Amberlyst-15 catalysed sonochemical synthesis of 2-amino-4,6-disubstituted nicotinonitrile derivatives and their biological evaluation

Article abstract of DOI:10.1016/j.molstruc.2021.130541

The 2-amino nicotinonitrile framework has been explored first time for the identification of potential inhibitors of SIRT1. Thus a series of targeted 2-amino-4,6-disubstituted nicotinonitrile derivatives were synthesized by employing an ultrasound assisted MCR of ketones, aldehydes, malononitrile and ammonium acetate. The MCR was carried out in the presence of Amberlyst-15 in MeCN under mild conditions to give the desired product in good yields. The reaction was less efficient in the absence of air whereas combination of Amberlyst-15, ultrasound, air and MeCN was essential for the success of this MCR. Several of the synthesized compounds showed good activities when tested for their SIRT1 inhibitory potential in vitro among which 5c, 5e and 5n were identified as the most potent (IC₅₀ ~ 3 μM) and were better than the known inhibitor nicotinamide (IC₅₀ ~109 μM). In the in silico docking studies these three compounds showed better binding energy (> 100 kcal/mol) and higher number of interactions than nicotinamide (binding energy -88.38 kcal/mol). While both amino (–NH₂) and cyano (–CN) groups of nicotinonitrile derivatives formed H-bonds with the ASN346 and HIS363 residue respectively the nicotinamide showed similar interactions with ASP348 and ILE347 through its amide (–CONH₂) moiety. Compound 5c, 5e and 5n has been identified as initial hits for further study.

Full text of DOI:10.1016/j.molstruc.2021.130541

Journal of Molecular Structure 1240 (2021) 130541
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Amberlyst-15 catalysed sonochemical synthesis of
2-amino-4,6-disubstituted nicotinonitrile derivatives and their
biological evaluation
a
b,∗
c
Chandra Sekhar Challa , Naresh Kumar Katari , Varadacharyulu Nallanchakravarthula ,
d,∗
a
d
Devanna Nayakanti , Ravikumar Kapavarapu , Manojit Pal
a
Department of Chemistry, Jawaharlal Nehru Technological University, Anantpur, Andhra Pradesh 515002, India
Department of Chemistry, School of Science, GITAM (Deemed to be University), Hyderabad Campus, Rudraram, Patancheru Mandal, Hyderabad, Telangana
02329, India
b
5
c
Department of Biochemistry, Sri Krishnadevaraya University, Anantpur, Andhra Pradesh 515003, India
Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India
d
a r t i c l e i n f o
a b s t r a c t
Article history:
The 2-amino nicotinonitrile framework has been explored first time for the identification of potential
inhibitors of SIRT1. Thus a series of targeted 2-amino-4,6-disubstituted nicotinonitrile derivatives were
synthesized by employing an ultrasound assisted MCR of ketones, aldehydes, malononitrile and ammo-
nium acetate. The MCR was carried out in the presence of Amberlyst-15 in MeCN under mild conditions
to give the desired product in good yields. The reaction was less efficient in the absence of air whereas
combination of Amberlyst-15, ultrasound, air and MeCN was essential for the success of this MCR. Several
of the synthesized compounds showed good activities when tested for their SIRT1 inhibitory potential in
vitro among which 5c, 5e and 5n were identified as the most potent (IC50 ~ 3 μM) and were better than
the known inhibitor nicotinamide (IC50 ~109 μM). In the in silico docking studies these three compounds
showed better binding energy (> 100 kcal/mol) and higher number of interactions than nicotinamide
Received 10 February 2021
Revised 31 March 2021
Accepted 17 April 2021
Available online 27 April 2021
Keywords:
Nicotinonitrile
MCR
Amberlyst-15
SIRT1
In silico study
(binding energy -88.38 kcal/mol). While both amino (–NH2) and cyano (–CN) groups of nicotinonitrile
derivatives formed H-bonds with the ASN346 and HIS363 residue respectively the nicotinamide showed
similar interactions with ASP348 and ILE347 through its amide (–CONH2) moiety. Compound 5c, 5e and
5
n has been identified as initial hits for further study.
