Bf3-oet2 catalyzed c3-alkylation of indole: Synthesis of indolylsuccinimidesand their cytotoxicity studies

Article abstract of DOI:10.3390/molecules26082202

A simple and efficient BF₃-OEt₂ promoted C3-alkylation of indole has been developed to obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent yields under mild reaction conditions. Furthermore,

Full text of DOI:10.3390/molecules26082202

molecules
Article
BF3-OEt2 Catalyzed C3-Alkylation of Indole: Synthesis of
Indolylsuccinimidesand Their Cytotoxicity Studies
Iqbal N. Shaikh 1 , Abdul Rahim 1, Shaikh Faazil 1,*, Syed Farooq Adil 2,
and Mohammad Rafe Hatshan 2
*
, Mohamed E. Assal 2
1
Department of Chemistry, Poona College of Arts, Science and Commerce, Camp, Pune 411 001, India;
shaikhiqbaln@gmail.com (I.N.S.); abdulrahimakot@gmail.com (A.R.)
Department of Chemistry, College of Science, King Saud University, P.O. Box 2455,
Riyadh 11451, Saudi Arabia; meassal@ksu.edu.sa (M.E.A.); mhatshan@ksu.edu.sa (M.R.H.)
Correspondence: faazil.shaikh@poonacollege.edu.in (S.F.); sfadil@ksu.edu.sa (S.F.A.)
2
*
Abstract: A simple and efficient BF3-OEt2 promoted C3-alkylation of indole has been developed to
obtain3-indolylsuccinimidesfrom commercially available indoles and maleimides, with excellent
yields under mild reaction conditions. Furthermore, anti-proliferative activity of these conjugates was
evaluated against HT-29 (Colorectal), Hepg2 (Liver) and A549 (Lung) human cancer cell lines. One
of the compounds, 3w, having N,N-Dimethylatedindolylsuccinimide is a potent congener amongst
the series with IC50 value 0.02
µM and 0.8
µM against HT-29 and Hepg2 cell lines, respectively,
and compound 3i was most active amongst the series with IC50 value 1.5
µM against A549 cells.
Molecular docking study and mechanism of reaction have briefly beendiscussed. This method is
better than previous reports in view of yield and substrate scope including electron deficient indoles.
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Keywords: C3-alkylation; indole; indolylsuccinimides; cytotoxicity; anticancer
Citation: Shaikh, I.N.; Rahim, A.;
Faazil, S.; Adil, S.F.; Assal, M.E.;
Hatshan, M.R. BF3-OEt2 Catalyzed
C3-Alkylation of Indole: Synthesis of
Indolylsuccinimidesand Their
Cytotoxicity Studies. Molecules 2021,
26, 2202. https://doi.org/10.3390/
molecules26082202
1. Introduction
The properties like anticancer [
1,2], antioxidant [3–5], antirheumatoidal [6,7] and
anti-HIV [ 10] has made indole a privileged scaffold and its derivatives such as indolyl-
8–
succinimide are important intermediates in organic synthesis and pharmaceuticals [11
The indole ring system is present in many commercially marketed drugs (Figure 1) [19
Moreover, different indole derivatives targeting regulation of PI3K/Akt/mTOR/NF-
–
–
18].
21].
κB
Academic Editor: Alice L. Perez
and other signaling pathways have been reported [22 24]. Maleimide and its N-substituted
derivatives are potent and selective telomerase inhibitors suitable for cancer therapy [25].
This moiety is used as a bridge to the disulfide bond present in protein and protein PE-
–
Received: 19 February 2021
Accepted: 2 April 2021
Published: 11 April 2021
Gylation [26
intra-tumoral drug delivery as well as to improve the therapeutic efficacy [28
Ru(II) and Pt(IV) based compounds with maleimide functionality have been prepared to
selectively deliver these compounds to the tumor [31 32]. Additionally, maleimide-derived
molecule MIRA-1 reactivates mutant p53 in living cells and induces mutant p53-dependent
cell death in different human tumor cells [33,34].
,
27] and as a linker in antibody-drug conjugates to increase their tolerability,
–
30]. Similarly,
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iations.
,
On the other hand, another interesting molecule, the succinimide which is found in
many natural products, is also noticed in several clinical drug candidates, indicating that
this scaffold plays a vital role in exhibiting a wide range of biological and pharmaceutical
Copyright:
© 2021 by the authors.
activities (Figure 1) [35–38]. Further, succinimides can be easily reduced into 5-membered
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
pyrrolidine rings, -lactams and lactims, which by themselves are useful natural product
γ
motifs and can be oxidized to maleimides [39,40].
Thus, importance of developing methods to synthesize indolyl-derivatives can never
be overestimated, which is also indicated by the large number of reports appearing consis-
tently in various journals from the past decades [41
with selective functionalization has become an active research area [47
–
46]. Most importantly, their synthesis
49]. In contrast
–
Molecules 2021, 26, 2202. https://doi.org/10.3390/molecules26082202
https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 2202
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to the conventional approaches, the direct functionalization of indole has emerged more
recently as a preferred methodology as it is more practical and reduces the number of
steps [50
tion metal catalyzed C-H activations are more attractive [55
and C3 are the most activated ones, thus direct C3 alkylations are still limited. Therefore,
allylic alkylations [59 65], Baylis–Hillman [66 69] and more frequently Friedel-Craft type
–54]. Among the several approaches for the direct substitution of indoles, transi-
–
58]. However, positions C2
–
–
of reactions [70–75] are especially useful to achieve this transformation.
Figure 1. Indole and succinimide rings present in natural products and drug candidates.
Apart from the various indolyl-derivatives synthesized, the preparation of indolylsuc-
cinimidesneeds to be paid attention to as the previously reported methods have several
drawbacks, such as the general method of preparation, which is carried out by the reaction
of indoles with maleimides by refluxing in acetic acid. However, this reaction requires long
reaction time (up to 3–5 days) and the products are obtained in low yields even after use of
excess amounts of reactants [76,77]. In case of acid-catalyzed conjugate addition of indoles,
careful control of the acidity to prevent side reactions such as dimerization or polymeriza-
tion is required [78]. Other methods involve the use of Pd and Ru metals for cross-coupling
between indole and dihalomaleimides for the synthesis of 3-indolylsuccinimides and 2-
indolylsuccinimides, respectively [79
were reported previously which involves the conjugate addition of indoles to maleimide
compounds in the presence of Lewis acids such as ZnCl2/AlCl3 (1 mmol) [76 78]. How-
–82]. To the best of our knowledge, only two reactions
–
ever, these reactions were performed in DCE or nitromethane under heating or refluxing
condition using electron rich indoles. It was observed that the electron-deficient indoles
provide unsatisfactory yield and more often very low reaction yield. Furthermore, there
are many methods to functionalize the C3 position of the indole nucleus but very few of
them allow the use of free N-H indole skeletons.
Thus, an efficient, economical and environmentally benign commercially available
or new catalyst is highly desirable for this procedure. In continuation of our work with
regard to the preparation of new catalyst for various organic transformations, [79
–81]
we herein report a strategy in which commercially available boron trifluoride diethyl

