Sonochemical synthesis of 2-substituted nicotinic acid ethyl ester derivatives: Their in vitro and in silico evaluation against SIRT1

Article abstract of DOI:10.1016/j.molstruc.2021.131069

Based on the initial docking studies of a representative compound in silico the evaluation of SIRT1 inhibitory potential of 2-substituted nicotinic acid ethyl ester derivatives was undertaken in vitro. A sonochemical method was developed and employed for the faster synthesis of this class of compounds. The methodology involved the iodine-mediated reaction of β-enamino esters with allylic alcohols in aqueous DMSO in the presence of air under mild conditions. A number of 2-substituted nicotinic acid ethyl ester derivatives were synthesized by employing this ultrasound assisted method in good to acceptable yield. The use of less expensive iodine and aqueous media, milder reaction condition and shorter reaction time are the key advantages of the current approach. All the synthesized compounds were tested for their SIRT1 inhibitory potential in vitro when some of them showed good activities and the compound 3g being the best among them. The docking studies suggested that the fused lactone ring of 3g played a key role in interacting with the SIRT1 in silico via formation of H-bonds. The overall outcome of the in vitro and in silico studies suggested the compound 3g as an initial hit molecule for further pharmacological studies.

Full text of DOI:10.1016/j.molstruc.2021.131069

Journal of Molecular Structure 1245 (2021) 131069
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Sonochemical synthesis of 2-substituted nicotinic acid ethyl ester
derivatives: Their in vitro and in silico evaluation against SIRT1
Chandra Sekhar Challaa, Naresh Kumar Katarib,∗, Varadacharyulu Nallanchakravarthulac,∗
Devanna Nayakantia, Ravikumar Kapavarapud, Manojit Pald,∗
,
a Department of Chemistry, Jawaharlal Nehru Technological University, Anantpur-515002, Andhra Pradesh, India
b Department of Chemistry, School of Science, GITAM (Deemed to be University), Hyderabad Campus, Rudraram, Patancheru Mandal, Hyderabad-502329,
Telangana, India
c Department of Biochemistry, Sri Krishnadevaraya University, Anantpur-515003, Andhra Pradesh, India
d Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500046, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Based on the initial docking studies of a representative compound in silico the evaluation of SIRT1 in-
hibitory potential of 2-substituted nicotinic acid ethyl ester derivatives was undertaken in vitro. A sono-
chemical method was developed and employed for the faster synthesis of this class of compounds. The
methodology involved the iodine-mediated reaction of β-enamino esters with allylic alcohols in aqueous
DMSO in the presence of air under mild conditions. A number of 2-substituted nicotinic acid ethyl ester
derivatives were synthesized by employing this ultrasound assisted method in good to acceptable yield.
The use of less expensive iodine and aqueous media, milder reaction condition and shorter reaction time
are the key advantages of the current approach. All the synthesized compounds were tested for their
SIRT1 inhibitory potential in vitro when some of them showed good activities and the compound 3g be-
ing the best among them. The docking studies suggested that the fused lactone ring of 3g played a key
role in interacting with the SIRT1 in silico via formation of H-bonds. The overall outcome of the in vitro
and in silico studies suggested the compound 3g as an initial hit molecule for further pharmacological
studies.
Received 15 May 2021
Revised 4 July 2021
Accepted 6 July 2021
Available online 11 July 2021
Keywords:
Nicotinic acid
Allyl alcohol
Iodine
SIRT1
In silico study
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
Accordingly, the synthesis as well as evaluation of a range of novel
derivatives of nicotinic acid has been reported for this purpose
The nicotinic acid or pyridine-3-carboxylic acid (A, Fig. 1) and
its derivatives constitute an important class of N-heterocyclic com-
pounds that have found numerous applications and importance in
both chemistry and biology. For example, as the most common
form of water soluble vitamin B3, also known as niacin [1], the
nicotinic acid has the potential to influence DNA repair, genomic
stability, and the immune system, eventually having an impact on
cancer risk [2]. Indeed, its importance for genomic stability thereby
possibility of reducing the cancer risk has been studied and docu-
mented [3]. Besides, the use of nicotinic acid in clinical practice
for the treatment of dyslipidemia is well known [4]. Nevertheless,
nicotinic acid and its derivatives have gained considerable interest
in the discovery and development of promising anticancer agents.
