their ground states. Using the
same method, the potential energy profile was generated to follow the above mentioned
pathways 1 and 2 leading to the formation of 4{1,1} and 4´{1,1} (Figure 3). As depicted in
Figure 2, path 1 involves the abstraction of proton from pyridine amine nitrogen by base
followed by the nucleophillic attack of C=S bond on 1,2-dibromoethane to form intermediate
A. The path 2 involves the abstraction of proton from aniline nitrogen by base followed by
the nucleophillic attack of C=S bond on 1,2-dibromoethane to form intermediate A´.
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Br
Br
Br
S
S
-HBr
S
N
N
N
NH
N
N
N
N
H
B-
N
H
S
Path 1
A
4{
1,1}
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N
N
N
H
H
Br
Br
NH
N
X
N
S
S
3
{1,1}
S
N
-HBr
N
Br
N
N
N
H
N
H
B-
4'{
}
1,1
Path 2
A'
Figure 2. Mechanistic Investigation for the possible formation of product 4{1,1} and
4´{1,1}.
It is likely that both Path 1 and 2 attacks are in the equilibrium. The computational results
revealed an insignificant energy difference between 4{1,1} and 4´{1,1}. The amidic
resonance of anilides is much higher than that of pyrimidyl-amides.29,30 Our investigations
revealed that the base catalysed proton abstraction and the nucleophillic attack of C=S bond
on 1,2-dibromoethane followed by intramolecular ring closure reaction favours the formation
of product 4{1,1}. The energy barrier for the formation of 4{1,1} is 2.87 kCal/mol lower than
the product 4´{1,1}. On the other hand, it is observed that product 4{1,1}is more stable than
the intermediate A by -3.03 kCal/mol while product 4´{1,1}is less stable than the
intermediate A´ by 4.94 kCal/mol. From the above results it could be concluded that the
thiazolidine-2-imine ring closure is favoured by the attack on aniline nitrogen rather than
pyridyl amine nitrogen as depicted in Figure 3.
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A
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B
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Figure 3. (A) Optimized geometries of transition states and products 4{1,1}, and 4´{1,1}. (B)
Relative energy profile for the thiazolidine-2-imine ring formation.
The progress of quantitative product conversion was monitored by regular proton NMR
spectroscopy. It has been found that the two NH protons of compound 3{1,1} appeared at
14.5, and 10.2 ppm, respectively in spectra A in Figure 4. The chemical shift of these two
protons was shifted to more downfield along with the appearance of five aromatic protons of
phenyl isothiocyanate moiety. Subsequent reaction of compound 3{1,1} with 1,2-
dibromoethane to compound 4{1,1} was observed by the disappearance of two NH protons
and the appearance of two triplets at 4.4, and 3.12 ppm in spectra B from the thiazolidine
moiety. After successfully executing the thiourea formation and base catalysed nucleophillic
addition on 1,2-dihaloalkane followed by the intramolecular ring closure reaction to obtain
the thiazolidine-2-imine 4, our next attempt was to obtain the synthetic manipulation in a
one-pot telescoped manner.
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A
S
6
7
N
N
N
Ha Hb
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9
3{
}
1,1
Ha
Hb
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Hd
Hd
S
B
Hc
Hc
Hc
Hd
N
N
N
4{
}
1,1
1
Figure 4. Stepwise monitoring of thiazolidine-2-imine 4{1,1} formation by H NMR
Spectroscopy.
For this purpose, we performed a one-pot telescoped reaction where the reaction of
substituted 2-aminopyridine 1{1-4,7} with substituted isothiocyanates 2{1-4} in DMSO as
o
solvent at 120 C for 4-5 mins under microwave irradiation resulted in the formation of
thiourea product 3. Without isolating the thiourea product 3, the same reaction mixtures were
irradiated under microwaves at 130oC for 10-15 mins with the in-situ addition of 1,2-
dibromoethane and K2CO3 as the base to obtain desired 1,3-thiazolidine-2-imines 4 as shown
in Scheme 4.