Molecules 2021, 26, 2202
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etherfunctions as an effective catalyst [82
,83] for the synthesis of indolylsuccinimides
(Scheme 1). Interestingly, unlike earlier procedures, it offers a convenient single step
reaction and works well with the electron-deficient indoles under mild reaction conditions.
These indolylsuccinimide conjugates were evaluated for their cytotoxicity against HT-29,
Hepg2 and A549 human cancer cell lines and moreover molecular docking studies were
also carried out to understand their binding mode to the receptor.
Scheme 1. Synthesis of indolylsuccinimides; a Reagents and conditions: BF3OEt2 (50 mol%), ethyl
◦
acetate, 60 C, 6 h.
2. Results and Discussion
2.1. Chemistry
Initially, 1H-indole (1) (Scheme 2) is taken as a model substrate to study this reaction,
because the product, 3-indolylsuccinimide 3a is a solidandcan be easily purified. As shown
in Table 1, the reaction between 1H-indole (1a) and maleimide (2a) does not take place at
room temperature in the absence of any catalyst up to 12 h (Table 1, entry 1). However,
use of iodine in ethanol solvent furnished the desired compound with very low yield
◦
(
Table 1, entry 2). Increasing the temperature to 60 C did not show any remarkable change
in the yield. Switching the solvent from ethanol to methanol and acetonitrile slightly
increased the yield (Table 1, entries 3 and 4). Lewis acid catalyzed addition of indole to
maleimide has been previously reported employingZnCl2, however this catalyst is found
to be inefficient as it also provided very low yield for the reaction under the aforesaid
conditions (Table 1, entries 5–7). Moreover, attempts using copper and silver catalyst also
failed to give the desired products in this reaction (Table 1, entries 8–12). Similarly, the
use of cerium ammonium nitrate (CAN) and boric acid as catalysts too did not yield the
required products (Table 1, entries 13 and 14).
Scheme 2. Optimization of reaction.

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Table 1. Optimization of the reaction conditions a.
◦
Yield(%) b
Entry
Catalyst
Solvent *
Temp ( C)
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
-
I2
I2
I2
DCE
EtOH
MeOH
MeCN
MeCN
DCE
EtOAc
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
DCE
r.t/60 c
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t/60
r.t
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
6
0
5
18
25
trace
10
trace
N.R
N.R
trace
N.R
N.R
N.R
0
ZnCl2
ZnCl2
ZnCl2
Cu(OAc)2
Cu(OTf)2
Cu(NO3)2
AgCl
AgOTf
CAN
H3BO3
BF3OEt2
BF3OEt2
BF3OEt2
BF3OEt2
BF3OEt2
30
52
44
62
60
60
60
60
EtOAc
78
a
b
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), catalyst (0.5 mmol), heated in 5 mL of solvent within 12 h.
Products were obtained in isolated yields based on indole. Reaction first stirred at r.t. if starting material not
c
consumed totally then temperature shifted to 60 ◦C. * DCE-dichloroethane, EtOH- ethanol, MeOH-methanol,
MeCN-acetonitrile, EtOAc-ethyl acetate.
Later, the use of classic Lewis acid boron trifluoride ethyl ether (BF3OEt2) as catalyst
is attempted and found to be efficient as the desired product is obtained in relatively good
yield (Table 1, entry 15) when compared to the other reaction◦s attempted. Moreover, in-
creasing the reaction temperature from room temperatureto 60 C in acetonitrile as solvent
displayed a nearly two-fold increases in the yield (Table 1, entry 16). However, decrease in
yield is reported when solvent is changed from acetonitrile to methyl alcohol (entry 17).
Further, change in solvent from protic to aprotic viz. 1,2-dichloroethane (entry 18) increased
in the product yield is observedA substantial yield i.e., ~78%, of 3-indolylsuccinimide 3a
is obtained when ethyl acetate is taken as solvent and the reaction time reduced signifi-
cantly from 12 h to 6 h (Table 1, entry 19). Thus, the optimal reaction conditions for the
efficient synthesis of 3-indolylsuccinimide 3a, catalyzed by BF3OEt2 (0.5 mmol) requires
1a (1.0 mmol) and 2a (1.0 mmol) wherein ethyl acetate will be used as a solvent at 60 ◦C
upon stirring for 6 h, hence this condition will be extended to the synthesis of a variety of
Indolylsuccinimides to afford the desired product in 78% yield.
With the optimized reaction conditions established, the substrate scope of BF3OEt2-
catalysed C3-alkylation reaction with different indole substrates is investigated. A series of
5-substituted indoles are found to undergo the desired coupling to give the corresponding
products in moderate to excellent yield (56 86%, Scheme 3). The structure of resultant
−
compounds is established on the basis of their 1H, 13C NMR and HRMS spectra. However,
some of the products were reported previously are corroborated with their reported data
and found in accordance (Appendix A.) [76,77,84].
The electronic nature of the indoles was shown to have more influence on the reaction
efficiency. The presence of electron-donating groups (5-OMe) significantly increased the
yield as it is obvious in case of electrophilic substitution reaction of indole that provides 86%
of 3b. However, electron-deficient groups (5-CN and 5-NO2) had drastic effect on reactivity,
and the corresponding 3-indolylsuccinimides were obtained in relatively low yields (56%
and 60% for 3e and 3f) than the electron-neutral group containing compound 3a with 78%
yield. The time required for the completion of this reaction is found between 2and 6 h. The
optimal reaction conditions are also compatible with halogenated indole (i.e., 5-F and 5Br),
with the corresponding products 3c and 3d obtained in 75% and 84% yields (Scheme 3).

