In silico studies and β-cyclodextrin mediated neutral synthesis of 4-oxo-4,5,6,7-tetrahydroindoles of potential biological interest

Article abstract of DOI:10.1016/j.tetlet.2020.151972

Prompted by the in silico docking study predictions the first β-cyclodextrin (β-CD) mediated synthesis of 4-oxo-4,5,6,7-tetrahydroindoles in water was achieved via a 3-component reaction under neutral conditions. A range of compounds was prepared by using

Full text of DOI:10.1016/j.tetlet.2020.151972

Journal Pre-proofs
In silico studies and β-cyclodextrin mediated neutral synthesis of 4-
oxo-4,5,6,7-tetrahydroindoles of potential biological interest
G. Dhananjaya, A.V. Dhanunjaya Rao, Kazi Amirul Hossain, Venkateswara
Rao Anna, Manojit Pal
PII:
S0040-4039(20)30415-9
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151972
TETL 151972
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 March 2020
21 April 2020
23 April 2020
Please cite this article as: Dhananjaya, G., Dhanunjaya Rao, A.V., Amirul Hossain, K., Rao Anna, V., Pal, M., In
silico studies and β-cyclodextrin mediated neutral synthesis of 4-oxo-4,5,6,7-tetrahydroindoles of potential
biological interest, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151972
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Elsevier Ltd. All rights reserved.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
In silico studies and β-cyclodextrin mediated neutral
synthesis of 4-oxo-4,5,6,7-tetrahydroindoles of
potential biological interest
Leave this area blank for abstract info.
G. Dhananjaya, A.V. Dhanunjaya Rao, Kazi Amirul Hossain, Venkateswara Rao Anna,* and Manojit Pal*
ß-cyclodextrin
H2O, 90-100 oC
O
O
ArCOCH2Br
Ar
+
N
Neutral
conditions
O
R-NH2
R
82-92% yield.
(Ar = aryl; R = aryl, alkyl)

1
Tetrahedron Letters
journal homepage: www.elsevier.com
In silico studies and β-cyclodextrin mediated neutral synthesis of 4-oxo-4,5,6,7-
tetrahydroindoles of potential biological interest
G. Dhananjaya, a,b A.V. Dhanunjaya Rao,a Kazi Amirul Hossain,c Venkateswara Rao Anna,b,* and Manojit
Palc,*
aTechnology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500049, Telangana, India.
bDepartment of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, 522502, Guntur District, Andhra Pradesh, India
cDr Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Prompted by the in silico docking study predictions the first β-cyclodextrin (-CD) mediated
synthesis of 4-oxo-4,5,6,7-tetrahydroindoles in water was achieved via a 3-component reaction
under neutral conditions. A range of compounds was prepared by using this environmentally
friendly method in good yields (82-92%). The catalyst -CD could be recovered and recycled.
The in silico docking studies predicted chorismate mutase (CM) inhibitory properties of some of
the tetrahydroindoles synthesized that was supported by the results of subsequent in vitro assay.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
β-cyclodextrin
water
tetrahydroindole
chorismate mutase
The conversion of chorismate to prephenate in the shikimate
biosynthetic pathway involves a Claisen rearrangement catalysed
by the enzyme called chorismate mutase or CM (EC 5.4.99.5).
This is a key step leading to the generation of essential amino
acids, phenylalanine and tyrosine. Thus inhibition of CM is
believed to hamper the supply of nutrients to the organism.
Moreover, due to its presence in bacteria, fungi and higher plants
but not in human1-3 targeting CM is regarded as one of the
promising strategies for the discovery of new antibacterial agents.
Over the years various efforts have been devoted towards the
identification of inhibitors of CM either via screening of existing
compound library or design, synthesis and screening of new
molecules.2 While several heterocyclic class has been explored
for this purpose the potential of 4-oxo-4,5,6,7-tetrahydroindoles
as inhibitors of CM has not been assessed previously. Indeed, a
relevant compound e.g. microindolinone A (A, Fig. 1) though
O
O
OH
Ar
Ar
N
N
N
H
R
R
C
B
A
Fig. 1. The bioactive 4,5,6,7-tetrahydroindole derivative A and B and the
target framework C.
potential of another class of tetrahydroindole derivatives have
been explored.6 Very recently, antibacterial activities of related
compounds e.g. fused pyrrole derivatives has been described.7
Nevertheless, due to our long standing interest in the
pharmacological evaluation of pyrrole derivative8,9 as well as CM
inhibitors2 we became curious about potential CM inhibitory
properties of 4-oxo-4,5,6,7-tetrahydroindole derivatives (C, Fig.
1) derived from A and B.
was isolated from
a
deep-sea-derived actinomycete
Microbacterium sp. MCCC 1A11207 but its effects on bacterial
cells are not studied.4 Notably, the utility of 2-aryl-4,5,6,7-
tetrahydro-1H-indole (B, Fig. 1) as an anti-hepatitis C virus
targeting scaffold has been reported5 whereas sirtuin inhibitory
The virtual screening of molecules via their docking into the
target protein in silico is considered as one of the fascinating
approaches in Med Chem efforts.10 The researchers employ this
technique for a variety of purposes and therefore applications of
docking studies has increased dramatically over the last decade.
In our effort, to verify the merit of the framework C for the
identification of potential inhibitor of CM the docking study of
two representative molecules e.g. C-1 and C-2 was performed
using AutoDock Vina and the binding energies are presented in
Table 1. Based on a previous study11a we pursued the interface
----------------
* Corresponding author: Tel.: +91 40 6657; fax: +91 40 6657 1581
E-mail address: manojitpal@rediffmail.com (MP);
chem2005.venkat@kluniversity.in (VRA)

