Synthesis of new chromeno-carbamodithioate derivatives and preliminary evaluation of their antioxidant activity and molecular docking studies

Article abstract of DOI:10.1016/j.bmcl.2017.01.047

New chromeno carbamodithioates (7a-i), have been synthesized from 2, 3-dimethyl-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5), carbondisulphide and commercially available acyclic and cyclic secondary amines in acetonitrile with good to excellent yields. The free radical scavenging activity of novel chromone-carbamodithioate analogues was quantitatively estimated by spectrophotometric method. Whereas, molecular docking studies were performed with the active site of cyclooxygenase-2 to identify hydrogen bonding, hydrophobic and ionic interactions between protein and ligands. The compounds 7g and 7h demonstrated potent antioxidant activity with IC₅₀ of 1.405?±?0.019?mM and 1.382?±?0.35?mM respectively compared to Ascorbic acid.

Full text of DOI:10.1016/j.bmcl.2017.01.047

Accepted Manuscript
Synthesis of new chromeno-carbamodithioate derivatives and preliminary eval-
uation of their antioxidant activity and molecular docking studies
Bandari Sampath Kumar, Kammari Bal Raju, Madda Jyothi, Kommu Nagaiah,
Lakkadi Arunapriya, Vuppala Srimai, Tigulla Parthasarathy
PII:
S0960-894X(17)30060-4
DOI:
http://dx.doi.org/10.1016/j.bmcl.2017.01.047
BMCL 24623
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
1 September 2016
17 December 2016
14 January 2017
Please cite this article as: Sampath Kumar, B., Bal Raju, K., Jyothi, M., Nagaiah, K., Arunapriya, L., Srimai, V.,
Parthasarathy, T., Synthesis of new chromeno-carbamodithioate derivatives and preliminary evaluation of their
antioxidant activity and molecular docking studies, Bioorganic & Medicinal Chemistry Letters (2017), doi: http://
dx.doi.org/10.1016/j.bmcl.2017.01.047
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Bioorganic & Medicinal Chemistry Letters
Synthesis of new chromeno-carbamodithioate derivatives and preliminary
evaluation of their antioxidant activity and molecular docking studies
a
a
a
a,
b
Sampath Kumar Bandari , Bal Raju Kammari , Jyothi Madda , Nagaiah Kommu *, Arunapriya Lakkadi ,
b
b
Srimai Vuppala , Parthasarathy Tigulla
a
Organic & Biomolecular Chemistry Division, CSIR – Indian Institute of Chemical Technology, Hyderabad 500 067, India
Department of Chemistry, University College of Science, Saifabad, Osmania University Hyderabad 500 067, India
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
New chromeno carbamodithioates (7a-i), have been synthesised from 2, 3-dimethyl-7-(oxiran-2-
ylmethoxy)-4H-chromen-4-one (5), carbondisulphide and commercially available acyclic and
cyclic secondary amines in acetonitrile with good to excellent yields. The free radical
scavenging activity of novel chromone-carbamodithioate analogues was quantitatively estimated
by spectrophotometric method. Whereas, molecular docking studies were performed with the
active site of cyclooxygenase-2 to identify hydrogen bonding, hydrophobic and ionic
interactions between protein and ligands. The compounds 7g and 7h demonstrated potent
antioxidant activity with IC50 of 1.405 ± 0.019mM and 1.382 ± 0.35mM respectively
compared to Ascorbic acid.
Keywords:
Carbamodithioates
Antioxidant activity
Charge transfer complex
Molecular docking
Radical scavenger
2
009 Elsevier Ltd. All rights reserved.
12,13
1. Introduction
chromeno analogues and their biological activity,
here we
have synthesized some promising chromone-carbamodithioate
analogues with good to excellent yields and inspected their
antioxidant activity by Charge Transfer Complex (CTC), a
simple spectrophotometric method. Molecular docking studies
were also performed on these analogues to suggest the binding
site interactions between protein and ligands. To the best of our
knowledge, this is the first aspect of study of antioxidant activity
on chromeno-carbamodithiates.
Reactive Oxygen Species (ROS) and free radicals play an
important role in a number of biological processes, some of
which are necessary for life such as the intra cellular killing of
1
bacteria by phagocytic cells. However, excessive production of
Reactive Oxygen Species and free radicals can cause damage to
bio-molecules such as lipids, proteins, enzymes, and DNA in
2
cells and tissues. This triggers to various diseases such as
atherosclerosis, heart failure, neuro degenerative disorders, aging,
cancer, diabetes mellitus, hypertension. Furthermore, the free
radicals can also be generated from environmental pollutants,
radiation, chemicals, toxins, deep fried and spicy food, oxidative
2. Results & Discussion
Epoxy chromone 5 is an ideal source for diversity of reactions,
as they can be opened with various nucleophiles. The epoxide
opening took place in highly regioselective manner preferentially
from less hindered site in appropriate reaction times by terminal
3
stress, physical stress, which cause depletion of immune system .
Thus, the utility of antioxidants in diet would combat the attacks
caused by the free radicals and ROS and reduce the risk of
1
4-17
4,5
attack of the nucleophiles . In most of the epoxide ring
opening reactions nucleophiles were amines (primary or
various diseases . Apparently, the antioxidants have been
currently fabricated as drug candidate to counter these diseases.
It is known that chromone system is present in many
compounds widely found in plants and particularly in flavones
1
5-21
secondary)
in which, β-amino alcohols were formed by C-N
bond linkage with designed core moiety. The scrutiny of the
earlier reports on ring opening of 1,2-epoxide with thiol-derived
nucleophiles revealed that there are practically seldom reports on
6
and isoflavones. In recent years chromone heterocyclic synthesis
had attracted tremendous interest among researchers due to their
potential applications in medicinal chemistry. Scientific studies
on chromones make public hundreds of structures with laxative
22-25
only the synthesis of hydroxy dithiocarbamates
but not on
their biological activity studies. Hydroxy dithiocarbamates are
very important biologically active compounds and have diverse
7
8
9
effect,
anti-inflammation,
tyrosinase inhibition,
skin
2
6
27
10
11
applications in medicinal chemistry , agriculture , intermediates
protection, anti-ulcer and other biological activities. In this
context, in continuous of our study on the synthesis of different
28
29
in organic synthesis and multifunctional lubricant additives .