Scheme 4. One-pot telescopic approach to substituted 1,3-thiazolidine-2-imines 4.
Br
X
X
N
X
Br
MW,120oC
DMSO,4-5min
Y
S
Y
S
MW
K2CO3, DMSO
130oC,10-15 min
Y
R
R
R
+
R1-NCS
R1
N
N
N
N
H
N
N
NH2
H
R1
1
2
R1=Aromatic,
Aliphatic
3
X= CH,N
Y= CH,N
X=YN
4
Not isolated
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1
Upon completion of the reaction, the H NMR spectrum of the synthesized compound
5
6
7
8
indicated the formation of pure 1,3-thiazolidine-2-imines 4 in excellent yield. With the
optimized telescopic reaction conditions in hand, we next examined the substrate scope with
respect to 2-aminopyridine 1{1-4,7} and isothiocyanates 2{1-4} (Scheme 5). We found that
2-aminopyridines 1{1-4,7} with electron donating groups and electron withdrawing groups at
different positions gave corresponding products in very good yields. To further examine the
efficiency of this one-pot telescopic reaction, we extended our methodology to 2-
aminopyrazine 1{5} and 2-aminopyrimidine 1{6}. We were pleased to find that under
optimized reaction conditions, 2-amino pyrazine/pyrimidine 1{5,6} derivatives gave products
4 in excellent yields as well. Subsequently, the scope of isothiocyanate such as alkyl, aralkyl,
and aryl derivatives 2{1-4} with functional groups was examined under the optimized
conditions and were successful for excellent product yields.
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Scheme
5.
One-pot,
telescopic
approach
with
respect
to
2-
aminopyridine/pyrazine/pyrimidine 1 and substituted isothiocyanates 2.a,b
Br
X
N
X
N
X
Br
MW,120oC
DMSO,4-5min
Y
S
Y
S
MW
K2CO3, DMSO
130oC,10-15 min
Y
R
R
R
+
R1-NCS
R1
N
N
N
H
N
N
1
NH2
H
R1
2
R1=Aromatic,
Aliphatic
3
X= CH,N
Y= CH,N
X=YN
4
Not isolated
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N
N
Cl
Br
N
N
NH2
N
NH2
NH2
N
NH2
N
NH2
N
NH2
N
NH2
1
{1}
1
{7}
1
1
{6}
{2}
1
1
{4}
{3}
1
{5}
9
NCS
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NCS
NCS
NCS
2
{4}
2
{1}
2
{2}
2
{3}
N
S
S
S
S
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
4
, 95%c
4
, 95%c
4
, 92%c
4
, 90%c
4{
, 90%c
1,2}
{1,1}
{2,1}
{3,1}
{5,1}
Br
S
S
S
S
N
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
90%c
4
, 89%c
4
, 87%c
4
{1,3}
, 91%c
4
, 90%c
{2,3}
4
{2,2},
{3,2}
{4,2}
Br
N
S
S
S
S
S
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
, 90%c
4
, 91%c
4
{2,4}
{3,4}
4
, 90%c
4
, 89%c
{4,3}
{5,3}
4
, 92%c
{3,3}
N
Cl
S
S
S
N
N
S
N
N
N
N
N
N
N
N
N
N
N
, 85%c
, 90%c
4
, 85%c
{7,1}
4
{6,1}
4
, 93%c
4
{5,4}
{1,4}
a
b
1
2
1,2-dibromethane (
Reaction Conditions: (1 mmol), (1mmol),
1 mmol), K2CO3 (1 mmol) Microwave
reactions were carried out in Microwave Model No. CATA R (Catalyst systems, Pune) using power 280
watt, cYield of the isolated product.