2
Tetrahedron Letters
site of MtbCM for docking of our molecules. The comparable
selective binding of substrates thereby facilitating the reactions
with high selectivity. Indeed, this supramolecular catalysis
involves reversible formation of host-guest complexes via
noncovalent bonding that actually facilitates the reaction.21b
Nevertheless, in addition to their remarkable inclusion
capabilities with small organic molecules, nontoxic nature and
water solubility, and the favorable properties amenable for eco-
friendly approaches prompted us focusing on CDs. Herein we
report the -cyclodextrin (-CD) mediated efficient and neutral
synthesis of 4-oxo-4,5,6,7-tetrahydroindole derivatives (4) in
pure water (Scheme 1). To the best of our knowledge the use of
-CD for the synthesis of compound 4 has not been explored
previously.
binding energies of these molecules with the known inhibitor11b
(D) suggested that molecules based on framework C might
inhibit the CM too. Indeed, the molecule C-1 formed
hydrophobic / Vander Wall interactions with the hydrophobic
residues and hydrophobic regions of polar and charged residues
(see Fig S-1, Suppl. data). Similar interactions were also
observed for the molecule C-2 (see Fig S-2, Suppl. data).
Table 1. Docking of molecules into MtbCM
AutoDock Vina score
Molecules
(Kcal/mol)
O
CH3
Acidic
CH3
-7.3
Ph
N
Wang-OSO3H
H2O, 80-85 oC
Ph
O
C-1
O
O
ArCOCH2Br
ref 15
Ar
1
CH3
CH3
+
N
-7.5
O
R-NH2
Neutral
R
N
4
2
3
H3CO
ß-cyclodextrin
H2O, 90-100 oC
Ph
C-2
NO2
H
N
current work
-7.3
Scheme 1. The reported and current synthesis of 4-oxo-
4,5,6,7-tetrahydroindole derivatives
MeO
H2NO2S
OMe
COOH
D
Non-polar cavity at the center
H
O
There are not many methods known for the synthesis of
compounds containing the 4-oxo-4,5,6,7-tetrahydroindole
framework. For example, synthesis of this class of compounds
was carried out (i) via the K2CO3 mediated reaction of phenacyl
bromide with dimedone followed by the reaction with aniline in
presence of HOAc12a or (ii) via a sulfamic acid (H2NSO3H)
mediated three component reaction in the absence of any solvent
under ball milling conditions.12b or (iii) other methods.12c,d
Alternatively, 4-oxo-4,5,6,7-tetrahydroindole derivatives were
synthesized via the reaction of aryl glyoxal with 3-(aryl/aralkyl
amino)-cyclohex-2-enone.13
OH
7
Primary hydroxyl rim
Fig. 2. -Cyclodextrin (-CD).
At the beginning the reaction of 2-bromo-1-phenylethanone
(1a), aniline (2a) and dimedone (3) was examined in the absence
or presence of a range of commercially available catalysts either
in water or in other organic solvents (Table 2). These reactions
were performed nearly at refluxing temperature of the solvent
used for 6h. While the reaction did not proceed well in the
absence of a catalyst (entry 1, Table 2) or in the presence of
NaHSO3-SiO2 (entry 2, Table 2) the use of 5-15% w/w INDION
225H as a catalyst improved the yield of desired product 4a
significantly (entries 3-5, Table 2). Indeed, the use of 10% w/w
of this catalyst afforded the best product yield (entry 4, Table 2)
though it was not the maximum. Changing the catalyst to -CD
maintained the product yield in the range 58-75% when the
reaction was performed in solvents such as PEG-400, MeOH,
MeCN, i-PrOH (entries 8-11, Table 2), n-BuOH, DMF, DMA or
1,4-dioxane. Indeed, no significant improvement in product yield
was observed when water was used as solvent (entry 12, Table
2). However, the reaction temperature was 60-65 ºC instead of
refluxing temperature of the solvent used in this case. Hence the
reaction was performed at higher temperature e.g. at 80-85 ºC
when an improvement in product yield was observed (entry 13,
Table 2). Further increase in reaction temperature to 90-100 ºC
increased the yield to 90% (entry 14, Table 2). Notably, all these
reactions were performed using 10 mL of solvent. Increase in
volume of water used (to 15 or 20 mL) decreased the reaction
rate whereas decrease in volume (to 5 mL) affected the product
yield. Similarly, these reactions were carried out using w/w 10%
-CD and increase in catalysts quantity did not improve the
product yield (entry 15, Table 2). Thus, the conditions of entry 14
Multicomponent reactions (MCRs), known for over 150 years
since the report of Strecker’s synthesis14a of α-amino cyanides in
1850 are generally defined as synthetic protocols that allow
assembly of three or more substrates in
a regio- and
stereoselective manner to afford complex organic molecules.14b
These protocols offer significant advantages (e.g. operational
simplicity, atom economy etc) over the stepwise construction of
complex molecules and hence have become powerful tools for
the direct and one-pot access to a variety of molecules including
heterocyclic compounds.14c Thus the dramatic rise in applications
of MCRs in all fields of organic synthesis is not surprising.14d
Recently, 3-component approach has been reported for the
preparation of 4-oxo-4,5,6,7-tetrahydroindoles via the reaction of
phenacyl bromide (1), primary amine (2) and dimedone (3) in
water (Scheme 1).15 While, a range of compounds was prepared
efficiently by using this green methodology the process however
involved the use of acidic Wang-OSO3H as a catalyst. Notably,
the preparation of this catalyst from the Wang resin required the
use of a harmful and lachrymator agent i.e. chlorosulfonic acid.16
Thus, establishing a better and neutral method that is free from
the use of hazardous or acidic agents was desirable. The reactions
assisted by cyclodextrin (CD) in aqueous or other media have
been explored17-21 for the development of economic and eco-
friendly methodologies that are thought to be the central focus of
green and sustainable chemistry. Cyclodextrins, the inexpensive
and commercially available cyclic oligosaccharides22 [consisting
of -(1,4) linked glucose units] contain non-polar cavities at
center (Fig. 2) that are less hydrophilic than water and allow