©
2021 Elsevier B.V. All rights reserved.
1. Introduction
Compounds containing the 2-amino nicotinonitrile A (or 2-
amino-3-cyanopyridine, Fig. 1) framework are known to possess
numerous pharmacological activities [1–4] including anticancer as
well as antitumor properties [5,6]. Indeed, this framework seemed
to play crucial roles for various pharmacological functions and
hence attracted considerable interest in medicinal and pharma-
ceutical chemistry. In spite of a number of reports on their anti-
cancer activities [7–10], none of the 2-amino nicotinonitrile deriva-
tives have been reported to enter into the any phase of clini-
cal studies till date as potential anticancer agents. Moreover, the
structure–activity relationship (SAR) was not clearly elaborated in
Fig. 1. 2-Amino nicotinonitrile A, the template B and nicotinamide C.
some of these studies though the overall findings were promising
or remarkable in several cases. Further, the thorough studies on
molecular interactions of 2-amino nicotinonitrile based anticancer
agents with their pharmacological targets via in silico or similar ap-
proaches are not common in the literature. Hence it was desirable
to adopt a fresh Med Chem approach for studying anticancer prop-
erties of this class of compounds. This is particularly desirable from
∗
Corresponding authors.
E-mail
addresses:
dr.n.k.katari@gmail.com
(N.K.
Katari),
manojitpal@rediffmail.com (M. Pal).
https://doi.org/10.1016/j.molstruc.2021.130541
0
022-2860/© 2021 Elsevier B.V. All rights reserved.

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
Table 1
Effect of reaction conditions on the MCR of 1a, 2a, 3 and 4a.
the view point of the fact that identification of new drugs is one
of the key solutions to the multifaceted problem of drug resistance
[
11]. Notably, drug resistance often causes a major hurdle resulting
in failure of chemotherapy based approaches on several occasions.
Due to our interest in bioactive nicotinonitriles [12] herein we re-
port the synthesis, in vitro and in silico evaluation of a series of
compounds based on the template B (Fig. 1) derived from A. We
have chosen SIRT1 as the pharmacological target for our study be-
cause (i) being considered as important targets for cancer thera-
peutics sirtuins (class III NAD-dependent deacetylases) are shown
to up-regulated in various types of cancer [13] whereas (ii) inhibi-
tion of sirtuins allows re-expression of silenced tumor suppressor
genes, leading to the decreased growth of cancer cells. Moreover,
the rational for choosing SIRT1 as a potential pharmacological tar-
get for the nicotinonitrile derivatives based on B stem from the fact
that the structurally similar nicotinamide C (Fig. 1) is one of the
earliest inhibitors of sirtuins including SIRT1 [14]. While the tem-
plate B, as shown in Fig. 1, has three centers (e.g. C-4, C-5 and C-6)
for the introduction of diversity into the central pyridine ring, we
initially focused on the modification of C-4 and C-6 substituents.
This is because the nature and type of substituents present at these
positions were reported to play key roles in biological activities.
Hence, we aimed to examine the effect of variation of C-4 and C-6
groups on biological activities of such derivatives and consequently,
we required a quick access to 2-amino-4,6-disubstituted nicotinon-
itrile derivatives based on template B.
Yieldb
Entry
Catalyst
Solvent
T (°C)
1
2
.
.
No
No
100
88c
75c
76c
No
Toluene
Toluene
Toluene
MeCN
MeCN
EtOH
DCE
100
3.
4.
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
Amberlyst-15
No
45–50
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
25–30
84
5
6
7
8
.
.
.
.
93
89d
77
74
9.
THF
61
1
1
1
1
0.
No
60
12e
1.
2.
3.
MeCN
MeCN
MeCN
MeCN
49
27c
39c
No
14
Amberlyst-15
a
Reactions were carried out using acetophenone 1a (1 mmol.),
benzaldehyde 2a (1 mmol), 3 (1 mmol), 4 (1 mmol) and a catalyst
in a solvent (5 mL) under ultrasound irradiation for 10 min in the
presence of air.
b
Isolated yields.
c
The reaction was performed in the absence of ultrasound for
3
h.
d
The reaction was performed for 20 min.
e
2. Results and discussion
The reaction was performed under nitrogen atmosphere.
Due to their importance not only in the area of medicinal /
pharmaceutical chemistry but also as valuable precursors in or-
ganic synthesis a diverse range of methods have been reported
for the synthesis of 2-amino nicotinonitrile derivatives [15]. Among
them the multicomponent reaction (MCR) of aldehydes, ketones,
malononitrile, and ammonium acetate has become the most com-
mon route towards the synthesis of this class of compounds. A
wide range of reaction conditions have been reported for this
MCR of which some selected examples include the use of (i) cat-
alysts such as Yb(PFO)4 [16], MgO [17], graphene oxide [18], sil-
[26–30] due to its non-hazardous nature and easy removal from
the reaction mixture, for example, via simple filtration [31]. We
have observed that the use of Amberlyst-15 not only allowed the
reaction to proceed at room temperature but also reduced the re-
action time though marginally. Thus the ultrasound assisted MCR
of ketones (1), aldehydes (2), malononitrile (3), and ammonium ac-
etate (4) was carried out in the presence of Amberlyst-15 in MeCN
under mild conditions to give the desired product 5 in good yields
(Scheme 1). Notably, the use of Amberlyst-15 for the rapid synthe-
sis of 5 is not known in the literature.
