A pd-mediated new strategy to functionalized 2-aminochromenes: Their in vitro evaluation as potential anti tuberculosis agents

Article abstract of DOI:10.1016/j.bmcl.2011.08.088

A multi component based synthesis involving palladium catalyzed C-C bond forming reaction has been developed as a new strategy to access systematically modified functionalized 2-aminochromenes. This MCR involves the use of bromobenzaldehyde as a key component and is highlighted by generating a new compound library. Many of these compounds showed Mycobacterium tuberculosis H37Rv chorismate mutase inhibiting properties in vitro representing the lead example of chorismate mutase inhibition by heteroarene based compounds.

Full text of DOI:10.1016/j.bmcl.2011.08.088

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6433–6439
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
A Pd-mediated new strategy to functionalized 2-aminochromenes:
Their in vitro evaluation as potential anti tuberculosis agents
T. Ram Reddy a,b, L. Srinivasula Reddy a,b, G. Rajeshwar Reddy a, Venkata Subbaiah Nuthalapati a,
Y. Lingappa b, Sandhya Sandra c, Ravikumar Kapavarapu c, Parimal Misra c, Manojit Pal c,
⇑
a Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
b Department of Chemistry, Sri Venkateswara University, Tirupati 517 502, Andhra Pradesh, India
c Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A multi component based synthesis involving palladium catalyzed C–C bond forming reaction has been
developed as a new strategy to access systematically modified functionalized 2-aminochromenes. This
MCR involves the use of bromobenzaldehyde as a key component and is highlighted by generating a
new compound library. Many of these compounds showed Mycobacterium tuberculosis H37Rv chorismate
mutase inhibiting properties in vitro representing the lead example of chorismate mutase inhibition by
heteroarene based compounds.
Received 15 June 2011
Revised 16 August 2011
Accepted 18 August 2011
Available online 25 August 2011
Keywords:
Multi-component reactions (MCRs)
Palladium
Ó 2011 Elsevier Ltd. All rights reserved.
2-Aminochromenes
Chorismate mutase
Tuberculosis (TB) is one of the deadly diseases that kills more
than two million people a year worldwide. The growing incidences
of multi-drug-resistance TB and its synergism with HIV is a rising
threat that needs immediate attention. Thus characterization of
new enzyme targets and the identification of new anti tubercular
agents are exceedingly desirable. Shikimate pathway for the
biosynthesis of aromatic amino acids such as phenylalanine and
tyrosine involve the Claisen rearrangement of chorismate to pre-
phenate in the presence of chorismate mutase or CM (EC
5.4.99.5). Due to the absence of this pathway in animals but not
in bacteria CM is considered as a valuable target for the identifica-
tion of effective antibacterial agents.1 However, to our knowledge
only few small molecules2 have been reported to possess inhibi-
tory activity against CM and none based on heteroarene frame-
work. In this Letter we wish to present our initial work on the
discovery of novel small molecules as inhibitors of CM synthesis
of which was carried out via a multi component reaction involving
palladium catalyzed C–C bond forming reaction.
reactions in tandem in a single-pot are not common in the litera-
ture.6 In 2006, the Ugi/Heck combination has been demonstrated
to work well for high-throughput combinatorial library production
of indol-2-ones having four points of diversity.6c This prompted us
to explore the combination of other MCRs with Pd-catalyzed reac-
tions to develop a new strategy for the generation of a library
based on small molecules of potential pharmacological interest.
Herein we present the synthesis of 2-aminochromene based small
molecules as potential inhibitors of Mycobacterium tuberculosis
H37Rv chorismate mutase. 2-Aminochromenes (especially 2-ami-
no benzochromenes) attracted our attention because of their
occurrences in many natural products and wide range of pharma-
cological activities.7,8 These include antibacterial activities of
2-amino benzo[h]chromene derivatives against standard strains
of Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aur-
eus in vitro.7 Thus, generation of a small-molecule library A (Fig. 1)
based on 2-amino benzo[h]chromene was undertaken (particularly
Multi-component reactions (MCRs)3 that usually involve three
or more different starting materials to afford the target compound
in a one-pot operation have become a powerful tool4 in modern
drug discovery. While combination of MCRs with other reactions
for example Ugi and Asinger5 have been reported a similar exam-
ple on combining MCRs with Suzuki/Heck/Sonogashira coupling
NH2
2
O
Various
substituents
3 CN
1
4
R
various
groups
A
⇑
Corresponding author. Tel.: +91 40 6657 1500, fax: +91 40 6657 1581.