3
i.e. 10% w/w of -CD in water at 90-100 ºC were found to be
optimum in terms of product yield.
Table 3. Recyclability of the catalyst in the MCR of 1a, 2a
and 3 to afford 4a under the reaction condition of entry 14 of
Table 2.
Table 2. Study to establish the optimized reaction conditions.a
Cycle
1st
Time (h)
6.0
Yield (%)
O
O
90
90
88
85
PhCOCH2Br
catalyst
1a
Ph
2nd
6.5
+
N
solvent
O
PhNH2
3rd
Ph
7.0
4a
2a
3
4th
8.0
Entry
Catalyst (%w/w)
Solvent
Temp (°C)
Yield (%)b
1
2
No catalyst
H2O
H2O
90-100
90-100
15
20
Having established the optimized reaction conditions a range
of analogues of 4a were prepared using the -CD-mediated MCR
(Table 4). The phemacyl bromide (1) containing electron
donating e.g. OMe and electron withdrawing group e.g. CN was
employed for this purpose. Similarly, a range of aromatic /
aliphatic amines (2) were employed in this MCR. The aromatic
amines may contain mono substituent like Me, F, Cl or Br group
or combination of two substituents like Me and Me or Me and Cl.
The -naphthyl amine was also employed in this MCR. The
aliphatic amine may contain a cyclopropyl ring or a linear
hydrocarbon chain. The reaction proceeded smoothly in all these
cases affording the desired product in good to excellent yield.
However the use of p-nitoaniline as the amine component (2)
under the conditions employed was not successful indicating the
limitation of the current MCR. Nevertheless, as reported earlier18
the reaction proceeded well when dimedone (3) was replaced by
pentane-2,4-dione (5) affording the polysusbtituted pyrrole
derivatives (6) in 88-92% yield (Scheme 2). The duration of the
reaction was somewhat lower in these cases perhaps due to
NaHSO3–SiO2 (10)
3
4
5
8
INDION 225H (5)
INDION 225H (10)
INDION 225H (15)
β-CD (10)
H2O
90-100
90-100
90-100
90-100
50
70
75
75
H2O
H2O
PEG-400
9
β-CD (10)
β-CD (10)
MeOH
MeCN
60-65
80-85
58
68
10
11
β-CD (10)
i-PrOH
80-85
60
12
13
β-CD (10)
β-CD (10)
H2O
H2O
60-65
80-85
76
80
14
15
β-CD (10)
β-CD (20)
H2O
H2O
90-100
90-100
90
90
COMe
2i
aReaction conditions: phenacy bromide 1a (1.0 mol), amine
N
Ph
C6H4Me-o
2a (1.0 mol), dimedone 3 (1.2 mol) and a catalyst in a solvent for
6h.
NH2
6a
(88%)
OMe
bIsolated yields
O
O
COMe
We then examined the recovery and reuse of the catalyst used
i.e. -CD in the synthesis of 4-oxo-4,5,6,7-tetrahydroindole
derivative 4a. Accordingly, after completion of the reaction (1st
run) the mixture was cooled to room temperature and extracted
with dichloromethane (10 mL). The aqueous layer separated
containing -CD was collected and left overnight at 5 ºC when
because of its low solubility the -CD was precipitated at lower
temperature. After filtration and proper drying it was used for the
next reaction involving 1a (1.0 mmol), 2a (1.0 mmol) and 3 (1.2
mmol) in water a reaction vessel. The reaction was carried out at
90-100 ºC for 6.5 h. The recyclability of the catalyst was
examined for up to four cycles and results are summarized in
Table 3. It is evident that the product 4a could be obtained in
each cycle without significant loss of product yield up to the third
cycle and a marginal loss of yield (~ 5%) was observed after the
fourth cycle.
5
2j
1a
ß-cyclodextrin
H2O
N
NH2
Ph
C6H4OMe-o
90-100 oC
6 h
6b
(90%)
OMe
2k
COMe
Ph
N
C6H4OMe-p
6c (92%)
Scheme 2. -CD mediated synthesis of polysustituted pyrrole
derivatives (6).
Table 4. -CD mediated synthesis of 4-oxo-4,5,6,7-tetrahydroindole derivatives (4).a
Entry Phenacyl bromide (1) Amine (2) Product
Yieldb (%)