[5a–c]. In another study [6] nicotinic acid has been reported to at-
tenuate the vascular inflammation via modulation of SIRT1 path-
way [6a]. Notably, SIRT1 [or Sirtuin1, a NAD(+)-dependent class
III histone deacetylase (HDACs) is one of the 7 members (SIRT1-
SIRT7) in the sirtuin family in mammals] is known to participate
in the regulation of cellular inflammation [6b]. On the other hand,
being considered as important targets for cancer therapeutics [7a–
d] sirtuins are shown to up-regulated in various types of cancer
whereas inhibition of sirtuins allows re-expression of silenced tu-
mor suppressor genes, leading to the decreased growth of cancer
cells. Further, the nicotinamide B (Fig. 1) a derivative of nicotinic
acid has been reported to be one of the earliest inhibitors of sirtu-
ins including SIRT1 [7c]. All these reports and observations as well
as our interest in this area [8a,b] prompted us to explore the tem-
plate C derived from A for the identification of new and potential
inhibitors of SIRT1. The substituent R1 was introduced at the C-2
position of the pyridine ring (i) due to the key role played by the
C-2 substituents in the anticancer activities [9a,b] and (ii) to con-
∗
Corresponding authors.
E-mail
addresses:
dr.n.k.katari@gmail.com
(V.
(N.K.
Katari),
nchvaradacharyulu@yahoo.com
Nallanchakravarthula),
manojitpal@rediffmail.com (M. Pal).
https://doi.org/10.1016/j.molstruc.2021.131069
0022-2860/© 2021 Elsevier B.V. All rights reserved.

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1245 (2021) 131069
Fig. 1. Nicotinic acid A, nicotinamide B and the template C.
Fig. 3. Binding interactions and docked pose of nicotinamide at the catalytic site of
SIRT1 (PDB: 4I5I).
in the H-bond interactions with HIS363 and ILE347 through its
pyridine nitrogen atom and the ester carbonyl group, respectively.
Notably, a similar H-bond interaction with ILE347 was shown by
nicotinamide through its amide carbonyl moiety (Fig. 3, see also
Fig S-2 in suppl data). Further, C-1 also interacted with other
residues such as ALA262, ILE347, GLN345, HIS363, ILE411, PHE297
and PHE273 commonly through the van der Waals, pi-pi, pi-lone
pair and pi-alkyl interactions in the catalytic domain of SIRT1. The
outcome of this in silico studies encouraged us to gain a direct and
convenient access to the compound C-1 and its analogues for fur-
ther evaluation.
Fig. 2. Binding interactions and docked pose of compound C-1 at the catalytic site
of SIRT1 (PDB: 4I5I).
struct a library of small molecules based on C via varying the sub-
stituent R1 for studying the Structure-Activity-Relationship (SAR)
within the series thereby identifying the best active molecules. No-
tably, our current research effort is of particular interest because
the discovery of novel agents is considered as one of the way for-
wards to address the multifaceted problem of drug resistance [10].
The drug resistance is known to be a major cause in the failure of
chemotherapy based approaches on several occasions.
2. Results and discussion
To assess the merit of template C the in silico docking studies
of a representative molecule C-1 were carried out using the SIRT1
protein (PDB: 4I5I) (Fig. 2, see also Fig S-1 in suppl data). The
compound C-1 showed good binding with the catalytic residues of
SIRT1 with the binding energy of -90.39 kcal/mol that was compa-
rable to nicotinamide’s -88.38 kcal/mol. The molecule participated
The 2-aryl substituted pyridine derivatives are commonly pre-
pared [11] by Pd-catalyzed direct arylation of pyridine N-oxides
[11a] or by addition of Grignard reagents to pyridine N-oxides fol-
lowed by treatment with Ac2O [11b]. They are also prepared via
AlCl3 induced C-C bond forming reactions between 2-halopyridines
2

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1245 (2021) 131069
Table 1
Effect of conditions on the reaction of 1a with 2.a
Scheme 1. Sonochemical synthesis of 2-substituted nicotinic acid ethyl ester
Entry
Temp (°C)
Time (h)
Yield (%)b
derivatives.