ica nanoparticle [19], Bi(NO3)2•5H O [20] etc., or (ii) ionic liquid
2
e.g. 1-butyl-3-methylimidazolium tetrafluroroborate ([Bmim][BF ])
Initially, the MCR of acetophenone (1a), benzaldehyde (2a),
malononitrile (3), and ammonium acetate (4) was carried out in
the absence of any catalyst and solvent under conventional heat-
ing conditions in the presence of air (entry 1, Table 1). While the
desired product 5a was obtained in good yield however the re-
action required maintaining a high temperature e.g. 100 °C and
longer duration e.g. 3 h. The use of toluene (as a solvent) (entry
2, Table 1) or combination of toluene and Amberlyst-15 (as a cat-
alyst) (entry 3, Table 1) did not change the situation significantly
though the reaction temperature could be decreased drastically in
the latter case. However, the use of ultrasound irradiation using a
laboratory ultrasonic bath SONOREX SUPER RK 510H model pro-
ducing irradiation of 35 kHz not only improved the product yield
but also decreased the reaction temperature as well as time (entry
4, Table 1). Indeed, a further improvement in product yield was
observed when the nonpolar solvent toluene was replaced by the
relatively more polar solvent MeCN (entry 5, Table 1). Encouraged
by this observation we carried out the reaction for a longer time
i.e. 20 min however no significant improvement in product yield
was observed (entry 6, Table 1). The use of more polar solvent such
as EtOH or less polar solvents such as DCE (1,2-dichloroethane) or
THF was examined and found to be less effective under the con-
ditions employed (entries 7–9, Table 1). Indeed, the omission of
solvent but not catalyst was also found to be less effective (entry
10, Table 1). To understand the role of air, the MCR was performed
under nitrogen atmosphere when the desired product was isolated
4
[
21] or (iii) only solvent such as polyethylene glycol (PEG) [22]. The
use of microwave [23,24] and ultrasound irradiation [25] has also
been reported for the faster synthesis of this class of compounds.
Indeed, the ultrasound-assisted synthesis of 2-amino nicotinoni-
trile particularly attracted our attention [25] because the method-
ology was free from the use of any catalyst and organic media.
Moreover, the MCR proceeded at 50 °C in pure water affording
the desired products in good yield (75–97%). All these features en-
couraged us to adopt this sonochemical protocol for the synthesis
of our target compounds based on B. However, in our effort we
encountered with some difficulties like sluggishness of the reac-
tion thereby requirement of either longer reaction time or apply-
ing higher temperature. In some cases, the reaction afforded the
intermediate product rather than the desired compound or did not
proceed at all. The reason for such observation appeared to be par-
tially due to the poor solubility of reactants especially the ace-
tophenones in pure water. Indeed, we noted that generally ace-
tophenones containing a phenolic hydroxyl group were used in
the previous study that perhaps aided their solubility in pure wa-
ter. It was therefore necessary to establish an appropriate reac-
tion condition that could serve our purpose. The previous reports
on successful use of acidic catalysts in the synthesis of 2-amino
nicotinonitriles prompted us to explore the use of Amberlyst-15
for accessing the compounds based on B. As a low-cost and readily
available heterogeneous catalyst Amberlyst-15 gained our attention
2

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
Table 2
Amberlyst-15 catalyzed synthesis of 2-amino-4,6-disubstituted nicotinonitrile derivatives (5) under ultrasound irradiationa,b (Scheme 1).
a
All reactions were carried out using the ketone 1 (1 mmol.), aldehyde 2 (1 mmol), 3 (1 mmol), 4 (1 mmol) and Amberlyst-15 (10% w/w) in MeCN
(
5 mL) at 25–30 °C under ultrasound irradiation for 10 min in the presence of air.
b
Figure in the bracket represents isolated yield.
in poor yield (entry 11, Table 1) indicating the need of presence
of air in the current transformation. Finally, the reaction was per-
formed in the absence of catalyst in MeCN, in the absence of cat-
alyst and ultrasound in MeCN and in the absence of ultrasound
only (entries 12–14, Table 1). Results of all these studies suggested
that the combination of Amberlyst-15, ultrasound, air and MeCN
was most effective for the preparation of 5a and therefore this
combination was used for the preparation of its other related ana-
logues (Scheme 1 and Table 2). A variety of ketones (1) including
substituted acetophenones as well as 1-(naphthalen-2-yl)ethanone,
cyclohexanones, aliphatic ketones etc. and aldehydes (2) includ-
ing substituted benzaldehydes, heteroaryl aldehydes, acetaldehyde
etc. were employed in this MCR under the optimized conditions.