4
Tetrahedron Letters
O
O
NH2
Br
CH3
CH3
1
2
90
Ph
N
1a
2a
Ph
4a
Br
O
O
NH2
CH3
CH3
82
N
H3CO
2a
OCH3
Ph
4b
1b
O
NH2
CH3
CH3
CH3
Ph
N
3
4
92
1a
CH3
CH3
CH3
2b
4c
O
NH2
CH3
CH3
CH3
Cl
Ph
88
N
1a
CH3
Cl
2c
4d
O
NH2
CH3
CH3
Ph
N
5
87
1a
Br
2d
Br
N
4e
O
CH3
NH2
CH3
6
7
90
Ph
1a
2e
4f
O
NH2
CH3
CH3
86
1a
Ph
N
2f
4g

5
O
NH2
CH3
CH3
Ph
N
F
8
1a
87
F
2g
4h
O
H2N
CH3
CH3
9
1a
88
Ph
N
H3C
CH3
2h
4i
O
O
NH2
CH3
CH3
Br
CH3
10
11
12
86
N
NC
NC
CH3
2i
1c
1c
4j
O
NH2
CH3
82
CH3
N
NC
2a
Ph
4k
O
NH2
CH3
CH3
CH3
CH3
1c
85
N
NC
CH3
CH3
2b
4l
O
O
NH2
CH3
CH3
Br
13
14
84
N
Cl
Cl
2a
1d
1a
4m
O
NH2
CH3
CH3
CH3
Ph
88
N
CH3
2i
4n
aAll reactions were carried out using phenacyl bromide 1 (1 mmol), amine 2 (1 mmol), dimedone 3 (1.2 mmol) and β-cyclodextrin
(10% w/w) in water (10 mL).
bIsolated yield.

6
Tetrahedron Letters
193.4 ppm
52.1 ppm
O
Nevertheless, since the MCR was less efficient in the absence of

~2.5
105.6 ppm

~1.1
28.6 ppm

~6.8
CH3
CH3
-CD (entry 1, Table 2), the catalyst appeared to play an
important role in increasing the efficiency of the reaction
especially by activating the bromo group of the phenacyl
bromide (1) in addition to aiding the water solubility of all the
reactants (because of its ability24 to form inclusion complexes
with reactants). A subsequent nucleophilic attack by the
dimedone (3) via its enol form on the bromo group bearing
carbon was also facilitated by -CD afforded the tri-keto
intermediate E-1. On further reaction with amine (2) the E-1
afforded an enamine intermediate E-2 that on intramolecular
cyclization furnished the desired product 4. In order to gain
evidences on intermediacy of E-1 in the reaction of 1a, 2a and 3
(under the conditions of entry 14, Table 2) was halted after 2h
when the tri-keto compound i.e. 5,5-dimethyl-2-(2-oxo-2-
phenylethyl)cyclohexane-1,3-dione (see Supplementary data)
was isolated though in low yield after usual work-up.
N
35.5 ppm