1
2
3
4
5
6
30
50
50
50
50
80
3
3
1
1
1
5
0
0
71c
74d
43e
29f
and arenes [12]. More recently, this class of compounds has been
prepared via the reaction of aryl ketone with 1,3-diaminopropane
in the presence of a catalyst or reagents such as Cu(OSO2CF3)2
ꢀ
[13], LiCl [14], I2-HCl [15], Ru(2,2 -bipyridine)3Cl2.6H2O [16] and
a
All reactions were performed using the β-enamino ester 1a
(0.4 mmol) and allyl alcohol 2 (0.8 mmol.) in aqueous DMSO (1:9,
5 mL) under open air.
Pd(OAc)2-PTSA-O2 [17]. In our effort the synthesis of 2-substituted
nicotinic acid ethyl ester derivatives were carried out earlier via
the IBX (2-iodoxybenzoic acid) mediated reaction of β-enamino
esters with allylic alcohols [18]. While this one-pot reaction pro-
ceeded under a metal free conditions however the methodology
involved the use of an elevated temperature (70 °C) and relatively
longer reaction time (3h). Moreover, the oxidant IBX though read-
ily available but is not an inexpensive reagent. On the other hand,
ultrasound plays an important role in accelerating the reaction
rate substantially affording the desired product within short re-
action time. Further, the ultrasound assisted reactions (i) are con-
sidered as green approaches in organic synthesis [19], (ii) are ef-
fective in waste minimization and reduction of energy require-
ments [20] and (iii) play key role in developing new, cost effec-
tive and environmentally safe methodologies for accessing numer-
ous organic molecules [21,22]. We therefore decided to adopt ul-
trasound assisted method for the faster access of our target com-
pounds based on C. Notably, during this study we found that the
elemental iodine in aqueous DMSO was an effective as well as
cheaper alternative agent for the reaction of β-enamino esters (1)
with allylic alcohols (2) under ultrasound irradiation (Scheme 1).
Notably, molecular iodine or iodine containing agents have found
considerable applications in organic synthesis [23–25] and we have
a long term interest in this area [26–28].
b
Isolated yields.
c
The reaction was performed in the presence of IBX (1.2 equiv.).
d
The reaction was performed in the presence of elemental io-
dine (1.5 equiv.).
e
0.8 equiv. iodine was used.
f
The reaction was performed in the absence of ultrasound.
products in good to acceptable yields (Table 2). The C-2 substituent
of the product 3 may include a substituted aryl ring, a phthalide
or indole or pyridine or furan ring, a methyl or substituted ben-
zyl moiety or a styryl group. The key advantages of the current
approach are the use of less expensive iodine and aqueous me-
dia, milder reaction condition and shorter reaction time. More-
over, since the reaction was performed under open air hence the
methodology is free from the risk of pressure development as ob-
served in case of reaction performed in an isolated system espe-
cially in the large scale preparation.