The scalability of the reaction was investigated on a gram scale with the reaction of 2-
aminopyridine 1{1} with phenyl isothiocyanate 2{1} under optimized reaction conditions
that gave the corresponding product 3-phenyl-N-(pyridin-2-yl)thiazolidin-2-imine 4{1,1} in
excellent yield (90%) without any significant loss in the optimized reaction yields (Scheme
6).
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NCS
S
Br
Br
MW,120oC
S
MW
N
N
N
+
DMSO,4 min
K2CO3, DMSO
130oC,10 min
N
N
N
N
NH2
H
H
4
{1,1}
2.29g, 90%
1 1
{ }
10 mmol
2
3
{1}
{1,1}
Not isolated
10 mmol
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Scheme 6. Gram-scale synthesis of 3-phenyl-N-(pyridin-2-yl)thiazolidin-2-imine 4{1,1}.
A plausible mechanistic pathway for this thiourea formation and base catalysed
intramolecular cyclization to thiazolidine-2-imine is outlined in Figure 5. The first step
involved the nucleophillic attack of 2-aminopyridine 1 with phenyl isothiocyanate 2 followed
by the electron reorganisation to obtain the thiourea intermediate 3. The second step involved
the base mediated proton abstraction from NH group attached to the pyridine moiety of 3
followed by the attack of C=S bond on 1,2-bromoethane and release of HBr to obtain the
intermediate A. Finally the lone pair electron on N atom attack the second Br atom completed
the heterocyclisation to obtain the thiazolidine-2-imine 4.
S
Br
C
N
Br
Br
-HBr
S
S-
S
+
N
NH2
NH
N
N
N
N
H
N
N
N
H
N
H
H
3
A
1
2
B-
S
N
N
N
4
Figure 5. Plausible mechanism for the formation of thiazolidine-2-imine 4.
Molecular Docking – In silico analysis to investigate the binding interactions of
substituted thiazolidine-2-imines 4 with acetylcholinesterase:
Acetylcholine is a neurotransmitter involved in the impulse transmission at the piloerector
muscle of the sympathetic autonomic nervous system and at the neuromuscular junction
between the motor nerve and skeletal muscle in the autonomous nervous system. This
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neurotransmitter in the interneurons is known to be involved in the long-axon cholinergic
pathways. Disruption of these pathways is one of the reasons for Alzheimer’s disease.
Acetylcholinesterase is an enzyme that can breaks down acetylcholine esters. Inhibitors of
acetylcholinesterase not only result in the accumulation and duration of action of the
neurotransmitter, but also excessively stimulates nicotinic and muscaranic acid receptors.
Numerous inhibitors are reported in the literature and based on their mode of action, they are
categorized into reversible and irreversible inhibitors.31 Herein we have investigated the role
of thiazolidine-2-imines 4 derivatives as inhibitors for acetylcholinesterase through molecular
docking studies.
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The X-ray structure of human acetylcholinesterase (PDB id: 4PQE) obtained from
Brookhaven Protein Data Bank was considered for docking studies. The water molecules
were removed to further refine the crystal structure. With the help of AutoDockTools-1.5.632
hydrogen atoms were added and in the case of protein Kollman charges33 were assigned to
the residues. Whereas for geometry optimized ligands as thiazolidine-2-imines 4 derivatives
Gasteiger partial atomic charges were added to the optimized. The 3D coordinates of the
synthesized thiazolidine derivations were constructed and further optimization was carried
out using Gaussian 09 software.34 The initial geometry and the input files were generated
with Gaussview 05.35 Energy minimization was done by employing density functional theory
with 6-31G**All the calculations were performed in the absence of any solvent molecules in
the environment. DFT calculations basis set following the same B3LYP functional. The
energy minimized structures were considered for docking calculations. Auto Tors was used to
define the possible flexibility and torsional strain of the ligand molecules. For the purpose of
docking all the thiazolidine derivatives were treated as flexible using AutoDock. The identical
binding pocket as reported by Shehzadi et al14 was considered for our studies also and was
considered for ligand interaction by generating a grid box to enclose the active site
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residues. The Grid maps of interaction energies between the enzyme and various atom types
of thiazolidine derivatives were precalculated using Auto Grid program. Lamarckian genetic
algorithm was adopted to investigate the interactions and docking calculations were
performed by considering the above binding site for all the derivatives. Further, to assess the
conformational states of the flexible ligand molecules the Lamarckian genetic algorithm
coupled with energy assessments based on AMBER force fields was employed. All the
docking calculations were performed using inbuilt default parameters. The scoring function
employed to evaluate the binding energy is given below.