~ 2.4
37.0 ppm
144.7
Fig. 3. Partial representation of 1H and 13C NMR spectral data of
compound 4a.
the use of relatively higher reaction temperature though the
product yields were comparable. Thus the current MCR is
amenable for the synthesis of two different class of N-
heterocyclic compounds depending on the nature of 1,3-diketone
employed. Notably, the use of other cyclic 1,3-diketone e.g.
cyclohexane-1,3-dione (7) in place of dimedone (3) afforded the
desired product i.e. 1,2-diphenyl-1,5,6,7-tetrahydro-4H-indol-4-
one (4o) (albeit in low yield i.e. 33%) when reacted with 2-
bromo-1-phenylethanone (1a) and aniline (2a). However, the
MCR did not afford the desired product when cyclopentane-1,3-
dione was used in place of 3. Nevertheless, all compounds
synthesized were characterized by spectral (NMR, IR, and
HRMS) data. The partial 1H and 13C NMR data of a
representative compound 4a is presented in Fig 3. It is evident
In an initial study most of the 4-oxo-4,5,6,7-tetrahydroindole
derivatives (4) synthesized were tested for their CM inhibitory
properties in vitro25,26 using an assay that involved measurement
of catalytic activity of enzyme (CM) in the conversion of
chorismate (substrate) to prephenate. The known inhibitor11b
D
(Table 1) was used as a reference compound (IC50 < 10 mM).
The compound 4a, 4b and 4h showed significant inhibition i.e.
43.67±3.14, 49.92±1.74 and 59.6±2.51% of CM respectively
when tested at 50 µM. This was supported by the docking of 4h
into the CM (Fig. 4). While 4h showed similar interactions as
observed for the molecule C-1 (or 4a) and C-2 (or 4b) an
additional hydrophobic interaction with LYS60 (that was not
present in earlier two molecules) along with other interactions
was observed in this case. This perhaps justified the better
binding energy (-7.6 Kcal/mol) as well as activities of 4h over C-
1 (or 4a) and C-2 (or 4b). While detailed pharmacological
studies of this class of compounds are currently ongoing the
compound 4h appeared to be of further interest in view of the
fact that tuberculosis is a leading cause of death worldwide.
1
that the C-3 pyrrole proton appeared at ~ 6.8 δ in the H NMR
spectra whereas the presence of two CH2 groups was indicated by
the appearance of two singlets near ~2.5 and ~2.4 δ.
Additionally, the two Me groups appeared at ~1.1 δ. The
presence of C=O group was confirmed by the 13C signal at 193.4
ppm in the 13C NMR spectra whereas C-3 of pyrrole ring
appeared at 105.6 ppm. The 13C NMR signals at 52.1 and 37.0
ppm were due to the two CH2 groups. Further the 13C NMR
signals at 28.6 and 35.5 ppm were due to the two Me groups and
the carbon bearing these groups, respectively.
A plausible reaction mechanism22 for the formation of
compound 4 via the -CD mediated MCR is presented in Scheme
3 that involved the formation of a -CD complex from the
primary rim of the cylinder. The -CD is often presented as a
doughnut-shaped truncated cone23 as shown in Scheme 3. It is
known that the primary hydroxy groups (-CH2OH) of glucose
units are located on the narrower rim of the cone (making -CDs
soluble in water), whereas the secondary hydroxy groups
(>CHOH) remain on the wider side (Fig 2 and Scheme 3).

-Cyclodextrin
( -CD)
1 + 3

4
- H2O
3
HO
Br
H
O
O
RHN
O
H
O
O
O
1
RNH2
2
H
O
O
O
OH
O
OH
- HBr
E-2
- H2O
OH
E-1
Scheme 3. Proposed reaction mechanism for the formation
product 4.