The reaction proceeded well irrespective of the nature of groups
Fig. 2. Partial representation of 1H and 13 C NMR spectral data of azaindole deriva-
tive 5c.
/
substituents present in the ketone and aldehyde affording the
CDCl3 but at different value in DMSO-d . The presence of amine
6
desired 2-amino-4,6-disubstituted nicotinonitrile derivatives (5) in
good yields.
and CN moiety was also indicated by the IR absorptions near 3350
and 2200 cm 1 respectively. The partial 1H and 13C NMR data of
a representative compound i.e. 5c is shown in Fig. 2. The -OMe
group appeared near δ 3.8 and 56.4 ppm in the 1H and 13C NMR
spectra, respectively. Similarly, the proton and carbon at 5-position
appeared near δ 7.2 and 115.3 ppm in the 1H and 13C NMR spec-
tra, respectively. Moreover, the 13C NMR spectra showed that the
carbon at 2, 3, 4 and 6-position appeared near 161.9, 86.9, 155.7
−
All the 2-amino nicotinonitrile derivatives synthesized were
characterized by spectral (NMR, MS) data. While the C-5 proton
could be detected for most of the compounds (except 5f and 5 g
that lack this proton) in their 1HNMR spectra generally as a sin-
glet in the range δ 7.5–7.0 depending on the substituent present
at C-4 and C-6 position the NH2 group appeared near δ 5.5 in
3

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
Table 3
SIRT1 inhibition of compound 5 in vitroa.
Compounds
Enzymatic assay
%
inhibition @ 10 μMa
IC50 (μM)
Control
0
–
–
Nicotinamide
109.2 ± 1.73
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
b
c
38.9
43.5
79.2
49.8
76.4
38.4
37.8
39.5
69.2
42.7
46.8
65.8
28.4
78.1
49.4
26.8
67.9
–
–
2.78 ± 0.43
d
e
f
–
2.93 ± 0.12
–
g
h
i
–
–
3.45 ± 0.92
j
–
Fig. 3. Summary of SAR for SIRT1 inhibitory activities of 2-amino nicotinonitriles
(5).
k
l
–
3.57 ± 0.87
m
n
o
p
q
–
2.89 ± 0.51
ing the pyridine ring fused with a cyclohexane moiety appeared to
be less attractive in the current in vitro assay.
–
–
The compounds possessing good activities along with the ref-
erence compound nicotinamide were taken further for concentra-
tion dependent study and the corresponding IC50 values are pre-
sented in Table 3. While all these compounds appeared to be sev-
eral fold potent than nicotinamide the compound 5c, 5e and 5n
were identified as the most potent among them (IC50 ~ 3 μM).
In order to understand their interactions with SIRT1 the in silico
docking studies were carried out using these compounds includ-
ing nicotinamide against the SIRT1 protein (PDB: 4I5I). The iGEM-
DOCK version2.1 software [35], a program for computing ligand
conformation and orientation relative to the active site of the pro-
tein was used for the docking studies and results are presented
in Table 4. All the test compounds showed binding activity with
the catalytic residues of SIRT1. Indeed, the docking interactions oc-
curred with the catalytic domain residues of 241–516. The com-
pound 5c and 5n showed better binding energy than others that
correlated their activity observed against SIRT1 in vitro (Table 3).
Notably, nicotinamide showed binding energy lowest among them
that also accounted its low potency compared to the current series
of nicotinonitrile derivatives examined. Nevertheless, the amino (–
3.51 ± 0.75
a
Data represent the mean values of three independent de-
terminations.
and 160.7 ppm whereas the CN appeared at 112 ppm. The carbon
bearing -OMe group appeared near 161.4 ppm.
A plausible reaction mechanism for the Amberlyst-15 catalyzed
synthesis of 2-amino-4,6-disubstituted nicotinonitrile derivatives
under ultrasound irradiation is presented in Scheme 2. The reac-
tion proceeded via activating the aldehyde (2) and ketone (1) by
the catalyst Amberlyst-15 to react with malononitrile and in-situ
generated NH3 [from ammonium acetate (4)] under ultrasound re-
spectively. As a result of this the corresponding intermediate E-1
and the imine was formed. Then E-1 on reaction with the tau-
tomeric form of imine afforded the intermediate E-2 that on in-
tramolecular cyclization assisted by ultrasound furnished E-3. No-
tably, the catalyst Amberlyst-15 was regenerated during this pro-
cess. The tautomeric form of E-3 then underwent aerial oxidation
in the presence of aerial oxygen and Amberlyst-15 assisted by ul-
trasound to give the product 5.