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(1)
∆퐺 ∆퐺푣푑푤 + ∆퐺ℎ푏표푛푑 + ∆퐺푒푙푒푐 + ∆퐺푡표푟 + ∆퐺푑푒푠표푙푣
=
The parameters including Gvdw (dispersion/repulsion), Gelec (electrostatic interaction),
Ghbond (hydrogen bonding), Gtor (torsional constraints) and Gsol (desolvation effects) were
used to evaluate the variation in free energy upon binding of the derivatives to the rigid
target.
The interaction of thiazolidine-2-imine derivatives with acetyl cholinesterase was
investigated at a suitable binding pocket. We have considered (Z)-N-((Z)-5-benzylidene-4-
tert-butyl-3-propylthiazolidin-2-ylidene)-3-methoxybenzenamine as the reference standard.8
Our results indicate that the binding affinity varies in the following order: 4{2,4}> 4{3,4}>
4{2,3} > 4{3,1} > 4{3,3}> 4{2,1} > 4{4,2} > 4{2,2} > 4{3,2} > 4{4,3} > 4{1,4} > 4{1,3} >
4{1,2} > 4{1,1} > 4{5,4}~4{6,1}> 4{5,3} > 4{5,1}. All the derivatives were predominantly
stabilized by hydrophobic interactions with the non-polar residues F295, F297, F338, W86,
W286 and polar residues Y72, Y124, Y337, and Y341 for electrostatic interactions in the
binding pocket. Further stabilization was provided by hydrogen bond interactions in the case
of 4{1,1}, 4{2,1}, 4{3,1}, 4{1,2}, 4{2,2}, 4{4,2}, 4{3,3}, and 4{2,4}, 4{1,4}, 4{6,1}. The
hydrogen bond acceptors in the case of 4{1,1}, 4{2,1}, 4{3,1}, 4{2,2}, 4{4,2}, and 4{3,3}
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was the thio S, for 4{1,2}, it was the imine N while for 4{2,4}, and 4{1,4}, it was the
pyridine N and for 4{6,1}, it was the pyrimidine N The relevant data are given in Table 3.
Table 3: The binding energy (∆GBE) and intermolecular energy (∆Gintermol) of
derivatives 4 with acetylcholinesterase protein are given below. All the energies are
reported in kcal/mol.