7
9.
Layek, M.; Reddy M. A., Rao, A. V. D.; Alvala, M.; Arunasree,
M. K.; Islam, A.; Mukkanti, K.; Iqbal, J.; Pal, M. Org. Biomol.
Chem. 2011, 9, 1004.
Fig. 4. 2D followed by 3D interaction diagram between interface residues
of MtbCM (where red color indicates A chain and orange is B chain) (PDB
code: 2FP2) and 4h that were prepared in Maestro visualizer (Schrödinger,
LLC).
10. (a) Taylor, R.D.; Jewsbury, P.J.; Essex, J.W. J. Comput. Aided
Mol. Des. 2002, 16, 151; (b) Ciemny, M.; Kurcinski, M.; Kamel,
K.; Kolinski, A.; Alam, N.; Schueler-Furman, O.; Kmiecik, S.
(2018-05-04). "Protein–peptide docking: opportunities and
challenges". Drug Disc. Today. 2018, 23, 1530.
In summary, the first β-CD mediated synthesis of 4-oxo-4,5,6,7-
tetrahydroindoles in water has been achieved via a 3-component
reaction of phenacyl bromide (1), primary amine (2) and
dimedone (3). A range of compounds was prepared by using this
environmentally friendly method in good yield (82-92%). The
catalyst β-CD could be recovered and recycled. Being neutral and
free from the use of any metal / hazardous catalyst the
methodology appeared to have advantages over to the previously
reported methods for the synthesis of this class of compounds.
The in silico docking studies predicted chorismate mutase (CM)
inhibitory properties of some of the tetrahydroindoles
synthesized that was supported by the results of in vitro assay.
Indeed, the compound 4h appeared to be best among them. Thus,
our effort facilitated identification of a new class of potential
inhibitors of CM and further studies are in progress towards this
direction. Overall, the current work involving green chemistry
approaches, small organic molecules and their in silico as well as
pharmacological studies would be of further interest.
11. (a) Prakash, P.; Aruna, B.; Sardesai, A. A.; Hasnain, S. E. J. Biol.
Chem. 2005, 280, 19641; (b) Agrawal, H.; Kumar, A.; Bal, N. C.;
Siddiqi, M. I.; Arora, A. Bioorg. Med. Chem. Lett. 2007, 17, 3053.
12. (a) Dagher, C.; Hanna, R.; Terentiev, P. B.; Boundel, Y. G.; Kost,
A. N.; Maskimov, B. I. J. Hetrocyclic Chem. 1982, 19, 645; (b)
Lambat, T. L.; Abdala, A. A.; Mahmood, S.; Ledade, P. V.;
Chaudhary, R. G.; Banerjee, S. RSC Advances, 2019, 9, 39735; (c)
Lee, I.; Kwon, M.; Lee, C. Bull. Korean Chem. Soc., 2012,33,1;
(d) Tanyeli, C.; Akhmedov, I.; Yazıcıoˇglu, E. Tetrahedron Lett.,
2004, 45, 9627
13. (a) Jiang, B.; Li, Y.; Tu, M. S.; Wang, S. L.; Tu, S. J.; Li, G. J.