NH ) and cyano (–CN) groups of nicotinonitrile derivatives inter-
2
acted with the ASN346 and HIS363 residue respectively through a
H-bond in most of the cases including 5c and 5n (Figs. 4 and 5, see
also Fig. S-1, 2, 3, 4, 5, 6 and 7, suppl data). These compounds also
interacted with ALA262, ILE347, ILE270, HIS363, ILE411, PHE297
and PHE273 commonly through Van der Waals, pi-pi and pi-alkyl
interactions in the catalytic domain of SIRT1. While similar interac-
tions with ASP348 and ILE347 was shown by nicotinamide through
Next we choose to assess the inhibitory activities of syn-
thesized 2-amino-4,6-disubstituted nicotinonitrile derivatives (5)
against SIRT1 in vitro. The structurally similar nicotinamide, a
known inhibitor of sirtuins including SIRT1 (the reported IC50
value against SIRT1 = 120 μM) [14] was used as a reference
compound in this assay. Indeed, nicotinamide is known to block
the proliferation and promote apoptosis in leukemic cells and re-
ported to inhibit the growth and viability of human prostate can-
cer cells [32,33]. Nevertheless, all these compounds were tested
at 10 μM using a reported biochemical enzymatic assay method
its amide (–CONH ) moiety (Fig. 6) the lower number of total in-
2
teractions compared to nicotinonitrile derivatives was responsible
for its lower binding energy thereby potency. Overall, the current
series of nicotinonitrile derivatives especially the compound 5c and
[
34]. The compounds that showed good activities in this assay (>
0% inhibition, Table 3) include 5c, 5e, 5i, 5l, 5n and 5q whereas
compound 5b, 5d, 5j, 5k and 5o showed mediocre activities (>
0% inhibition, Table 3). While understanding a precise Structure-
Activity-Relationship (SAR) within the current series of 2-amino-
,6-disubstituted nicotinonitrile derivatives was not straightfor-
5n are of further medicinal interest.
5
4
3. Conclusions
4
In conclusion, 2-amino nicotinonitrile framework was explored
for the identification of potential inhibitors of SIRT1. Accordingly,
the ultrasound assisted MCR was employed for the synthesis of a
series of targeted 2-amino-4,6-disubstituted nicotinonitrile deriva-
tives. The methodology involving the reaction of ketones, alde-
hydes, malononitrile and ammonium acetate was carried out in
the presence of Amberlyst-15 in MeCN under mild conditions to
give the desired product in good yields. The reaction was found
to be less efficient in the absence of air whereas combination of
Amberlyst-15, ultrasound, air and MeCN was found to be essen-
tial for the success of this MCR. Notably, the use of Amberlyst-15
ward the nature as well as type of substituents at C-4 and C-6 po-
sition appeared to play a key role in activities (Fig. 3). In general,
arene (with a particular group) / heteroarene (e.g. thienyl and fu-
ran etc.) moieties were favored at these positions though a t-butyl
group at C-6 position was also favored e.g. compound 5n. Simi-
larly, a bulky naphthyl ring at C-6 position was well tolerated e.g.
compound 5e whereas smaller substituents e.g. i-Pr or Me at this
position was not favored. Among the groups attached to the arene
ring the OMe substituent was found to be the most favored (e.g. 5c
and 5i) over others e.g. Cl, Me CO Me etc. The compounds contain-
2
4

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
Table 4
Summary of interactions of test compounds with SIRT1 in silico.
Compounds
Estimated Total Energy (kcal/mol)
Active site interacting residues
5
5
5
5
5
5
c
e
i
−105.78
−100.14
−97.03
−95.52
−103.91
−96.94
−88.38
ASN346, HIS363, PHE273, PHE297, PHE414, ILE411, ILE347, ILE270
ASN346, HIS363, PHE297, PHE273, PHE414, ALA262, ILE270, ILE316, ILE347
ASN346, PHE273, ILE411, ILE316, ILE347, ILE270
l
HIS363, ILE347, ILE270, ILE411, VAL412, PHE273
n
q
ASN346, HIS363, PHE273,PHE297, ALA262, ILE347, ILE270, ILE411
ASN346, ALA262, PHE273, ILE347, ILE316, ILE270
Nicotinamide
ASP348, ILE347, PHE273, ALA262, ILE279
Fig. 4. Binding interactions and docked pose of compound 5c at the catalytic site
of SIRT1 (PDB: 4I5I).