Molecules 2021, 26, 2202
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We next investigated the scope of N-alkylated maleimides as substrates and the results are
displayed in Scheme 4. All the N-alkylated maleimides reacted well, giving the desired
products 3g–3i in 78–88% yield. Notably, N-methyl and N-benzyl maleimides exhibited
excellent reactivity than N-Phenyl (3h, 78%) to give corresponding products 3g and 3i in
83% and 88% yield. These results indicate that N-protected maleimides havesome effect on
the reaction.
Scheme 3. Substrate scope of indoles; c Reaction conditions: 1a-1f (1.0 mmol), 2a (1.0 mmol), BF3OEt2 (0.5 mmol), heated in
5 mL of solvent within 6 h.
To extend the scope, we also made substituted indoles products (3j-3x) with good
to excellent yield (58–90%). Electron-deficient groups (5-CN and 5-NO2) containing com-
pounds were formed in relatively low yield (3j, 3n, 3r and 3v with 64%, 58%, 68% and
64%) than electron donating group (MeO, 3k, 74%) and halogenated compounds (Br and
Cl, 3l-3m, 70% and 72%). Moreover, the reaction of N-benzyl maleimides furnished the
products in excellent yield compared to their N-methyl and N-phenyl counterparts. Inter-
estingly, when N-alkylated indole and N-alkylatedmaleimide was investigated, the yield
of the products can rise drastically (3w-3x, 84% and 90%) as shown in Scheme 5.

Molecules 2021, 26, 2202
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Scheme 4. Substrate scope of maleimides; d Reaction conditions: 1a (1.0 mmol), 2a-2d (1.0 mmol), BF3OEt2 (0.5 mmol),
heated in 5 mL of solvent within 6 h.
Plausible Mechanism
BF3-etherate catalyst serves as a source of boron trifluoride via the equilibrium [85
,
86]
shown below. The BF3 coordinate with the oxygen of maleimide, inducing reactions of
the resulting adducts A with indole nucleophile to generate intermediate B which on
deprotonationconverted to intermediate C hence restoration of aromaticity. Finally, this
gives rise to the desire product Scheme 6.
2.2. Biological Evaluation
To access the cytotoxicity, all compounds were screened against three human cancer
cell lines namely HT-29, Hepg2 and A549 by MTT assay [87
found to be the most potent congener amongst the series with IC50 value 0.02
0.8 M against HT-29 and Hepg2 cell lines, respectively and compound 3i was most active
,
88]. The compound 3w was
µM and
µ
amongst the series with IC50 value 1.5 µM against A549 cells.
2.2.1. Structure Activity Relationship
Indole based bioactive molecules are reported in literature for diversified activity
including anti-canceractivity [89].
It is observed from the Table 2 that compounds having unprotected indole and succin-
imide moieties (3a–3f) showed favorable activity against HT-29 and Hepg-2 cell lines with
IC50 values ranging from 3.6 to 9.1 µM. Interestingly, compound 3b has IC50 value of 3.6 µM
against Hepg-2 cells. However, N-methylated, N-phenylandN-benzylatedsuccinimids with
unprotected indoles were relatively less active against these cell lines. Moreover, N-
methylated and N-benzylatedsuccinimides (3i, 3k-3m, 3u and 3v) are more active against
A549 cells than N-phenyl compounds with IC50 ranging from 1.5 to 8.7
compound 3w having N-methyl on both indole as well as succinimide rings showed poten-
tial cytotoxicity with IC50 values of 0.02 and 0.8 M against HT-29 and Hepg-2 cell lines,
µM. Remarkably,
µ
respectively. In view of electron rich and deficient indoles no remarkable distintion was
observed, however these indoles were more active against HT-29 and Hepg-2 cells than
A549 cells. Interestingly, halogenated indoles showed enhanced effect against A549 cells.

Molecules 2021, 26, 2202
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Scheme 5. Scope of indole and maleimides; e Reaction conditions: 1a-1f (1.0 mmol), 2a-2d (1.0 mmol), BF3OEt2 (0.5 mmol),
heated in 5 mL of solvent within 6 h.
Scheme 6. Plausible mechanism.

Molecules 2021, 26, 2202
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Table 2. Cytotoxicity of indolylsuccinimide analogues.
Cancer Cell Lines (IC50 µ/M) f
Entry
Compound
HT-29 g
Hepg2 h
A549 i
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
3u
3v
3w
4.32 (±0.06)
4.67 (±0.16)
4.36 (±0.33)
7.9 (±0.32)
06.2 (±0.23)
05.4 (±0.13)
10.7 (±0.23)
08.4 (±0.06)
24.8 (±0.02)
07.8 (±0.03)
10.6 (±0.12)
10.9(±0.03)
19.9 (±0.12)
09.1(±0.06)
06.6(±0.4)
5.2 (±0.03)
03.6 (±0.02)
05.8 (±0.03)
09.1 (±0.04)
05.6 (±0.06)
04.9 (±0.01)
11.4 (±0.03)
15.9 (±0.03)
20.3 (±0.03)
06.9 (±0.11)
13.0 (±0.13)
13.6 (±0.035)
14.5 (±0.6)
7.8 (±0.21)
16.5 (±0.22)
18.7 (±0.20)
5.9 (±0.05)
12.5 (±0.07)
19.5 (±0.56)
18.6 (±0.05)
16.7 (±0.67)
07.2 (±0.09)
0.8 (±0.05)
17.3 (±0.22)
01.8 (±0.01)
10.9 (±0.03)
9.7 (±0.22)
2.1 (±0.20)
6.4 (±0.14)
18.2 (±0.22)
10.7 (±0.05)
9.6 (±0.13)
10.6 (±0.34)
1.5 (±0.45)
9.1 (±0.33)
2.5 (±0.12)
3.9 (±0.34)
3.5 (±0.01)
12.9 (±0.22)
14.4 (±0.03)
11.3 (±0.03)
7.6 (±0.03)
8.7 (±0.06)
15.8 (±0.22)
11.4 (±0.17)
2.4 (±0.14)
3.6 (±0.24)
6.3 (±0.12)
14.7 (±0.12)
0.9 (±0.10)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
12.5±0.03
10.2 (±0.33)
10.3 (±0.45)
23.6 (±0.67)
22.5 (±0.34)
10.7 (±0.23)
08.5 (±0.13)
0.02 (±0.02)
28.2 (±0.34)
01.2 (±0.03)
3x
Doxorubicin
f
50% Inhibitory concentration after 48 h of compounds treatment and the values are average of three individual
experiments. Human colorectal adenocarcinoma cells, h Human liver cancer and i Human lung cancer.
g
2.2.2. Molecular Docking Studies
Molecular docking studies were carried out with a view to understand the site of
binding by these compounds. It is evident from the literature that various indolylmaleimid-
ederivatives show cytotoxic properties by inhibiting the cyclin-dependent kinases and
therefore molecular docking studies were performed at the ATP binding pocket of CDK2
as a model kinase [90]. A number of structural studies have demonstrated that most of
inhibitors bind to CDK2 in a fashion similar to Staurosporine (which is a known kinase
inhibitor), the adenine ring of ATP, forming a triplet of hydrogen bonds to the peptide
backbone of residues Glu81 and Leu83, which resides in the hydrophilic hinge region at
the back of the binding pocket [91]. The crystal structure of Staurosporine in complex
with CDK2 provides insight into the interactions responsible for high-affinity binding to
a variety of kinases. The crystal structure of the protein was obtained from Protein Data
Bank (PDB ID 1AQ1) [31], necessary corrections to the protein were carried out using Pro-
tein Preparation Wizard from the Schrodinger package and 3D structures were generated
by Schrödinger suite (Schrödinger’sLigPrep program). Molecular docking studies were
performed by using a GLIDE docking module of Schrödinger suite and the results were
analyzed on the basis of the GLIDE docking score and molecular recognition interactions.
All the 3D figures were obtained using Schrödinger Suite 2014-3 [92].
Docking studies were performed on 3c and 3w, which suggests a reasonable binding
mode in the ATP-binding pocket of CDK2 (Figure 2). This binding mode is very similar to
the Staurosporine binding mode. Likewise, compound 3c hydrogen bond to the backbone
carbonyl of Glu81 and to the backbone amine of Leu83 are formed, compound 3w formed
hydrogen bond with leu83. The indole ring is located in the hydrophobic cleft formed by
the amino acids Ile10, Val18, Lys33, Phe80, Leu134, and Asp145.