E-mail addresses: manojitp@ilsresearch.org, manojitpal@rediffmail.com (M. Pal).
Figure 1. Diversity-based 2-aminochromene scaffold.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.08.088

6434
T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
Table 1
via functionalization of C-4 substituent) for their pharmacological
evaluation against CM.
The effect of reaction conditions on the Suzuki coupling of 4 with 4-methoxyphenyl
boronic acida
While a number of methods have been reported for the synthesis
and modification of 2-amino chromenes9 only few are known for
2-amino benzochromenes.7,8,10 Moreover, none has been reported
on the structural elaboration of 2-amino benzochromenes using
Pd-mediated methods especially C–C bond forming reactions. One
of the commonly used method for the preparation of 2-amino-
chromenes generally involved refluxing malononitrile, aldehyde
and activated phenol in the presence of organic bases like piperi-
dine in an organic solvent such as ethanol or acetonitrile for several
hours.11 A number of modifications of this reaction conditions have
been reported including the use of aqueous K2CO3 under a micro-
wave irrediation7 or Preyssler type heteropolyacid, H14[NaP5-
W30O110], in water8 or NaHCO3 under a solvent-free condition10a
or Et3N in EtOH under refluxing condition.10b Nevertheless, in our
approach we had to fulfill two major objectives for example, (i)
identification of a suitable base or catalyst for MCR compatible for
subsequent Pd-mediated transformation in the same pot, (ii)
establishing appropriate reaction condition for efficient C–C cou-
pling to complete the functionalization step. Accordingly, 2-ami-
no-4-(3-bromophenyl)-4H-benzo[h]chromene-3-carbonitrile (4)
was prepared in 52% yield following a standard method via reacting
1-naphthol (1) with malononitrile (2) and 3-bromobenzaldehyde
(3) in the presence of NaHCO3 under a solvent free condition
(Scheme 1).10a We choose Suzuki coupling as the Pd-mediated step
to be conducted with MCR in the same pot and the bromo derivative
4 was used for our initial study. Thus compound 4 was coupled with
4-methoxyphenyl boronic acid under various conditions including
the conventional Suzuki condition (Table 1). Initially the reaction
was carried out under a standard Suzuki condition that is, in a 2:1
mixture of toluene–H2O in the presence of NaHCO3 at 100 °C for
12 h (Table 1, entry 1). While the reaction proceeded well to give
the desired product 5a the product yield however was not impres-
sive. Considering the poor solubility of the bromide 4 in an aqueous
mixture we carried out the reaction in neat toluene (Table 1, entry
2). However, no improvement in yield was observed. The use of
1,4-dioxane in place of toluene increased the product yield perhaps
due to the better solubility of NaHCO3 in 1,4-dioxane (Table 1, entry
3). We then replaced NaHCO3 with an organic base such as pyrrol-
idine which is miscible with 1,4-dioxane when the product 5a was
isolated in 85% yield (Table 1, entry 4). Notably, the reaction could
be performed at 70 °C in this solvent. Changing the solvent from
1,4-dioxane to DMF decreased the yield (Table 1, entry 5). The
use of other Pd-catalysts for example, Pd(OAc)2 (Table 1, entry 6)
and (PPh3)4Pd (Table 1, entry 7) was examined when (PPh3)4Pd
was found to be equally effective in terms of product yield. The
reaction did not proceed in the absence of a Pd catalyst (Table 1,
entry 8).
OMe
NH2
NH2
CN
OMe
CN
O
O
Br
B(OH)2
Pd-catalyst
solvent
5a
4
Entry Pd cat.