Scheme 1: Reaction Conditions: (i) CH
h, 90%; (iv) epichlorohydrine (excess), K
3
CH
2
COOH, Fused ZnCl
2 2 3
, 140-150 °C, 2 h, 82%; (ii) Ac O, NaOAc, reflux, 14 h; (iii) NaHCO /MeOH, (1:1, v:v), rt, 3
2
CO
3
, 100 -110 °C, 4-5 h.
Hence, it was thought of considerable interest to undertake the
synthesis and activity of novel chromeno-carbamodithiates via
nucleophilic epoxide ring opening reaction with carbondisulphide
demonstrated comparatively the more potent activity with IC50
values of 1.405 ± 0.019mM, 1.382 ± 0.35mM respectively
(Table-1).
2
(CS ) and aliphatic cyclic and acyclic secondary amines wherein,
alkylcarbamodithioate, the nucleophile was in situ generated and
Table-1: Antioxidant activity of tested compounds
C-S bond takes place with interior moiety. The target compounds
Entry Compound
%RS
IC50 mM
Activity
(7a, 7b-i), were synthesized using a straight forward chemistry
±
SD
from epoxy chromone 5. The epoxy chromone 5 was prepared
from resorcinol as shown in Scheme 1, Friedel-Crafts reaction of
1
2
3
4
5
6
7
8
9
1
7a
7b
7c
7d
7e
7f
7g
7h
7i
29.475
29.455
24.760
24.755
31.603
31.835
35.605
36.785
30.895
30.40
1.709±0.15
1.721±0.206
2.241±0.70
2.042±0.21
1.588±0.095
1.573±0.058
1.405±0.019
1.382±0.35
1.618±0.012
1.644±0.01
0.7673
0.7643
0.6496
0.6568
0.7992
0.8033
0.8516
0.8595
0.7911
0.7840
recorcinol 1 with propanoic acid in presence of fused ZnCl
2
at
0
140-150 C for 2h afforded the compound 2 a good yield of 82%.
The hydroxy chromone derivative 4 was prepared starting from
the compound 2 in two simple steps according to previous
20,21
reports.
A mixture of compound 2, acetic anhydride and
sodium acetate was heated under reflux condition for 14h yielded
the compound 3, which upon de-acetylation with 1:1 mixture of
MeOH and sat. aq NaHCO
The epoxy chromone precursor 5 was prepared by reaction of
hydroxy chromone 4 with epichlorohydrine in presence of K CO
3
at rt for 6h to afford 4 in 90% yield.
0
Ascorbic
acid
2
3
0
at 100-110 C for 4-5 h with excellent yield of 89%. Finally 2,3-
dimethyl-7-(oxiran-2-ylmethoxy)-4H-chromen-4-one (5) moiety
was easily transformed into chromeno-carbamodithioates, by the
It was interesting to note that the compounds-7e, 7f and 7i
reaction of 5 with carbondisulphide (CS
2
), commercially
also showed appreciable free radical scavenging activity with
IC values of 1.588 ± 0.095mM, 1.573 ± 0.058mM and 1.618 ±
available diethyl amine (acyclic secondary amine) (Table 2,
Entry 1) and cyclic secondary amines (Table 2, Entry 2-9) in
acetonitrile as a solvent at 0°C to room temperature for the period
of 30 min. Later the reaction mixture was refluxed for 5-6 h to
afford 7a and 7b-i with good to excellent yields (72-96 %).
50
0.012mM respectively. The other compounds such as 7a, 7b, 7c,
and 7d exhibited comparatively less activity with IC50 values
1.709 ± 0.15mM, 1.721 ± 0.206mM, 2.241 ± 0.70mM and 2.042
± 0.21mM in comparison with reference compound, ascorbic
acid (1.644 ± 0.01mM). By observing the structural activity
relationships (SAR) of these compounds revealed that the
antioxidant activity was associated with basic skeleton of
3. Antioxidant activity
Several methods were reported for the estimation of
chromeno-carbamodithioate and N-substituted moieties.
A
antioxidant activity of synthetic or natural source. In order to
develop simple and sensitive spectrophotometric method, CTC
can be used as free radical source. The CTC which was formed
between DDQ and tri ethylamine was used to investigate
reduction in the activity was observed when the substituted N-
methyl group was replaced by a N-phenyl ring, which was
observed in compounds 7b and 7c with respective IC50 values
(1.721±0.206mM and 2.241±0.70mM). The radical scavenging
activity seems to increase with presence of the electron donating
groups on the N-substituted moieties compared to electron
withdrawing substituents.
3
0
chromeno-carbamodithioate
antioxidant
activity .
The
antioxidant activity of the extracts was expressed as IC50 and
compared with standard. The capacity to scavenging the DDQ
radical was calculated using the following equation.
ꢌ ꢔꢌꢕ
ꢓ
4
. Genetic optimization for ligand docking
ꢀ
ꢁꢂꢃꢄꢅꢂꢆꢀꢇꢅꢂꢈꢉꢊꢋꢄꢊꢋꢀꢌꢅꢍꢄꢈꢄꢍꢎꢀꢏꢁꢑꢒ
ꢀꢖꢀꢗꢘꢘ
ꢐ
ꢌꢓ
Where, Ab = Initial absorbance of the CTC, Aa = Absorbance of
the test/ standard compound.
In the present study, version 2.0 of the GOLD (Genetic
optimization for ligand docking) docking program was evaluated.
The GOLD program used a genetic algorithm (GA) to explore
The most of the chromeno-carbamodithioates analogue’s have
shown higher percentage of radical scavenging activity than the
reference compound, ascorbic acid. The compounds 7g and 7h