Fig. 5. Binding interactions and docked pose of compound 5n at the catalytic site
for the rapid synthesis of 2-amino-4,6-disubstituted nicotinonitrile
derivatives is not known in the literature. All the synthesized com-
pounds were tested for their SIRT1 inhibitory potential in vitro and
several of them showed good activities. The SAR study suggested
that the inhibitory activity was dependent on the nature and type
of substituents present at C-4 and C-6 positions. The compound
of SIRT1 (PDB: 4I5I).
been identified as initial hits that deserves further study. Thus, the
current study not only demonstrated the utility of Amberlyst-15
for the rapid synthesis of 2-amino-4,6-disubstituted nicotinonitrile
derivatives but also indicated potential of 2-amino nicotinonitrile
as a new framework for the identification of promising inhibitors
of SIRT1.
5c, 5e and 5n were identified as the most potent inhibitors (IC50
~
3 μM) and were better than the reference compound nicoti-
namide (IC50 ~109 μM). This was further supported by the in sil-
ico docking studies where these three compounds showed better
binding energy (> 100 kcal/mol) and higher number of interactions
than nicotinamide (binding energy −88.38 kcal/mol). While both
Authors’ statement
amino (–NH ) and cyano (–CN) groups of nicotinonitrile deriva-
2
tives formed H-bonds with the ASN346 and HIS363 residue respec-
tively the nicotinamide showed similar interactions with ASP348
Chandra Sekhar Challa and Devanna Nayakanti were involved
in the investigation, methodology development and formal anal-
ysis related related to all the target compounds presented in the
current manuscript.
and ILE347 through its amide (–CONH ) moiety. Nevertheless, be-
2
ing potent inhibitors of SIRT1 the compound 5c, 5e and 5n has
5

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
Scheme 2. Proposed reaction mechanism for the Amberlyst-15 catalysed sono-
chemical synthesis of 2-amino-4,6-disubstituted nicotinonitrile derivatives (5).
Acknowledgement
The authors thank the management of GITAM University, Hy-
derabad, India for continuous support and encouragement. Authors
also than Dr. Rambabu Gundla for his valuable inputs.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2021.130541.
Fig. 6. Binding interactions and docked pose of nicotinamide at the catalytic site of
SIRT1 (PDB: 4I5I).
References
[
1] M. Mantri, O. de Graaf, J. van Veldhoven, A. Göblyös, J.K. von Frijtag
Drabbe Künzel, T. Mulder-Krieger, R. Link, H. de Vries, M.W. Beukers,
J. Brussee, A.P. IJzerman, 2-amino-6-furan-2-yl-4-substitutednicotinonitriles as
A2A adenosine receptor antagonists, J. Med. Chem. 51 (2008) 4449–4455.
2] D.H. Vyas, S.D. Tala, J.D. Akbari, M.F. Dhaduk, K.A. Joshi, H. Joshi, Synthesis
and antimicrobial activity of new cyanopyridine andcyanopyrans towards My-
cobacterium tuberculosis and other micro-organisms, Indian J. Chem. Sect. B
[
4
8 (2009) 833–839.
[3] A.A. Bekhit, A.M. Baraka, Novel milrinone analogs of pyridine-3-carbonitrile
derivatives as promising cardiotonic agents, Eur. J. Med. Chem. 40 (2005)
1405–1413.
[
4] T. Murata, M. Shimada, H. Kadono, S. Sakakibara, T. Yoshino, T. Masuda, M. Shi-
mazaki, T. Shintani, K. Fuchikami, K.B. Bacon, K.B. Ziegelbauer, T.B. Lowinger,
Synthesis and structure-activityrelationships of novel IKK-beta inhibitors. Part
Scheme 1. Amberlyst-15 catalysed sonochemical synthesis of 2-amino-4,6-
2:
improvement of in vitro activity, Bioorg. Med. Chem. Lett. 14 (2004)
disubstituted nicotinonitrile derivatives.
4013–4017.
[
5] D.R. Anderson, S. Hegde, E. Reinhard, L. Gomez, W.F. Vernier, L. Lee, S. Liu,
A. Sambandam, P.A. Snider, L. Masih, Aminocyanopyridineinhibitors of mitogen
activated protein kinase-activated proteinkinase 2 (MK-2), Bioorg. Med. Chem.
Lett. 15 (2005) 1587–1590.
Ravikumar
Kapavarapu
and
Varadacharyulu
Nallan-
chakravarthula was involved in the investigation and formal
analysis using the software.
[
6] S.D. Krens, G. Lassche, F.G.A. Jansman, I.M.E. Desar, N.A.G. Lankheet,
D.M. Burger, C.M.L. van Herpen, N.P. van Erp, Dose recommendations for an-
ticancer drugs in patients with renal or hepatic impairment, Lancet Oncol 20
Naresh Kumar Katari and Manojit Pal were responsible for con-
ceptualization, supervision and project administration of the entire
work presented in the submitted manuscript.