Solvent
Base
Time (h)/T
(°C)
%
Yieldb
1
(PPh3)2PdCl2 Toluene–H2O
(2:1)
(PPh3)2PdCl2 Toluene
(PPh3)2PdCl2 1,4-Dioxane
(PPh3)2PdCl2 1,4-Dioxane
(PPh3)2PdCl2 DMF
NaHCO3
12; 100
55
2
3
4
5
6
7
8
NaHCO3
NaHCO3
12; 100
10; 80
67
75
85
55
69
80
0
Pyrrolidine 4; 70
Pyrrolidine 4; 70
Pyrrolidine 4; 70
Pyrrolidine 4; 70
Pyrrolidine 4; 70
Pd(OAc)2
(PPh3)4Pd
No Pd cat.
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
a
All the reactions were carried out using compound 4 (10 mmol), 4-methoxy-
phenyl boronic acid (12.0 mmol), a Pd-catalyst (0.002 mmol) and a base (5 mmol)
in a solvent (5 mL).
b
Isolated yield.
NH2
CN
O
pyrrolidine
1
2
3
+ ArB(OH)2
Ar
+
+
(PPh3)2PdCl2
0-5 oC (30 min)
70 o
C
5
Scheme 2. Suzuki coupling based MCR strategy for the preparation of 4-biaryl
substituted 2-amino benzochromenes (5).
temperature (70–80 °C) hence we conducted the reaction at a low-
er temperature that is, at 0–5 °C. To our satisfaction the reaction
was still found to be faster under this condition and was completed
within 10 min to give the product 4 in quantitative yield. To assess
the role of solvent and base in this one-pot reaction we conducted
few more experiments and observed that the use of DMF as a sol-
vent required longer reaction time whereas replacing pyrrolidine
with NaOAc required elevated temperature for the initiation of
reaction. Thus combination of pyrrolidine and 1,4-dioxane was
not only identified as an appropriate medium for a faster MCR un-
der mild conditions but also found to be favorable for subsequent
Suzuki coupling in the same pot. Overall, this combination ap-
peared to be a promising and significant for the realization of pres-
ent approach leading to the library of 2-amino benzochromene. We
then performed a reaction by combining all the reactants that is, 1,
2, 3 and 4 and catalysts/reagents for example, (PPh3)2PdCl2 and
pyrrolidine in 1,4-dioxane at 0–5 °C. The mixture was stirred for
30 min at 0–5 °C initially and then at 70 °C for 4 h. We were de-
lighted to observe the formation of desired product 5a without
any significant side products. The initial step was not affected by
the presence of a Pd-catalyst or boronic acid and 5a was finally iso-
lated in 82% yield.
With the optimized reaction conditions for the Suzuki coupling
of 4 with an arylboronic acid in hand we then examined the MCR to
prepare 4 in situ under a similar reaction conditions. Thus the reac-
tion of 1, 2 and 3 was examined in 1,4-dioxane in the presence of
pyrrolidine initially at room temperature. Since
a vigorous
exothermic reaction was observed with the sharp rise in reaction
To demonstrate the utility of our approach a variety of 4-biaryl
substituted 2-amino benzochromenes (5) were synthesized
(Scheme 2) and the results are presented in Table 2.