Org. Chem. 2012, 77, 7497; (b) Maity, S.; Pathak, S.; Pramanik,
A. Eur. J. Org. Chem. 2013, 2013, 2479.
14. (a) Strecker, A. Justus Liebigs Annalen der Chemie. 1850, 75, 27–
45. doi:10.1002/jlac.18500750103; (b) Dömling, A.; Ugi, I.
Angew. Chem. Int. Ed. 2000, 39, 3168; (c) Zhu, J.; Bienaymé, H.
Eds., Multicomponent Reactions. Wiley-VCH: Weinheim, 2005,
468 Pages, ISBN: 3-527-30806-7; (d) For recent examples, see:
Multicomponent Reactions: https://www.organic-
chemistry.org/topics/multicomponent-reactions.shtm, accessed on
April 17, 2020.
15. Dinnea, N. K. R.; Mekalaa, R.; Reddya, S. P.; Sivaa, G. Y. S.;
Bannoath, C. K. Synth. Commun. 2018, 48, 1649.
Acknowledgements
https://doi.org/10.1080/00397911.2018.1458240
The authors thank the management of Dr. Reddy’s Lab
Ltd, Hyderabad, India, for continuous support and
encouragement. Authors also thank Prof P. Misra and his group
of DRILS, Hyderabad for in vitro assay.
16. Dhanunjaya Rao, A. V.; Vykunteswararao, B. P.; Bhaskarkumar,
T.; Jogdand, N. R.; Kalita, D.; Jaydeep, K. D.; Lilakar, J. K. D.;
Siddaiah, V.; Sanasi, P. D.; Raghunadh, A. Tetrahedron Lett.
2015, 56, 4714.
17. Kumar, A.; Tripathi, V. D.; Kumar, P. Green Chem. 2011, 13, 51.
18. Murthy, S. N.; Madhav, B.; Kumar, A. V.; Rao, K. R.; Nageswar,
Y. V. D. Helv. Chim. Acta 2009, 92, 2118.
Supplementary data
19. Reddy, G. R.; Reddy, T. R.; Chary, R. G.; Joseph, S. C.;
Mukherjee, S.; Pal, M. Tetrahedron Lett. 2013, 54, 6744.
20. (a) Konkala, K.; Chowrasia, R.; Manjari, P. S.; Domingues, N. L.
C.; Katla, R. RSC Adv., 2016, 6, 43339; (b) Patil, D. R.; Wagh, Y.
B.; Ingole, P. G.; Singh, K.; Dalal, D. S. New J. Chem., 2013,37,
3261.
21. (a) Karnes, J. J.; Benjamin, I. J. Phys. Chem. C 2017, 121, 19209;
(b) Shivhare, K. N.; Siddiqui, I. R. Supramol. Chem. 2019, 31, 52-
61.
22. (a) De, P.E.; Cereda, C.M.; Fraceto, L.F.; de Araújo, D.R.; Franz-
Montan, M.; Tofoli, G. R.; Ranali, J.; Volpato,M. C.; Groppo, F.
C. Expert Opin. Drug Deliv. 2012, 9, 1505; (b) Bai, C. C.; Tian,
B. R.; Zhao, T.; Huang, Q.; Wang, Z. Z. Molecules 2017, 22,
1475; doi:10.3390/molecules22091475
23. (a) Szejtli. J. Chem. Rev., 1998, 98, 1743; (b) Rekharsky, M. V.;
Inoue, Y. Chem. Rev., 1998, 98, 1875.
24. Ji, H.B.; Shi, D.P.; Shao, M.; Li, Z.; Wang, L.F. Tetrahedron Lett.
2005, 46, 2517.
25. 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.
26. Sasso, S.; Ramakrishnan, C.; Gamper, M.; Hilvert, D.; Kast, P.
FEBS J., 2005, 272, 375.
Supplementary data associated with this article can be found,