Molecules 2021, 26, 2202
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Figure 2. (A) Binding pose of compound 3c in ATP binding pocket of CDK2. (B) Binding pose of compound 3w in ATP
binding pocket of CDK2. Compounds 3c and 3w shown in stick and colored by the atom type (carbon: grey; oxygen: red;
nitrogen: blue; fluorine: green).
3. Materials and Methods
3.1. Preparation of Compounds
The detailed procedure of the synthesis is given in Appendix A section.
3.2. Biological Activity
The detailed procedure employed for the biological activity is given in Appendix A section
.
4. Conclusions
A simple and efficient BF3-OEt2 promoted C3-alkylation of indoles has been devel-
oped to access 3-indolylsuccinimidesfrom commercially available indoles and maleimides,
in good to excellent yields (64–90%) (under mild reaction conditions. This is an improved
protocol compared to the previously reported ones, in view of yield and substrate scope
including electron-deficient indoles. Furthermore, anti-proliferative activity of these con-
geners was evaluated against HT-29, Hepg2 and A549 human cancer cell lines. Compound
3w was found to be the most potent amongst the series with IC50 value of 0.02
0.8 M against HT-29 and Hepg2 cell lines, respectively and compound 3i was most active
amongst the series with IC50 value 1.5 µM against A549 cell line.
µM and
µ
Author Contributions: Conceptualization, I.N.S. and S.F.; formal analysis, I.N.S., A.R. and S.F.A.;
funding acquisition, M.R.H.; investigation, S.F.A.; methodology, A.R. and S.F.; resources, M.R.H.;
software, M.E.A.; writing—original draft, S.F.; writing—review and editing, S.F.A. and M.E.A. All
authors have read and agreed to the published version of the manuscript.
Funding: The authors extend their appreciation to the Deputyship for Research & Innovation,
“Ministry of Education“ in Saudi Arabia for funding this research work through the project number
IFKSURG-2020-142.
Institutional Review Board Statement: Not Applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: The data presented in this study are available on request from the
corresponding author.

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Acknowledgments: The authors I.N.S., A.R. and S.F. thankful to Y & M AnjumanKhairul Islam’s
Trust, Mumbai, INDIA for infrastructural support.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds can be checked with the author, Faazil Shaikh
(faazil.shaikh@poonacollege.edu.in).
Appendix A. Experimental Section
Appendix A.1. Chemistry
All reagents, starting materials, and solvents were purchased from Aldrich (Sigma-
Aldrich, St. Louis, MO, USA) or Alfa Aesar (Johnson Matthey Company, Ward Hill, MA,
USA) and used without further purification. Reactions were monitored by TLC, performed
on silica gel glass plates containing 60 F-254, and visualization on TLC was achieved by
UV light or using an iodine indicator. Column chromatography was performed with
Merck 60–120 mesh silica gel. 1H and 13C NMR spectra were recorded with 75, 100, 300,
400, and 500 MHz spectrometer in CDCl3 and DMSO-d6 solutions. Chemical shifts (δ)
are expressed in ppm relative to the internal standard TMS and multiplicities of NMR
signals are represented as singlet (s), doublet (d), triplet (t), quartet (q), double doublet
(dd), triplet of doublet (td) and multiplets (m). High-resolution mass spectra (ESI-HRMS
were obtained by using ESI-QTOF mass spectrometer. Melting points were determined on
an Electro-thermal melting point apparatus and are uncorrected.
)
Appendix A.2. General Procedure for the Synthesis of Compounds (3a–3x)
A mixture of 117 mg (1 mmol) indole, 97 mg (1 mmol) maleimide andapproximately a
drop of BF3OEt2 (0.5 mmol) in 5 mL of ethyl acetate solvent was stirred at 60 ◦C for 6 h.
Completion of reaction was monitor by TLC. After completion, the mixture was cooled
to room temperature. In some cases where the product succinimide appeared as a solid
from the reaction mixture filtered and recrystallized. Otherwise, H2O (20 mL) was added
to the solution and extracted with EtOAc (2
×
25 mL). The combined organic layer was
dried over anhydrous Na2SO4 and concentrated by rotary evaporation to afford crude
product which was further purified by column chromatography using EtOAc and hexane
as solvent system.
3-(1H-Indole-3-yl) pyrrolidine-2,5-dione (3a). White solid (80%), M.P.: 192–194 ◦C; 1H
NMR (300 MHz, DMSO-d6)
δ 11.31 (s, 1H), 11.03 (s, 1H), 7.39 (dd, J = 12.5, 8.1 Hz, 2H), 7.33
(s, 1H), 7.10 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 4.33 (dd, J = 9.4, 5.2 Hz, 1H), 3.18 (dd,
J = 18.0, 9.5 Hz, 1H), 2.76 (dd, J = 18.0, 5.2 Hz, 1H); 13C NMR (75 MHz, CDCl3+ DMSO-d6):
δ
178.9, 177.0, 136.0, 124.9, 122.0, 120.9, 118.3, 117.5, 111.1, 110.0, 38.7, 37.0; HRMS (ESI)
calculated for C12 H11O2N2 [M+ H]+ 215.0815; found: 215.0817.
3-(5-MetHoxy-1H-indole-3-yl) pyrrolidine-2,5-dione (3b). White solid (86%), M.P.: 206–208 ◦C
1H NMR (300 MHz, DMSO-d6)
11.08 (s, 1H), 10.27 (s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.05 (d,
;
δ
J = 2.1 Hz, 1H), 6.82 (d, J = 1.9 Hz, 1H), 6.71 (dd, J = 8.8, 2.2 Hz, 1H), 4.18 (dd, J = 9.4, 5.1
Hz, 1H), 3.73 (s, 3H), 2.74 (dd, J = 18.2, 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3+ DMSO-d6)
δ
178.8, 177.0, 152.9, 131.2, 125.4, 122.5, 111.7, 110.9, 109.7, 99.7, 55.0, 38.7, 37.0; HRMS (ESI)
calculated for C13 H13O3N2 [M+ H]+ 245.0920; found: 245.0923.
3-(5-Fluoro-1H-indole-3-yl) pyrrolidine-2,5-dione (3c). White solid (75%), M.P.: 198–199 ◦C
;
1H NMR (300 MHz, DMSO-d6)
δ 11.30 (s, 1H), 11.14 (s, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.37
(dd, J = 8.8, 4.6 Hz, 1H), 7.19 (dd, J = 10.1, 2.3 Hz, 1H), 6.95 (td, J = 9.2, 2.5 Hz, 1H), 4.33 (dd,
J = 9.4, 5.5 Hz, 1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.78 (dd, J = 18.0, 5.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3+ DMSO-d6)
δ 179.1, 177.4, 158.6 (d), 155.5, 132.9, 125.6, 125.5, 124.1, 112.3,
112.2, 110.5, 110.0, 109.6, 102.9, 102.6, 39.0, 37.2; HRMS (ESI) calculated for C12H10FO2N2
[M+ H]+ 233.0720; found: 233.0725.
3-(5-Bromo-1H-indole-3-yl) pyrrolidine-2,5-dione (3d). White solid (84%), M.P.: 210–212 ◦C
;
1H NMR (300 MHz, DMSO-d6)
J = 2.1 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 8.6, 1.6 Hz, 1H), 4.36 (dd, J = 9.3, 5.5 Hz,
δ 11.32 (s, 1H), 11.26 (s, 1H), 7.64 (d, J = 1.1 Hz, 1H), 7.40 (d,