All the compounds synthesized were characterized by spectral
(1H and 13C NMR and HRMS) data. This is exemplified by the
partial 1H and 13C NMR spectral data of two representative com-
pounds e.g. 3g and 3h (see Fig S-0 in suppl data). A triplet near 1.1
δ and a quartet near 4.2 δ in the 1H NMR spectra was due to the
OEt (ester) protons of 3g whereas a singlet near 5.3 δ accounting
two protons was due to its methylene moiety of the fused lactone
ring. Similarly, the OEt protons appeared near 1.0 and 4.1 δ in case
of 3h whereas a triplet near 6.5 δ, a doublet near 7.1 δ and a sin-
glet near 3.8 δ were due to the C-3, C-2 and NMe protons of the
indole ring, respectively. The C-6 proton of the pyridine ring ap-
peared near 8.8 or 8.7 δ in both the cases. The two C=O groups of
fused lactone and the ester moiety and the OCH2 carbon appeared
near 170.7, 166.9 and 69.6 ppm, respectively in the 13CNMR spec-
tra of 3g whereas the C-6 of the pyridine ring and the ester car-
bons appeared near 157.6, 61.7 and 13.7 ppm. In case of 3h the key
13C signals and the corresponding carbons were identified as 169.0
(C=O), 159.6 (C-6 of the pyridine ring), 101.7 (C-3 of the indole
ring) and 32.9 (NMe) ppm. The IR absorption near 1760 and 1725
cm−1 in case of 3g also indicated the presence of lactone and ester
C=O group, respectively whereas rest of the compounds showed IR
signal near 1720 cm−1 due to the ester moiety.
Firstly, a brief study was carried out to establish the opti-
mized reaction conditions and the reaction of (E)-ethyl 3-amino-
3-phenylacrylate (1a) with allyl alcohol (2) in aqueous DMSO (1: 9
H2O-DMSO) was used as a model reaction for this purpose. The re-
action was performed at 30 °C for 3 h in the presence of air under
ultrasound using a laboratory ultrasonic bath SONOREX SUPER RK
510H model producing irradiation of 35 kHz. No catalyst or reagent
was used in this case and the reaction did not proceed at this or
elevated temperature (entry 1 and 2, Table 1). Notably, the reac-
tion was completed within 1h affording the desired product 3a in
good yield when IBX was used (entry 3, Table 1). Next we explored
the use of elemental iodine as an inexpensive and alternative agent
for the current transformation. Indeed, we were encouraged by the
fact that the use of iodine for the oxidation of allylic alcohol (pro-
tected or unprotected) has been reported previously [29]. To our
satisfaction the reaction proceeded well in the presence of iodine
affording the product 3a in 74% yield (entry 4, Table 1). The reac-
tion was carried out using 1.5 equivalent of iodine when the use of
lower quantity of iodine decreased the product yield significantly
(entry 5, Table 1). The product yield was decreased further when
the reaction was performed in the absence of ultrasound even at
higher temperature for a longer time (entry 6, Table 1). Overall,
the reaction condition of entry 4 appeared to be optimum for the
preparation of 3a and was used for the preparation of its ana-
logues.
Based on the earlier reports [18,29] a plausible reaction mecha-
nism for the I2-mediated reaction of 1 with 2 under ultrasound ir-
radiation is proposed in Scheme 2. The reaction seems to proceed
via (i) ultrasound assisted disproportionation reaction of I2 with
water to generate hydroiodous acid (HOI) (along with HI) in situ
[30], (ii) oxidation of allylic alcohol (2) by HOI (via providing the
electrophilic I+ species) [31] promoted by ultrasound to give the
aldehyde E-1 that on (iii) sonochemical Michael addition with β-
enamino ester (1) followed by (iv) intramolecular cyclization gives
the 1,4-dihydropyridine intermediate E-3 via E-2, (v) oxidation of
E-3 in the presence of air under ultrasound to give the product 3.
Notably, HI along with water are the by-products formed during
A number of 2-substituted nicotinic acid ethyl ester derivatives
(3) were synthesized by employing various β-enamino esters (1).
The ultrasound assisted reaction in the presence of iodine under
open air proceeded well in all these cases affording the desired
3

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1245 (2021) 131069
Table 2.
List of 2-substituted nicotinic acid ethyl ester derivatives (3) synthesized following the method shown in
Scheme 1.a,b
a
All reactions were performed using the β-enamino ester 1 (0.4 mmol), allyl alcohol 2 (0.8 mmol), iodine (1.5
equiv.) in aqueous DMSO (1:9, 5 mL) under ultrasound irradiation in the presence of open air.
b
Figure in the bracket represents the isolated yield.
waves are produced by this collapse outside the bubble. Thus, the
overall effects induced by cavitation could be involved in the ox-
idation of 2 followed by Michael addition with 1 and subsequent
intramolecular cyclization followed by oxidation (Scheme 2). Nev-
ertheless, the combined effect of ultrasound, iodine and air was
essential for the successful preparation of 3.