in the on line version, at xxxxxxxxx
References and notes
1.
2.
Haslam, E. Shikimic Acid: Metabolism and Metabolites; Wiley:
New York, 1993.
For a review, see: Khanapur, M.; Alvala, M.; Prabhakar, M.;
Kumar, K. S.; Edwin, R. K.; Saranya, P. S. V.K.S.; Patel, R. K.;
Bulusu, G.; Misra, P.; Pal, M. Bioorg. Med. Chem. 2017, 25,
1725.
3.
End to killer TB? Scientists identify an enzyme that may hold
clue; https://researchmatters.in/article/end-killer-tb-scientists-
identify-enzymemay-hold-clue.
4.
5.
Niu, S.; Zhou, T. -T.; Xie, C. -L.; Zhang, G. -Y.; Yang, X. -W.
Mar. Drugs 2017, 15, 230; doi:10.3390/md15070230
Andreev, I. A.; Manvar, D.; Barreca, M. L.; Belov, D. S.; Basu,
A.; Sweeney, N. L.; Ratmanova, N. K.; Lukyanenko, E. R.;
Manfroni, G.; Cecchetti, V.; Frick, D. N.; Altieri, A.; Kaushik-
Basu, N.; Kurkin, A. V. European J. Med. Chem. 2015, 96, 250.
Vojacek, S.; Schulig, L.; Wössner, N.; Geist, N.; Langel, W.;
Jung, M.; Schade, D.; Link, A. ChemMedChem 2019, 14, 853.
Baral, N.; Mishra, D. R.; Mishra, N. P.; Mohapatra, S.; Raiguru,
B. P.; Panda, P.; Nayak, S.; Nayak, M.; Kumar, P. S. J.
Heterocycl. Chem. 2020, 57, 575.
6.
7.
8.
Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Reddy,
L. S.; Kumar, P. M.; Krishna, G. R.; Reddy, C. M.; Rambabu, D.;
Kapavarapu, R.; Lakshmi, C.; Meda, T.; Priya, K. K.; Parsa, K. V.
L.; Pal, M. Chem. Commun., 2011, 47, 7779.
.
relationships that could have appeared to influence
the work reported in this paper.
Declaration of interests
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
☒ The authors declare that they have no known
competing financial interests or personal

8
Tetrahedron Letters
Graphical Abstract
None
To create your abstract, type over the instructions in the
template box below.
Fonts or abstract dimensions should not be changed or altered.
In silico studies and β-cyclodextrin mediated neutral
synthesis of 4-oxo-4,5,6,7-tetrahydroindoles of
potential biological interest
Leave this area blank for abstract info.
G. Dhananjaya, A.V. Dhanunjaya Rao, Kazi Amirul Hossain, Venkateswara Rao Anna,* and Manojit Pal*
ß-cyclodextrin
H2O, 90-100 oC
O
O
ArCOCH2Br
Ar
+
N
Neutral
conditions
O
R-NH2
R
82-92% yield.
(Ar = aryl; R = aryl, alkyl)
.
 Few tetrahydroindoles showed chorismate
mutase inhibition in vitro.
Highlights
 First β-cyclodextrin (-CD) mediated
synthesis of 4-oxo-4,5,6,7-tetrahydroindoles
in water was achieved.
 The synthesis involved a 3-component
reaction under neutral conditions.