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1H), 3.17 (dd, J = 18.0, 9.5 Hz, 1H), 2.80 (dd, J = 18.0, 5.5 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6)
δ 180.2, 178.5, 135.6, 128.5, 125.3, 124.3, 121.4, 114.2, 111.8, 111.3, 39.1, 37.6;
HRMS (ESI) calculated for C12H10BrO2N2 [M+ H]+ 292.99; found: 292.99.
3-(2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile (3e). Yellowish solid (56%), M.P.:
218–220 ◦C; 1H NMR (300 MHz, DMSO-d6)
δ
11.57 (s, 1H), 11.30 (s, 1H), 8.45 (d, J = 1.2Hz,
1H), 7.94 (dd, J = 8.7, 1.8Hz, 1H), 7.42 (s, 2H), 4.39 (dd, J = 9.0, 5.4 Hz, 1H), 3.18 (dd, 1H),
2.79 (dd, 1H); 13C NMR (100 MHz, DMSO-d6)
δ 177.4, 175.7, 139.0, 138.0, 124.6, 123.9,
118.6,115.0, 114.3, 112.0, 110.23, 36.9, 35.4; HRMS (ESI) calculated for C13H9N3O2 [M+ H]+
240.0732; found: 240.0640.
3-(5-Nitro-1H-indole-3-yl) pyrrolidine-2,5-dione (3f). Yellow solid (60%), M.P.: 224–226 ◦C
;
1H NMR (300 MHz, DMSO-d6)
J = 9.0, 2.0 Hz, 1H), 7.44 (s, 2H), 4.41 (dd, J = 9.4, 5.5 Hz, 1H), 3.20 (dd, J = 18.1, 9.5 Hz, 1H),
2.81 (dd, J = 18.1, 5.5 Hz, 1H); 13C NMR (100 MHz, DMSO-d6)
177.6, 175.9, 139.1, 138.1,
δ 11.59 (s, 1H), 11.32 (s, 1H), 8.47 (d, J = 1.6 Hz, 1H), 7.96 (dd,
δ
124.8, 124.0115.2, 114.4, 112.1, 110.3, 37.0, 35.5; HRMS (ESI) calculated for C12H9O4N3Na
[M+ Na]+ 282.0485; found: 282.0491.
3-(1H-Indole-3-yl)-1-metHylpyrrolidine-2,5-dione (3g). WHite solid (85%), M.P.: 170–172 ◦C
;
1H NMR (300 MHz, DMSO-d6)
δ 11.05 (s, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 2.3 Hz,
1H), 7.10 (t, J = 7.2 Hz, 1H), 6.99 (t, J = 7.1 Hz, 1H), 4.36 (dd, J = 9.3, 5.0 Hz, 1H), 3.23 (dd,
J = 18.0, 9.4 Hz, 1H), 2.92 (s, 3H), 2.79 (dd, J = 18.0, 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3+
DMSO-d6)
δ 177.4, 175.9, 175.6, 135.9, 124.8, 121.9, 120.9, 118.4, 117.3, 111.0, 109.7, 37.2, 35.6,
24.0; HRMS (ESI) calculated for C13 H13O2N2 [M+ H]+ 229.0971; found: 229.0973.
3-(1H-indol-3-yl)-1-pHenylpyrrolidine-2,5-dione (3h). WHite solid (78%), M.P.: 102–104 ◦C
;
1H NMR (500 MHz, DMSO-d6)
δ
11.10 (s, 1H), 7.55–7.49 (m, 3H), 7.46–7.41 (m, 2H), 7.40
(d, J = 8.1 Hz, 1H), 7.37–7.33 (m, 2H), 7.15–7.09 (m, 1H), 7.07–7.00 (m, 1H), 4.56 (dd, J = 9.5
5.4 Hz, 1H), 3.41 (dd, J = 18.0, 9.6 Hz, 1H), 3.00 (dd, J = 18.0, 5.4 Hz, 1H); 13C NMR
,
(100 MHz, DMSO-d6)
δ 178.1, 176.2, 137. 0, 133.2, 129.4, 128.7, 127.6, 126.4, 124.2, 121.8,
119.4, 118.8, 112.2, 111.1, 38.4, 36.9; HRMS (ESI) calculated for C18 H15O2N2 [M+ H]+