NH2
CN
O
OH
CHO
A range of aryl boronic acids were employed in this reaction
separately and the reaction proceeded well to give the expected
products in good to excellent yields.12 Various functional groups
such as alkoxy (Table 2, entries 1, 5 and 6), hydroxyalkyl (Table
2, entry 2), alkyl (Table 2, entry 3), cyano (Table 2, entry 4), halo
(Table 2, entries 7, 8, 9 and 12), trifluoroalkyl (Table 2, entry 10)
CN
NaHCO3
Br
Br
+
+
CN
4
2
3
1
Scheme 1. Preparation of compound 4 according to a known method.10

T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
6435
Table 2
Synthesis of 4-biaryl substituted 2-amino benzochromenes (5) using Suzuki coupling based MCRa
Entry
Aryl boronic acid
B(OH)2
4-Biaryl substituted 2-amino benzochromenes (5)
Timeb (h)
%Yieldc
NH2
CN
CN
CN
CN
OCH3
O
O
H3CO
1
5a
5b
5c
4
82
87
79
B(OH)2
B(OH)2
NH2
NH2
NH2
2
3
4
5
HO
OH
O
O
CN
O
B
O
4
5d
6
93
NC
F
F
B(OH)2
NH2
NH2
NH2
CN
CN
CN
O
O
O
OCH3
5
6
7
5e
5f
4
4
6
83
87
78
80
91
84
95
OCH3
OCH3
B(OH)2
OCH3
B(OH)2
Cl
5g
Cl
Cl
B(OH)2
NH2
NH2
NH2
CN
CN
CN
CN
CN
O
O
O
O
O
8
9
5h
5i
5
5
5
4
6
Cl
B(OH)2
Cl
Cl
B(OH)2
CF3
F3C
H3CO
Cl
10
11
12
5j
B(OH)2
NH2
NH2
OCH3
N
5k
5l
N
B(OH)2
Cl
Cl
90
Cl
(continued on next page)

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T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
Table 2 (continued)
Entry
Aryl boronic acid
4-Biaryl substituted 2-amino benzochromenes (5)
Timeb (h)
%Yieldc
89
B(OH)2
NH2
CHO
CN
O
13
5m
4
CHO
a
All the reactions were carried out using 1-naphthol 1 (10 mmol), malononitrile 2 (10 mmol), bromo aldehyde 3 (10 mmol), aryl boronic acid (12.0 mmol), (PPh3)2PdCl2
(0.002 mmol) and pyrrolidine (5 mmol) in dioxane (5 mL) at 0–5 °C for 30 min and then at 70 °C.
b
After stirring the mixture at 0–5 °C for 30 min.
Isolated yield.
c
Z
NH2
CO2tBu
CN
CH2=CHZ
pyrrolidine
O
OH
Br
PPh3
CN
+ 2 + 3
CO2tBu
5m
(PPh3)2PdCl2
0-5 oC (30 min)
100-120 °C
Et3N
THF, rt
O
NH2
6
8
(85% yield)
7
Scheme 4. Fictionalization of compound 5m.
Scheme 3. Heck reaction based MCR strategy for the preparation of 4-alkenylaryl
substituted 2-amino benzochromenes (7).
of (PPh3)2PdCl2 and pyrrolidine in 1,4-dioxane (5 mL) at 0–5 °C
for 30 min and then at 70 °C for 24 h (Table 3, entry 1). While
the desired product 7a was obtained in this case but the yield of
isolated product was not satisfactory. However, replacing 1,4-diox-
ane by DMF and conducting the reaction at higher temperature
that is, 100–120 °C afforded the better yield of 7a (Table 3, entry
2). The reaction time was also reduced to 7 h under this condition.
The use of other alkenes provided the corresponding products in
good yields (Table 3, entries 3–5).
and aldehyde (Table 2, entry 13) present in the aryl boronic acid
was well tolerated. Notably, the use of a heteroaryl boronic acid
(Table 2, entry 11) was also successful in the present reaction.
Encouraged by these results we then examined the feasibility of
MCR based on Heck reaction (Scheme 3 and Table 3). Initially, a
reaction was carried out using 2-naphthol 6, malononitrile 2,
bromo aldehyde 3 and ethyl acrylate (15.0 mmol) in the presence
Table 3
Synthesis of 4-alkenylaryl substituted 2-amino benzochromenes (7) using Heck reaction based MCRa
Entry
Aryl boronic acid
4-Alkenylaryl substituted 2-amino benzochromenes (7)
Timeb (h)
%Yieldc
CO2Et
1
2
CH2@CHCO2Et
CH2@CHCO2Et
7a
7a
24
6
40d
85
CN
O
O
NH2
CO2Me
3
4
5
CH2@CHCO2Me
CH2@CHCO2tBu
CH2@CHCOMe
7b
7c
7d
6
6
5
85
89
79
CN
NH2
CO2tBu
COMe
CN
O
O
NH2
CN
NH2
a
All the reactions were carried out using 2-naphthol 6 (10 mmol), malononitrile 2 (10 mmol), bromo aldehyde 3 (10 mmol), alkene (15.0 mmol), (PPh3)2PdCl2
(0.002 mmol) and pyrrolidine (5 mmol) in DMF (5 mL) at 0–5 °C for 30 min and then at 100–120 °C.
b
After stirring the mixture at 0–5 °C for 30 min.