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∆Gintermol
∆Gvdw_hb_deso
Comp
ounds
H-bond
interaction
∆GBE
Binding site
∆Gelec
l
F295, F297, F338, Y337,
-0.04 Y341, W86, Y124, W286,
D74, Y72
D74 and
thio S
4{1,1}
4{2,1}
4{3,1}
4{5,1}
4{1,2}
4{2,2}
4{3,2}
4{4,2}
4{1,3}
4{2,3}
4{3,3}
-6.58
-7.09
-7.18
-6.19
-6.61
-7.08
-7.05
-7.09
-6.70
-7.23
-7.12
-7.14
-7.65
-7.76
-6.73
-7.15
-7.68
-7.64
-7.74
-7.61
-8.08
-7.98
W286, Y72, Y124, D74, Y341,
-0.04 F297, F295, F338, Y337,
W439, G82, W86, T83
F295, F338, F297, Y337,
-0.01 Y341, Y124, W286, Y439,
W86, Y72, T83
Y72, W286, D74, Y124, Y341,
-0.06 T83, F295, F297, F338, Y337,
W86
W439, D74, Y341, Y449,
-0.05 Y337, W86, N87, H447, Y124,
W286
H447, Y337, Y449, W439,
0.00 Y341, W86, N87, D74, Y124,
W286
D74, N67, Y72, W439, Y341,
0.00 Y449, Y124, Y337, H447,
W86
W286, Y341, Y337, Y124,
0.06 S125, Y72, W86, D74, 2439,
Y449
D74 and
thio S
D74 and
thio S
Nil
Y337 and
imine N
Y124 and
thio S
Nil
Y124 and
thio S
Y72, Y341, W286, Y337,
0.01 F338, F297, S293,
F295, L289
V294,
Nil
Nil
T83, Y337, Y341, W86, D74,
-0.04 F295, V294, R296, Y124, Y72,
F297, W286
W286, Y124, D74, F297, N87,
-0.04 R296, V294, F295, Y341,
W86, T83, Y337
D74 and
thio S
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F295, V294, R296, F338,
0.01 S293, Y337, Y341, F297,
W286
Y337, F295, R296, F297,
0.02 S293, Y341, V294, W86, T83,
Y124, W286, D74, Y72
4{5,3}
4{4,3}
4{3,4}
4{2,4}
4{1,4}
4{5,4}
4{6,1}
-6.37
-7.03
-7.45
-7.47
-7.02
-6.51
-6.51
-7.28
-7.95
-8.05
-8.03
-7.55
-7.12
-6.79
Nil
Nil
nil
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F295, F338, Y337, W439,
Y341, F297, W86, Y124,
W286
W439, Y337, F338, F295,
Y341, F297, Y124, W286,
T83, D74, Y72
0.01
Y124 and
pyridine N
-0.04
F295, F338, Y337, Y341,
-0.08 F297, W86, Y124, W286, D74,
Y72
D74 and
pyridine N
D74, Y341, W86, Y337, F338,
Nil
0.02
F295, W286, F297, Y124
F295, F296, W286, F338,
Y124, Y72, Y341, Y337, D74, pyrimidine
W86
Y337 and
-0.32
N
The results from the above docking study reveal the possible binding pattern within the active
site of neurotransmitter acetylcholinesterase. All derivatives restricted inside the active site of
the target protein having different conformational positions are shown in Figure S1
(Supporting Information).
The best docked conformations with lowest binding energy of compound 4{2,4} are shown in
Figure 6.
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(a)
(b)
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(c)
(d)
Figure 6: (a) The secondary structure of the acetylcholinesterase highlighting the thiazolidine-2-imine ligand 4{2,4} binding site in green color.
(b) The secondary structure of the acetylcholinesterase (shown as colored ribbons) embedded with ligand 4{2,4} (shown as ball and stick) in the
active site along with interacting residues. (c) Dashed lines indicating the interactions between the amino acid residues in the active site of the
protein and ligand. (d) Dashed lines indicating the nature of type of interactions between the amino acid residues in the active site of the protein
and ligand.
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Conclusion:
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In conclusion, we have presented a one-pot, telescopic synthesis of substituted 1,3-thizolidin-
2-imines under microwave irradiation. This is the first report for the telescopic synthesis of
substituted 1,3-thizolidin-2-imines with an immense array of substrate scope. The significant
features of this telescopic approach include milder reaction conditions, readily available
reagents, a burgeoning opportunity for various kinds of structural modifications, and a clean
reaction profile as microwave-assisted in a single synthetic operation. The utility of the
present methodology was reflected with the molecular docking analysis of acetyl
cholinesterase inhibitors. Our investigations reveal that the (Z)-3-cyclohexyl-N-(4-
methylpyridin-2-yl)thiazolidin-2-imine 4{2,4}as a potent inhibitor for acetylcholinesterase.
The results advocated that these distinctive heterocyclic molecules offer as interesting lead
compounds for other drug discovery applications.