291.1128; found: 291.1128.
1-Benzyl-3-(1H-Indole-3-yl) pyrrolidine-2,5-dione (3i). WHite solid (88%), M.P.: 119–122 ◦C
;
1H NMR (300 MHz, CDCl3)
δ 8.18 (s, 1H), 7.45 (dd, J = 7.2, 2.2 Hz, 2H), 7.31 (dd, J = 5.4,
3.5 Hz, 3H), 7.24 (d, J = 4.5 Hz, 1H), 7.20 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.02 (d,
J = 7.7 Hz, 1H), 6.99 (d, J = 2.7 Hz, 1H), 4.89–4.65 (m, 2H), 4.27 (dd, J = 9.5, 4.9 Hz, 1H), 3.24
(dd, J = 18.4, 9.5 Hz, 1H), 2.89 (dd, J = 18.4, 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 178.1,
176.2, 136.5, 135.7, 129.0, 128.7, 128.1, 125.4, 122.5, 122.4, 119.9, 118.4, 111.6, 111.2, 42.7, 38.2,
36.4; HRMS (ESI) calculated for C19 H17O2N2 [M+ H]+ 305.1284; found: 305.1289.
1-Methyl-3-(5-nitro-1H-indole-3-yl)-pyrrolidine-2,5-dione (3j). Yellow solid (64%), M.P.:
◦
242–244 C; 1H NMR (400 MHz, DMSO-d6)
δ 11.82 (s, 1H), 8.56 (d, J = 2.1 Hz, 1H), 8.02 (dd,
J = 9.0, 2.2 Hz, 1H), 7.63 (d, J = 2.1 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 4.55 (dd, J = 9.2, 5.4 Hz,
1H), 3.25 (dd, J = 17.9, 9.3 Hz, 1H), 3.02–2.91 (m, 1H), 2.91 (s, J = 4.6 Hz, 3H); 13C NMR
(75 MHz, DMSO-d6)
δ 177.9, 176.4, 140.5, 139.5, 126.8, 125.8, 116.7, 116.2, 113.6, 112.1, 37.0,
35.4, 24.6; HRMS (ESI) calculated for C13H11O4N3Na [M + Na]+ 296.0641; found: 296.0647.
3-(5-MetHoxy-1H-indole-3-yl)-1-metHylpyrrolidine-2,5-dione (3k). WHite solid (74%),
M.P.: 138–140 ◦C; 1H NMR (300 MHz, DMSO-d6)
δ
10.89 (s, 1H), 7.27 (d, J = 8.8 Hz, 2H),
6.87 (d, J = 2.0 Hz, 1H), 6.76 (dd, J = 8.8, 2.3 Hz, 1H), 4.33 (dd, J = 9.2, 5.0 Hz, 1H), 3.73 (s,
3H), 3.23 (dd, J = 17.9, 9.3 Hz, 1H), 2.92 (s, 3H), 2.79 (dd, J = 17.9, 4.9 Hz, 1H); 3H); 13
C
NMR (75 MHz, CDCl3 + DMSO-d6) δ 177.7, 175.9, 153.2, 131.4, 125.5, 122.5, 112.0, 111.3,
109.7, 99.8, 55.1, 37.4, 35.7; HRMS (ESI) calculated for C14 H15O3N2 [M + H]+ 259.1077;
found: 259.1080.
3-(5-Bromo-1H-indole-3-yl)-1-metHylpyrrolidine-2, 5-dione (3l). WHite solid (70%), M.P.:
197–199 ◦C; 1H NMR (300 MHz, DMSO-d6)
δ
10.62 (s, 1H), 7.49 (s, 1H), 7.22 (d, J = 8.6 Hz,
1H), 7.17–7.07 (m, 2H), 4.22 (dd, J = 9.3, 4.9 Hz, 1H), 3.20 (dd, J = 18.2, 9.4 Hz, 1H), 2.98 (s,
3H), 2.77 (dd, J = 18.2, 5.0 Hz, 1H);13C NMR (75 MHz, CDCl3 + DMSO-d6)
177.3, 175.6,
δ
134.9, 127.0, 124.0, 123.2, 120.4, 112.8, 111.7, 109.6, 37.2, 35.7, 24.3; HRMS (ESI) calculated
for C13 H12BrO2N2 [M + H]+ 307.0076; found: 307.0081.