Isolated yield.
The reaction was carried out in 1,4-dioxane.
c
d

T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
6437
NH2
To demonstrate the further potential of the present strategy for
the introduction of additional diversity functionalization of com-
pound 5m was carried out under Wittig condition (Scheme 4).
We also examined the feasibility of MCR based on Sonogashira
reaction (Scheme 5) the results of which are summarized in
R
CHO
CN
R
O
OH
CN
+
PdCl2(PPh3)2
X
+
CN
2
DMF, pyrrolidine
0-5 oC (30 min)
3 or 9
x = Br or I
1 or 6
10
Table 4.
A number of 4-alkynylaryl substituted 2-amino
90-120 o
C
benzochromenenes (10) were prepared using this strategy in good
yields. Notably, the Sonogashira step does not require the use of cop-
per cocatalyst and therefore avoids the generation of side products
Scheme 5. Sonogashira reaction based MCR strategy for the preparation of
4-alkynylaryl substituted 2-amino benzochromenes (10).
Table 4
Synthesis of 4-alkynylaryl substituted 2-amino benzochromenes (10) using Sonogashira reaction based MCRa
Entry
Naphthol
Alkynes & araldehyde
4-Alkynylaryl substituted 2-amino benzochromenes (10)
Timeb (h)
%Yieldc
CN
1
1
CH„CCH2(CH2)6CH3 & 2-iodobenzadehyde (9)
10a
10b
10c
10d
4.5
92
(CH2)6CH3
O
O
O
O
NH2
CN
2
3
4
1
1
1
CH„CCH2(CH2)4CH3 & 9
5
3
4
87
85
75
(CH2)4CH3
NH2
CN
CH„CCH2(CH2)2CH3 & 9
(CH2)2CH3
NH2
OH
OH
CN
&
9
NH2
HO
OH
&
3
5
1
10e
3
80
CN
O
O
O
NH2
HO
&
HO
3
6
1
10f
2
85
CN
NH2
HO
&
HO
7
6
10g
3
84
3
CN
NH2
(continued on next page)

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T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
Table 4 (continued)
Entry
Naphthol
Alkynes & araldehyde
4-Alkynylaryl substituted 2-amino benzochromenes (10)
Timeb (h)
%Yieldc
& 3
OH
OH
8
6
10h
2
95
CN
O
NH2
a
All the reactions were carried out using naphthol 1 or 6 (10 mmol), malononitrile 2 (10 mmol), halo aldehyde 3 or 9 (10 mmol), alkyne (15.7 mmol), (PPh3)2PdCl2
(0.002 mmol) and pyrrolidine (5 mmol) in DMF (5 mL) at 0–5 °C for 30 min and then at 100–120 °C.
b
After stirring the mixture at 0–5 °C for 30 min.
Isolated yield.
c
Table 5
Inhibition of chorismate mutase by functionalized 2-amino benzochromenenes
Entry
Compounds
% Inhibitiona at 50
l
M
SDa
1
2
3
4
5
6
7
8
9
7a
7b
7c
30
33
64
10
50
55
57
24
28
32
70
69
0.049
0.016
0.057
0.153
0.049
0.090
0.122
0.060
0.130
0.119
0.055
0.025
7d
10a
10b
10c
10d
10e
10f
10g
10h
10
11
12
a
SD = standard deviation.
caused by homocoupling of terminal alkynes used. Nevertheless, the
present MCR based strategy appeared to be a general for the synthe-
sis of diversity based benzochromene derivatives via involving
Figure 2. Dose dependent inhibition of CM by compound 10g.
Figure 3. Docking of compound 10g at the active site of chorismate mutase.