All the 2-substituted nicotinic acid ethyl ester derivatives (3)
synthesized were assessed for their inhibitory activities against
SIRT1 in vitro using a reported biochemical enzymatic assay
[34]. The known inhibitor nicotinamide (the reported IC50 value
against SIRT1 = 120 μM) [35] was used as a reference compound.
At the concertation of 10 μM the compounds that showed good
activities (>50% inhibition) include 3a (72% inhibition), 3g (81% in-
hibition), 3h (59% inhibition), 3i (67% inhibition) and 3j (53% inhi-
bition) (see Table S-1 in suppl data). This was further supported by
the estimated total energy of these molecules obtained via the in
silico docking studies performed (using these compounds includ-
ing nicotinamide) against the SIRT1 protein (PDB: 4I5I). The iGEM-
DOCK version2.1 software [36], 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 3. The docking [37a-b] interactions occurred with the cat-
alytic domain residues of 241-516. The binding interactions and
docked pose of the best active molecule 3g at the catalytic site
of SIRT1 is shown in Fig 4 (see also Fig S-3 in suppl data). The
molecule 3g participated in the H-bond interactions with GLN345
and ALA262 through its lactone oxygen atom and the carbonyl
group, respectively. Notably, similar involvement of its carbonyl
group was also observed when the molecule was docked into other
Scheme 2. Proposed reaction mechanism for the I2-mediated reaction of 1 with 2
under ultrasound irradiation in the presence of air.
this transformation when HI participates in regenerating the HOI
to complete the reaction cycle. It is evident from Table 1 that ul-
trasound not only accelerated the reaction rate but also facilitated
the formation of the desired product. Indeed, the ultrasound facil-
itates cavitation involving the growth, oscillation, and collapse of
bubbles under the action of an acoustic field [32,33]. Consequently,
drastic conditions including the extremely high pressure (up to
1800 atmosphere) and temperature (e.g. 2000–5000 K) inside the
medium within a very short duration are produced chiefly by the
cavitational collapse. Additionally, the shear forces, jets, and shock
4

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1245 (2021) 131069
Table 3
Summary of interactions of compounds with SIRT1 in silico.a
Compounds
Estimated Total Energy (kcal/mol)
Active site interacting residues
3a
-90.39
-94.54
-77.67
-88.46
-74.43
-88.38
-110.5
HIS363, ILE347, ALA262, ILE411, PHE273, GLN345
GLN345, ALA262, HIS363, PHE273, ILE347, ILE411
ALA262, ILE347, ILE411, PHE273, PHE297
3g
3h
3i
HIS363, ILE347, ALA262, PHE273, GLN345
3j
ALA262, HIS363, PHE273, ILE347, VAL412
Nicotinamide
EX527a
ASP348, ILE347, PHE273, ALA262, ILE279
ASP348, ILE347, ILE316, ILE279, PHE273, PHE297, ILE411, PHE413
a
For binding interactions and docked pose see Fig S-3 to S-6 in the suppl data.
Fig. 5. 2D binding interactions and docked pose of EX527a at the catalytic site of
SIRT1 (PDB: 4I5I).
of in vitro assay. However, being a potent inhibitor of SIRT1 the
indole derivative EX527a (an analogue of EX527 or Selisistat and
also a co-crystallized ligand with PDB: 4I5I) [37a] showed superior
energy and interactions (Table 3 and Fig. 5) than 3g. Nevertheless,
an acceptable ADME (absorption, distribution, metabolism, and ex-
cretion) or pharmacokinetic properties was predicted for 3g when
the computational ADME prediction of this compound along with
3a and 3i (that showed good inhibition of SIRT1) was carried out
using Swiss ADME web-tool [38] (Table 4). Indeed, the molecule
3g may show high GI absorption, favorable drug likeness as well as
bioavailability score in addition to be a non-P-gp substrate though
it may penetrate the blood brain barrier. Overall, the compound 3g
appeared as an interesting hit molecule for further biological stud-
ies.