Table 2: Reaction of epoxide with amine
a
All products were characterised by 1H NMR, IR, and mass spectroscopy.
Isolated yields.
b

the full range of ligand flexibility and the rotational flexibility of
compound 7g seems to be an effective moiety to enhance the
antioxidant activity of the compound (Table-1). It was also noted
that the sulphur atom of carbamodithioate group also forms
hydrogen bond with TRP387 (NH). The sulphur containing
hydrogen bond was suggested to play an important role in the
process of protein ligand interactions. The binding mode of
compound 7h in the active of cyclooxygenase (4COX) was
shown in Figure 2. The best docked lowest energy mode of
compound 7h formed three interactions with amino acids of
active site. The two hydrogen bonds formed between OH group
and two residues of LEU531, SER530. The third hydrogen bond
formed between chromone ring oxygen and TYR385.
31
selected receptor hydrogens . There were two different built in
scoring functions in the GOLD program-Gold Score and Chem
Score. The interaction of the ligands with the receptor in the
modeled complexes was investigated and observed the fitness
function ability of oxidoreductase protein by different inhibitors.
The 3D structure of selected protein cyclooxygenase-2 (4COX)
32
was selected from PDB Bank RCSB with an X-ray resolution in
˚
the range of 2.90A . The protein active site can be viewed
33
through Swiss Protein Data Base Viewer (spdbv) 3.7 . Docking
has been performed and their corresponding Gold score and
Chem score have been produced in the Table-3.
The binding energy, inhibition constant, fitness score and
chem score values were in the range of -0.97 to -6.14 Kcal/mol,
0.037mM to 197.37mM, 80.73 to 60.51 and 58.67 to 39.31
respectively. The title compounds showed good antioxidant
activity compared to standard compound and also they have
shown significant binding scores. The compounds 7g and 7h
were found to have high activity. In the morpholine ring of
compound 7g, S and OH groups seemed to be effective groups to
enhance the antioxidant activity due to formation of multiple
hydrogen bonds in the active site of cyclooxygenase-2. The two
hydrogen bonds formed between OH group and two residues,
LEU531, SER530 and third hydrogen bond formed between
chromone ring oxygen and TYR385 seems to be responsible for
high efficacy of compound 7h.
4
.1. Autodock
3
4
Autodock4.0 was used to estimate binding free energy and
inhibition constant (K). Molecular docking studies were
performed on series of title compounds against
i
a
cyclooxygenase-2 target (4COX) to predict and compare the
ligand conformations and orientations of binding properties of
compounds with that of the experimental bioassay. The binding
mode analysis of the compounds with the active site residues
provided important information about catalytic activity. Figure 1
shows the lowest energy confirmation of compound 7g. It was
noted that the hydroxyl group formed one hydrogen bond from
residue of TYR385 oxygen atom on morpholine ring received
two hydrogen bonds from backbone residues of GLY527 and
ALA527 at the bottom of the active site. The morpholine ring in
Table-3 Gold score values of chromone molecules
Compound
Fitness
S(hb)
Chem score S(lipo)
B.E(Kcal/mol)
i
K (mM)
7
a
60.51
60.91
63.58
69.60
68.84
71.60
60.99
80.73
75.75
6.03
0.00
8.34
1.98
1.60
6.09
0.34
2.90
6.02
42.20
41.71
45.21
45.70
45.76
58.67
41.47
44.86
39.31
305.58
303.86
402.82
398.21
399.07
468.90
318.05
422.45
412.73
-2.48
-6.14
-5.71
-0.97
-1.54
-4.75
-5.50
-5.99
-3.18
15.09
0.031
0.064
193.97
73.79
0.327
0.093
0.044
4.66
7
b
7
c
7
d
7
7
e
f
7
7
g
h
7
i
S(hb)=Hydrogen bonding score, S(lipo)=Lipophilicity, K
i
=Inhibition constant.
Figure 1. Binding mode of compound 7g in the active site of cyclooxygenase (4COX). Ligand indicated in ball and cylinder low model residues were
indicated in cylinder high model. Red colour dotted lines indicated the hydrogen bonds.

Figure 2. Binding mode of compound 7h in the active site of cyclooxygenase (4COX). Ligand indicated in ball and cylinder low model residues were
indicated in cylinder high model. Red colour dotted lines indicated the hydrogen bonds
1
1
1
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Acknowledgments
We thank the Director of CSIR-Indian Institute of Chemical
Technology (IICT) for the generous support. B.S.K thanks the
Council of Scientific and Industrial Research for a Senior
Research Fellowship and CSIR, New Delhi for financial support
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Highlights

Our approach is straight forward and
involved standard reactions with good
yields.




Synthesis proceeds with economical and
available starting material resorcinol.
Friedel-craft acylation, Chromone formation
and epoxide opening as the key steps.
Chromone analogues with potent anti-
oxidant activity.
Chromones may be synthetic targets due to
their broad biological activity.

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Synthesis of new chromeno
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carbamodithioate derivatives and
preliminary evaluation of their antioxidant
activity and molecular docking studies
Sampath Kumar Bandari , Bal Raju Kammari, Jyothi Madda, Nagaiah Kommu, Arunapriya Lakkadi, Srimai
Vuppala , Parthasarathy Tigulla
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