T. Ram Reddy et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6433–6439
6439
various Pd-mediated C–C bond forming reactions as demonstrated
above.
analytical group of DRL for spectral data. M.P., S.S. and P.M. thank
Professor Seyed E. Hasnain and Professor J. Iqbal for encourage-
ment and DBT, New Delhi, India for financial support (Grant No.
BT/01/COE/07/02). Technical help in pharmacology from Dr. K.
Chatti is acknowledged.
Some of the compounds synthesized were tested for CM inhibit-
ing properties in vitro and the results are summarized in Table 5.
The assay13 involved determination of activity of enzyme CM which
catalyzes the conversion of chorismate to prephenate. Thus deter-
mination of activity of CM is based on the direct observation of con-
version of chorismic acid to prephenate spectrophotometrically at
OD274. This reaction is performed in the presence of test compounds
to determine their CM inhibiting activities. A known inhibitor of CM
that is, 4-(3,5-dimethoxyphenethylamino)-3-nitro-5-sulfamoyl-
benzoic acid2a was prepared and used as a reference compound
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.08.088.
the IC50 value of which was found to be less than 10
lM. While none
References and notes
of the compound 5 showed significant inhibition14 of CM at 50
lM
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compounds 7 and 10 however showed moderate to good inhibition
at the same concentration depending on the nature of substituents
present. In general, alkyne substituted compounds for example, 10
was found to be superior than alkenyl derivatives 7. Among the al-
kyne derivatives a linear side chain attached to the triple bond usu-
ally showed good inhibitory activities and presence of a hydroxy
group at the end of the side chain was found to be beneficial. Nev-
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in this series. Compound 10g showed dose dependent inhibition of
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CM with an IC50 value 15.63 lM (Fig. 2).
To understand the nature of interactions between 10g and CM
docking studies were performed (Fig. 3) which showed H-bonding
interactions between (i) the –CN group of 10g and the ARG72 res-
idue of CM, (ii) the –OH group of 10g and ASN142 and LYS79 res-
idues of the CM. The overall binding energy was found to be
À5.5 kcal molÀ1 indicating significant interactions of 10g with CM.
In conclusion, systematically modified functionalized 2-amino-
chromenes has been prepared via a new strategy involving a MCR
and palladium catalyzed C–C bond forming reaction. This strategy
involves the use of bromobenzaldehyde as a key component and
afforded a new compound library based on 2-aminochromene
framework. Many of these compounds showed M. tuberculosis
H37Rv chorismate mutase inhibiting properties in vitro and the
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12. The one-pot transformation was typically carried out as follows: a mixture of
1-naphthol 1 (10 mmol), malononitrile 2 (10 mmol) and bromo aldehyde 3
(10 mmol) in dioxane (5 mL) was cooled to 0–5 °C and then aryl boronic acid
(12.0 mmol), (PPh3)2PdCl2 (0.002 mmol) and pyrrolidine (5 mmol) was added
at 0–5 °C. The resulting mixture was stirred at 0–5 °C for 30 min and then at
70 °C for the duration as indicated in Table 2. The desired product 5 was
isolated after usual work-up (see the Supplementary data).
13. (a) Kim, S. K.; Reddy, S. K.; Nelson, B. C.; Vasquez, G. B.; Davis, A.; Howard, A. J.;
Patterson, S.; Gilliland, G. L.; Ladner, J. E.; Reddy, P. T. J. Bacteriol. 2006, 188,
8638; (b) Sasso, S.; Ramakrishnan, C.; Gamper, M.; Hilvert, D.; Kast, P. FEBS J.
2005, 272, 375.
IC50 value of one compound was found to be 15.63 lM. Overall,
2-aminochromene framework has been identified as a new tem-
plate for the design and discovery of small-molecule based inhibi-
tors of CM for the potential treatment of tuberculosis.
14. Precipitation of the compound 5 observed in most of the cases in assay
medium.
Acknowledgments
The authors (T.R.R., L.S.R., N.V.S. and G.R.R.) thank Dr. Vilas
Dahanukar and Dr. Amrendra Kumar Roy for support and the