(2019) e200–e207, doi:10.1016/S1470-2045(19)30145-7.
[
7] S. Liao, S. Sgang, M. Shen, X. Rao, H. Si, J. Song, Z. Song, Synthesis and anti-
cancer activity of (+)-nopinone-based 2-amino-3-cyanopyridines, Front. Agric.
Sci. Eng. 2 (2015) 335–340, doi:10.15302/J-FASE-2015079.
[
8] S.M. Gomha, M.M. Abdulla, S.M. Abou-Seri, Identification of novel aminoth-
iazole and aminothiadiazole conjugated cyanopyridines as selective CHK1 in-
hibitors, Eur. J. Med. Chem. 92 (2015) 459–470, doi:10.1016/j.ejmech.2015.01.
Declaration of Competing Interest
019.
[
9] S. Dev, S.R. Dhaneshwar, B. Mathew, Virtual combinatorial library design, syn-
thesis and in vitro anticancer assessment of -2-amino-3-cyanopyridine deriva-
tives, Comb. Chem. High Throughput Screen. 21 (2018) 138–148.
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared to
influence the work reported in this paper.
[
10] P.N. Kalaria, S.P. Satasia, J.R. Avalani, D.K. Raval, Ultrasound-assisted one-pot
four-component synthesis of novel 2-amino-3-cyanopyridine derivatives bear-
6

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1240 (2021) 130541
ing 5-imidazopyrazole scaffold and their biological broadcast, Eur. J. Med.
Chem. 83 (2014) 655–664, doi:10.1016/j.ejmech.2014.06.071.
[24] F. Shi, S. Tu, F. Fang, T. Li, One-pot synthesis of 2-amino-3-cyanopyridine
derivatives under microwave irradiation without solvent, Arkivoc
137–142.
1 (2005)
[
11] N. Vasan, J. Baselga, D.M. Hyman, A view on drug resistance in cancer, Nature
75 (2019) 299–309.
5
[25] J. Safari, S.H. Banitaba, S.D. Khalili, Ultrasound-promoted an efficient method
for one-pot synthesis of 2-amino-4,6-diphenylnicotinonitriles in water: a rapid
procedure without catalyst, Ultrason. Sonochem. 19 (2012) 1061–1069.
[26] S.K. Kumar, J. Iqbal, M. Pal, Amberlyst-15: a mild, efficient and reusable hetero-
geneous catalyst for N-tert-butoxycarbonylation of amines, Tetrahedron Lett.
50 (2009) 6244–6246.
[
[
[
12] T.R. Reddy, G.R. Reddy, L.S. Reddy, S. Jammula, Y. Lingappa, R. Kapavarapu,
C.L.T. Meda, K.V.L. Parsa, M. Pal, Montmorillonite K-10 mediated green syn-
thesis of cyano pyridines: their evaluation as potential inhibitors of PDE4, Eur.
J. Med. Chem. 48 (2012) 266–274, doi:10.1016/j.ejmech.2011.12.024.
13] A. Ghosh, A. Sengupta, G.P.K. Seerapu, A. Nakhi, E.V.V.S. Ramarao, N. Bung,
G. Bulusu, M. Pal, D. Haldar, A novel SIRT1 inhibitor, 4bb induces apoptosis
in HCT116 human colon carcinoma cells partially by activating p53, Biochem.
Biophys. Res. Commun. 488 (2017) 562–569.
[27] P.V. Murthy, D. Rambabu, G.R. Krishna, C.M. Reddy, K.R.S. Prasad, M.V.B. Rao,
M. Pal, Amberlyst-15 mediated synthesis of 2-substituted 2,3-dihydroquina-
zolin-4(1H)-ones and their crystal structure analysis, Tetrahedron Lett. 53
(2012) 863–867.
14] H. Yuan, Z. Wang, L. Li, H. Zhang, H. Modi, D. Horne, R. Bhatia, W.Y. Chen, Ac-
tivation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis,
Blood 119 (2012) 1904–1914.
[28] D. Rambabu, P.R.K. Murthi, B. Dulla, M.V.B. Rao, M. Pal, Amberlyst-15 catalyzed
synthesis of 2-substituted 1,3-benzazoles in water under ultrasound, Synth.
Commun. 43 (2013) 3083–3092.
[
15] M.A. Gouda, M.A. Berghot, G.E.A.E. Ghani, A.E.-G.M. Khalil, Chemistry of
2
-amino-3-cyanopyridines, Synth. Commun. 44 (2014) 297–330.