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3-(5-Fluoro-1H-indole-3-yl)-1-metHylpyrrolidine-2, 5-dione (3m). WHite solid (72%), M.P.:
◦
200–202 C; 1H NMR (300 MHz, DMSO-d6)
δ 11.15 (s, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.37 (dd,
J = 8.8, 4.6 Hz, 1H), 7.19 (dd, J = 10.0, 2.3 Hz, 1H), 7.00–6.89 (m, 1H), 4.35 (dd, J = 9.2, 5.2 Hz,
1H), 3.22 (dd, J = 17.9, 9.3 Hz, 1H), 2.91 (s, 2H), 2.87–2.75 (m, 1H); 13C NMR (125 MHz,
DMSO-d6)
δ 178.7, 177.0, 158.1 (d), 156.3, 133.5, 126.8, 126.8, 125.8, 113.1, 113.0, 111.4, 111.4,
110.1, 109.9, 103.9, 103.7, 37.8, 36.3, 25.0; HRMS (ESI) calculated for C13 H12FO2N2 [M + H]+
247.0877; found: 247.0879.
3-(5-Nitro-1H-indole-3-yl)-1-pHenylpyrrolidine-2,5-dione (3n). Yellow solid (58%), M.P.:
106–108 ◦C;1H NMR (500 MHz, DMSO-d6)
δ 11.87 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 8.03
(dd, J = 9.0, 2.2 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.7 Hz,
2H), 7.44 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 7.4 Hz, 2H), 4.74 (dd, J = 9.4, 5.7 Hz, 1H), 3.45–3.41
(m, 1H), 3.15 (dd, J = 18.0, 5.7 Hz, 1H); 13C NMR (100 MHz,)
δ 178.0, 176.2, 137.0, 133.2,
129.4, 128.7, 127.6, 126.4, 124.2, 121.8, 119.4, 118.8, 112.2, 111.1, 38.4, 36.9; MS–ESIMS:
[M + H]+m/z 336.
3-(5-MetHoxy-1H-indole-3-yl)-1-pHenylpyrrolidine-2,5-dione (3o). White solid (78%),
◦
M.P.: 102–104 C; 1H NMR (400 MHz, CDCl3)
δ
8.13 (s, 1H), 7.53–7.47 (m, 2H), 7.44–7.39 (m,
1H), 7.38–7.34 (m, 2H), 7.28 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 6.98 (d, J = 2.3 Hz
1H), 6.90 (dd, J = 8.8, 2.4 Hz, 1H), 4.48–4.43 (m, 1H), 3.83 (s, 3H), 3.45 (dd, J = 18.4, 9.6 Hz,
1H), 3.11 (dd, J = 18.4, 4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3)
177.1, 175.5, 154.4, 132.0,
,
δ
131.8, 129.2, 128.7, 126.5, 126.1, 122.8, 112.9, 112.5, 111.2, 100.5, 55.9, 38.4, 36.4; HRMS (ESI)
calculated for C19 H17O3N2 [M + H]+ 321.1233; found: 321.1234.
3-(5-Bromo-1H-indole-3-yl)-1-pHenylpyrrolidine-2, 5-dione (3p). White solid (66%), M.P.:
212–214 ◦C; 1H NMR (300 MHz, DMSO-d6)
δ 11.33 (s, 1H), 7.75 (s, 1H), 7.52 (t, J = 7.3 Hz,
2H), 7.44 (d, J = 7.2 Hz, 1H), 7.35 (dd, J = 13.4, 8.0 Hz, 2H), 7.23 (dd, J = 8.6, 1.5 Hz, 1H),
4.59 (dd, J = 9.3, 5.7 Hz, 1H), 3.05 (dd, J = 17.9, 5.6 Hz, 1H);13C NMR (75 MHz, DMSO-d6)
δ
177.3, 175.5, 135.1, 132.6, 128.9, 128.3, 128.1, 127.1, 125.1, 123.9, 121.0, 113.7, 111.5, 110.5,
37.6, 36.1; HRMS (ESI) calculated for C18 H14BrO2N2 [M + H]+ 369.0233; found: 369.0246.
3-(5-Fluoro-1H-indole-3-yl)-1-pHenylpyrrolidine-2, 5-dione (3q). WHite solid (74%), M.P.:
◦
1
130–132 C; H NMR (400 MHz, DMSO-d6)
δ 11.22 (s, 1H), 7.55–7.48 (m, 3H), 7.44 (d,
J = 7.4 Hz, 1H), 7.39 (dd, J = 8.9, 4.6 Hz, 1H), 7.36–7.32 (m, 2H), 7.30 (dd, J = 10.1, 2.4 Hz,
1H), 6.97 (td, J = 9.2, 2.5 Hz, 1H), 4.56 (dd, J = 9.4, 5.6 Hz, 1H), 3.03 (dd, J = 18.0, 5.7 Hz,
1H); 13C NMR (126 MHz, DMSO-d6)
δ 177.9, 176.1, 158.2 (d), 156.4, 133.6, 133.1, 129.4,
128.8, 127.6, 126.9, 126.9, 126.1, 113.2, 113.2, 111.4, 111.4, 110.2, 110.0, 103.9, 103.7, 38.2, 36.6;
HRMS (ESI) calculated for C18H14FO2N2 [M + H]+ 309.1033; found: 309.1040.
1-Benzyl-3-(5-nitro-1H-Indole-3-yl)-pyrrolidine-2,5-dione (3r). Yellow solid (68%), M.P.:
◦
182–184 C; 1H NMR (300 MHz, DMSO-d6)
δ
11.84 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.01 (dd,
J = 9.0, 2.0 Hz, 1H), 7.65 (d, J = 1.7 Hz, 1H), 7.55 (d, J = 9.0 Hz, 1H), 7.36–7.22 (m, 5H), 4.63
(s, 2H), 3.35–3.25 (m, 2H), 3.08 (dd, J = 18.1, 5.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6)
δ
177.7, 176.2, 140.5, 139.5, 136.1, 128.5, 127.4, 127.1, 125.7, 116.8, 116.3, 113.5, 112.1, 41.6, 37.1,
35.2; HRMS (ESI) calculated for C19 H15O4N3Na [M + Na]+ 372.0954; found: 372.0969.
1-Benzyl-◦3-(5-MetHoxy-1H-indole-3-yl)-pyrrolidine-2,5-dione (3s). WHite solid (84%),
δ 8.18 (s, 1H), 7.45 (d, J = 6.6 Hz, 2H), 7.31 (d,
M.P.: 139–141 C; 1H NMR (500 MHz, CDCl3)
J = 7.3 Hz, 3H), 7.19 (d, J = 8.8 Hz, 1H), 6.94 (s, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.71 (s, 1H),
4.77 (q, J = 14.0 Hz, 2H), 4.24 (dd, J = 9.3, 4.9 Hz, 1H), 3.66 (s, 3H), 3.23 (dd, J = 18.4, 9.5 Hz,
1H), 2.91 (dd, J = 18.4, 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 178.0, 176.1, 154.3, 135.9,
131.7, 129.0, 128.7, 128.1, 126.0, 122.9, 112.9, 112.4, 111.0, 100.2, 55.7, 42.7, 38.3, 36.3; HRMS
(ESI) calculated for C20H19O3N2 [M + H]+ 335.1390; found: 335.1398.
1-Benzyl-3-(5-Bromo-1H-indole-3-yl)-pyrrolidine-2,5-dione (3t). WHite solid (74%), M.P.:
167–169 ◦C; 1H NMR (300 MHz, CDCl3 + DMSO-d6)
δ 10.42 (s, 1H), 7.37 (s, 1H), 7.30 (t,
J = 7.4 Hz, 2H), 7.26 (s, 1H), 7.24–7.20 (m, 2H), 7.19 (s, 1H), 7.13 (dd, J = 8.6, 1.4 Hz, 1H),
7.04 (d, J = 2.2 Hz, 1H), 4.78–4.51 (m, 2H), 4.21 (dd, J = 9.4, 5.1 Hz, 1H), 3.19 (dd, J = 18.3,
9.5 Hz, 1H), 2.76 (d, J = 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3 + DMSO-d6)
δ 177.2, 175.4,
135.3, 135.0, 128.2, 128.0, 127.4, 127.0, 124.3, 123.5, 120.4, 113.0, 112.0, 109.8, 42.0, 37.5, 35.8;
HRMS (ESI) calculated for C19 H15BrO2N2Na [M + Na]+ 405.0209; found: 405.0220.