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Experimental Section
Representative Procedure for the Synthesis of 3-phenyl-N-(pyridin-2-yl)thiazolidin-2-
imine 4{1,1}. In a round bottomed flask, a mixture of 2-aminopyridine 1{1} (0.1 g, 1.06
mmol, 1.0 equiv), phenyl isothiocyanate 2{1} (0.144 g, 1.06 mmol, 1.0 equiv), was added to
5 mL of DMSO. The reaction mixture was irradiated under microwave at 280 watt for 4 min
at 120 oC. The progress of the reaction was monitored by TLC. After completion, to the same
reaction mixture was added 1,2-dibromoethane (0.200 g, 1.06 mmol, 1.0 equiv) and K2CO3
(0.146 g, 1.06 mmol, 1.0 equiv) and irradiated under microwave at 280 watt for 10 min at 130
oC. After checking the progress of the reaction by TLC, the reaction mixture was cooled to
room temperature and the solvent was removed under reduced pressure. The crude product
was washed with water and extracted with ethyl acetate (10 mL, twice). The combined
organic layer was dried over anhydrous MgSO4. The combined filtrate was subjected to
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evaporation to obtain the crude compound, which was purified over silica gel column (60–
120 mesh) using 5% ethyl acetate in hexane as eluent to obtain the 3-phenyl-N-(pyridin-2-
yl)thiazolidin-2-imine 4{1,1} as the product.
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3-Phenyl-N-(pyridin-2-yl)thiazolidin-2-imine 4{1,1}.
Yield = 0.242 g, 95%; White solid; Rf = 0.6 (20%EtOAc/n-hexane); 1H NMR (400 MHz,
CDCl3) δ 8.40 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.56 (t, J = 7.24 Hz, 1H), 7.22 (t, J = 7.6
Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.88 (t, J = 7.68 Hz, 3H), 4.37 (t, J = 6.88 Hz, 2H), 3.08 (t,
J = 6.88 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 156.3, 153.3, 151.6, 147.2, 137.1, 128.8,
123.6, 121.4, 118.3, 116.1, 50.8, 26.1; MS (GC-MS) 255; HRMS (EI, m/z) calcd for
C14H13N3S: m/z 255.0830; Found 255.0811; IR (cm-1, KBr) 3053,1622,1577,1089,694.
Acknowledgements
The authors thank the Chancellor and Vice Chancellor of Vellore Institute of Technology for
providing opportunity to carry out this study. Further, Kaushik Chanda wish to thank the
management of this institute for providing seed money as research grant. Kaushik Chanda
thanks ICMR-Govt of India for funding through Grant no 45/03/2019-BIO/BMS. Thanks are
also to Central instrumentation facility, Vellore Institute of Technology for recording the
spectra
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge at https://pubs.acs.org.
1
Full spectroscopic data of all compounds, H, 13C NMR HRMS, and IR spectra of
compounds 4{1,7, 2,1−6,1} and 3{1,1} (PDF)
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Docking images of compounds 4{1,1−6,1} within the active site of neurotransmitter
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acetylcholinesterase (PDF)
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Table of Content Use only
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Diversity-Oriented Synthesis of Thiazolidine-2-imines via Microwave-
assisted One-Pot, Telescopic Approach and its Interaction with
Biomacromolecule
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Ananya Anubhav Saikia,a Ramdas Nishanth Rao,a Barnali Maiti,a Musuvathi Motilal
Balamurali,b* Kaushik Chandaa*
Y
130 o
Y
S
10-15
C,
R
R1
min
o C
120
N
N
N
Br
H
H
X
N
Y
N
MW,
K2CO
Y
Br
Y
S
+
R
R1-NCS
NH2
Isothiocyanate
R1= Aromatic
Aliphatic
Not Isolated
DMSO3,
MW
DMSO,
4-5min
R
N
N
X=CH/N
Y=CH/N
X=YN
R1
Imine Bridged Thiazolidine
Evaluation of
Potential AChE
Inhibitor
Synthesis &
Characterization
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