16] J. Tang, L. Wang, Y. Yao, L. Zhang, W. Wang, One-pot synthesis of
-amino-3-cyanopyridine derivatives catalyzed by ytterbium perflurooctanoate
Yb(PFO)3], Tetrahedron Lett. 52 (2011) 509–511.
17] H. Shibani, K. Saidi, M. Abbasnejad, A. Derakhani, I. Moham-
madzadeh, convenient one-pot synthesis and anxietic activity of
-cyano-2(1H)-iminopyridines and halogen derivatives of benzo[h]chromenes.
[29] S.K. Kumar, D. Rambabu, C.V. Kumar, B.Y. Sreenivas, K.R.S. Prasad, M.V.B. Rao,
M. Pal, Catalysis by Amberlyst-15 under ultrasound in water: a green synthesis
of 1,2,4-benzothiadiazine-1,1-dioxides and their spiro derivatives, RSC Adv. 3
(2013) 24863–24867.
[
2
[
[
[
[30] P.R.K. Murthi, D. Rambabu, M.V.B. Rao, M. Pal, Synthesis of substituted pyrroles
via Amberlyst-15 mediated MCR under ultrasound, Tetrahedron Lett. 55 (2014)
507–509.
A
3
Arab, J. Chem. 9 (2016) S901–S906.
18] D. Khalili, Graphene oxide: a reusable and metal-free carbocatalyst for the
one-pot synthesis of 2-amino-3-cyanopyridines in water, Tetrahedron Lett. 57
[31] For a review, see R. Pal, T. Sarkar, S. Khasnobis, Amberlyst-15 in organic syn-
thesis, Arkivoc 1 (2012) 570–609.
[32] V. Audrito, T. Vaisitti, D. Rossi, D. Gottardi, G. D’Arena, L. Laurenti,
G. Gaidano, F. Malavasi, S. Deaglio, Nicotinamide blocks proliferation and
induces apoptosis of chronic lymphocytic leukemia cells through activation
of the p53/miR-34a/SIRT1 tumor suppressor network, Cancer Res. 71 (2011)
4473–4483.
(2016) 1721–1723.
[
19] S. Banerjee, G. Sereda, One-step, three-component synthesis of high substi-
tuted pyridines using silica nanopartical as reusable catalyst, Tetrahedron Lett.
50 (2009) 6959–6962.
[
20] C.H. Chandrashekhar, K.P. Latha, H.N. Vagdevi, V.P. Vaidya, One-pot synthe-
sis of 2-amino4-(substituted phenyl)-6-naphtho[2,1-b]furan-2-ylnicotinonitrile
derivatives by using bismuth nitrate pentahydrate as efficient catalyst, Pharm.
Sin. 4 (2013) 37–39.
[33] B. Jung-Hynes, M. Nihal, W. Zhong, N. Ahmad, Role of sirtuin histone deacety-
lase SIRT1 in prostate cancer. A target for prostate cancer management via its
inhibition? J. Biol. Chem. 284 (2009) 3823–3832.
[34] J. Milne, P.D. Lambert, S. Schenk, D.P. Carney, J.J. Smith, D.J. Gagne, L. Jin,
O. Boss, R.B. Perni, C.B. Vu, J.E. Bemis, R. Xie, J.S. Disch, P.Y. Ng, J.J. Nunes,
A.V. Lynch, H. Yang, H. Galonek, K. Israelian, W. Choy, A. Iffland, S. Lavu,
O. Medvedik, D.A. Sinclair, J.M. Olefsky, M.R. Jirousek, P.J. Elliott, C.H. West-
phal, Small molecule activators of SIRT1 as therapeutics for the treatment of
type 2 diabetes, Nature 450 (2007) 712–716.
[
21] S.S. Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan, [Bmim]BF4 ionic liquid:
an efficient reaction medium for the one-pot multicomponent synthesis of
2
-amino-4, 6-diphenylpyridine-3-carbonitrile derivatives, J. Saudi Chem. Soc.
0 (2016) 517–522.
2
[
22] S. Pal, V. Singh, P. Das, L.H. Choudhury, PEG-mediated one-pot multicompo-
nent reaction for the efficient synthesis of functionalzed dihydropyridines and
their functional group dependent DNA cleavage activity, Bioorg. Chem. 4 (2013)
[35] J.-M. Yang, C.-C. Chen, GEMDOCK: a generic evolutionary method for molecular
docking, Proteins 55 (2004) 288–304.
8–15.
[23] J.F. Zhou, G.X. Gong, F.X. Zhu, S.J. Zhi, Microwave-promoted one-pot synthesis
of 3-(20-amino-30-cyano-40-arylpyrid-60-yl) coumarins, Chin. Chem. Lett. 20
(2009) 37–39.
7