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1-Benzyl-3-(5-Fluoro-1H-indole-3-yl)-pyrrolidine-2,5-dione (3u). WHite solid (70%), M.P.:
◦
97–99 C; 1H NMR (400 MHz, DMSO-d6)
δ 11.16 (s, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.39 –7.28
(m, 6H), 7.09 (dd, J = 10.0, 2.3 Hz, 1H), 6.94 (td, J = 9.2, 2.5 Hz, 1H), 4.64 (s, 2H), 4.45 (dd,
J = 9.3, 5.2 Hz, 1H), 3.30 (dd, J = 18.1, 9.4 Hz, 1H), 2.91 (dd, J = 18.1, 5.2 Hz, 1H); 13C NMR
(100 MHz, DMSO-d6) δ 178.5, 176.8, 158.6 (d), 158.4, 156.0, 136.7, 133.6, 129.0, 128.1, 128.0,
126.7, 125.9, 113.2, 111.4, 110.2, 109.9, 103.9, 103.7, 42.1, 37.9, 36.2; HRMS (ESI) calculated
for C19H16FO2N2[M + H]+ 323.1190; found: 323.1194.
3-(1-meth◦yl-2,5-dioxopyrrolidin-3-yl)-1H-indole-5-carbonitrile (3v). Yellow solid (64%),
M.P.: 238–240 C; 1H NMR (400 MHz, DMSO-d6)
δ 11.81 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.0
(dd, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.53 (d, 1H), 4.54 (dd, 1H), 3.23 (dd, J = 17.6, 9.0 Hz, 1H),
3.0–2.90 (m, 1H), 2.90 (s, J = 4.3 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
δ
177.7, 176.3, 140.4,
139.3, 126.7, 125.7, 118.6, 116.6, 116.1, 113.4, 112.0, 36.9, 35.3, 24.5; HRMS (ESI) calculated
for C14H11N3O2Na [M + Na]+ 276.0732; found: 276.0633.
1-metHyl-3-(1-metHyl-1H-indol-3-yl)-pyrrolidine-2,5-dione (3w). WHite solid (84%), M.P.:
118–120 ◦C; 1H NMR (500 MHz, CDCl3)
δ 7.41 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H),
7.25 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.5 Hz, 1H), 7.03 (s, 1H), 4.29 (dd, J = 9.4, 4.9 Hz, 1H), 3.75
(s, 3H), 3.27 (dd, J = 18.3, 9.5 Hz, 1H), 3.10 (s, 3H), 2.92 (dd, J = 18.3, 4.9 Hz, 1H); 13C NMR
(125 MHz, CDCl3)
δ 178.4, 176.6, 137.4, 126.8, 126.2, 122.3, 119.7, 118.6, 110.0, 109.8, 38.2,
36.7, 32.8, 25.2; HRMS (ESI) calculated for C14H15O2N2 [M + H]+ 243.1128; found: 243.1131.
1-Benzyl-3-(1-Be◦nzyl-5-MetHoxy-1H-indole-3-yl) pyrrolidine-2,5-dione (3x). White solid
(90%), M.P.: 147–149 C; 1H NMR (300 MHz, CDCl3)
δ 7.48–7.39 (m, 2H), 7.28 (t, J = 6.6 Hz,
6H), 7.17–7.05 (m, 3H), 6.99 (s, 1H), 6.82 (dd, J = 8.9, 2.2 Hz, 1H), 6.73 (d, J = 2.0 Hz, 1H),
5.20 (s, 2H), 4.88–4.60 (m, 2H), 4.26 (dd, J = 9.4, 4.9 Hz, 1H), 3.65 (s, 3H), 3.25 (dd, J = 18.3,
9.5 Hz, 1H), 2.93 (dd, J = 18.3, 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 178.04, 176.16,
154.29, 135.86, 131.66, 129.00, 128.75, 128.0, 126.0, 123.0, 112.9, 112.4, 111.0, 100.2, 55.7, 42.7,
38.3, 36.3; HRMS (ESI) calculated for C27H25O3N2 [M + H]+ 425.1859; found: 425.1868.
Appendix A.3. Biology
Cell Cultures, Maintenance and Anti-Proliferative Evaluation
The cell linesHT-29, Hepg-2 and A549 (colorectal, liver and lung cancer cells) used in
this study was procured from American Type Culture Collection (ATCC), USA. Thesyn-
thesized test compounds were evaluated for theirin vitro anti-proliferative activity in
thesethree different human cancer cell lines. A protocol of 48 hcontinuous drug exposure
was used, and an SRB cell proliferation assay was used to estimate cell viability or growth.
All the cell lines were grown in Dulbecco’s modified Eagle’s medium (containing 10%
FBS in a humidified atmosphere of 5% CO2 at 37 ◦C). Cells were trypsinized when sub-
confluent from T25 flasks/60 mm dishes and seeded in 96-well plates in 100 µL aliquots at
plating densities depending on the doubling time of individual cell lines. The micro-titer
plates were incubated at 37 ◦C, 5% CO2, 95% air, and 100% relative humidity for 24 hprior
to the addition of experimental drugs and were incubated for 48 h with different doses
(0.01, 0.1, 1, 10, 100 µ
M) of the prepared derivatives. After incubation at 37 ◦C for 48 H,
the cell monolayer◦s were fixed by the addition of 10% (wt/vol) cold trichloroacetic acid
and incubated at 4 C for 1 hand were then stained witH0.057% SRB dissolved in 1% acetic
acid for 30 min at room temperature. Unbound SRB was washedwith 1% acetic acid.
Appendix A.4. Molecular Docking Study
Appendix A.4.1. Protein Preparation and Grid Generation
The 3D coordinates of the CDK2 catalytic core in complex withStaurosporine were
taken from theRCSB Protein Databank (PDB code: 1AQ1) The PDB protein-ligand struc-
tures were processed withthe Protein Preparation Wizard in theSchrodinger suite. The
protein structure integrity was checked and adjusted, and missing residues and loop seg-
ments near the active site were added using Prime. A 3D box was generated around each
ligand to enclose the entire vicinity of active site. The receptor grid for each target was

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prepared withthehelp of OPLS_2005 force field. The grid center was set to be the centroid
of the co-crystallized ligand, and the cubic grid Had a size of 20 Å.
Appendix A.4.2. Ligand Preparation
The 2D ligand structures were prepared using Chem-BioDraw Ultra 12.0, and the 3D
structures were generated by Schrodinger suite. Schrodinger’sLigPrep program was used
to generate different conformations of ligands.
Appendix A.4.3. Molecular Docking
Molecular docking studies were performed by using a GLIDE docking module of
Schrodinger suite. For the validation of docking protocol, the co-crystalized ligand (STU in
1AQ1) was subjected to re-docking into the CDK2 (PDB code: 1AQ1) using GLIDE. The
bound and docked conformations of STU (RMSD 0.8170 Å) showed similar interactions and
binding pose at their respective binding sites. Finally, prepared ligands were docked into
the generated receptor grids using Glide SP docking precision. The results were analyzed
on the basis of the GLIDE docking score and molecular recognition interactions. All the 3D
figures were obtained using Schrödinger Suite 2014-3.
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