From the viewpoint of Structure- Activity-Relationship (SAR)
within the current series of 2-substituted nicotinic acid ethyl es-
ter derivatives it was evident that the SIRT1 inhibitory activity was
varied considerably with the change in the nature as well as type
of substituent present at the C-2 position. In general, arene / het-
eroarene (e.g. indole, pyridine, furan etc.) moieties were favored at
this position whereas an alkylaryl (e.g. benzyl or substituted ben-
zyl) group at the same position was less effective. A smaller group
e.g. Me or an alkenyl moiety like styrene at this position was also
not favored. Notably, a halo benzene e.g. chloro or bromobenzene
ring at the C-2 position decreased the activity whereas a descend-
ing order of activity was observed for the compound possessing
phthalide > pyridine > indole > furan as the C-2 substituent.
Fig. 4. Binding interactions and docked pose of compound 3g at the catalytic site
of SIRT1 (PDB: 4I5I).
SIRT1 with PDB code as 5BTR, 4ZZH and 4KXQ (see Fig S-7 in
suppl data). Further, 3g also interacted with other residues such as
ILE347, HIS363, ILE411, PHE297, PHE273 etc via the van der Waals,
pi-pi, pi-lone pair and pi-alkyl interactions in the catalytic domain
of SIRT1. It is evident from Table 3 that 3g showed better inter-
actions with SIRT1 than nicotinamide as indicated by the outcome
5

C.S. Challa, N.K. Katari, V. Nallanchakravarthula et al.
Journal of Molecular Structure 1245 (2021) 131069
Table 4.
Computational ADME prediction of selected compounds.
Properties
Molecules
(i) Physicochemical
3a
3g
3i
Molecular Weight (g/mol)
Consensus Log Pa
Log S (ESOL)b
227.26
283.28
228.25
1.93
2.68
2.47
-3.23 (soluble)
-3.12 (soluble)
-2.56 (soluble)
(ii) Pharmacokinetics
GIc absorption
BBBd penetration
P-gpe substrate
High
Yes
No
High
Yes
No
High
Yes
No
(iii) Drug likeness
Lipinski rule
Yes; 0 violations
Yes; 0 violations
Yes; 0 violations
Veber rule
Yes
Yes
Yes
Bioavailability score
0.55
0.55
0.55
a
Log P: Lipophilicity.
b
Log
S (ESOL): water solubility, calculated by ESOL method which is a Quantitative
Structure-Property Relationship (QSPR) based model.
c
GI: Gastrointestinal.
d
BBB: Blood Brain Barrier
e
P-gp: permeability glycoprotein.
3. Conclusions
Declaration of Competing Interest
In conclusion, the 2-substituted nicotinic acid ethyl ester
derivatives were assessed for their potential SIRT1 inhibitory prop-
erties in vitro that was backed by the initial docking studies of
a representative compound in silico. Accordingly, a sonochemical
method was developed and employed for the fast time for the
quicker access to this class of compounds. The methodology in-
volved the iodine-mediated reaction of β-enamino esters with al-
lylic alcohols in aqueous DMSO in the presence of air under mild
conditions. A number of 2-substituted nicotinic acid ethyl ester
derivatives were synthesized by employing this ultrasound assisted
method in good to acceptable yield. The use of less expensive io-
dine and aqueous media, milder reaction condition and shorter
reaction time are the key advantages of the current approach. A
plausible reaction mechanism is proposed and discussed for this
sonochemical process. All the synthesized compounds were tested
for their SIRT1 inhibitory potential in vitro when some of them
showed good activities and the compound 3g appeared to be the
best among them. The docking studies suggested that the fused
lactone ring of 3g played a key role in interacting with the SIRT1
in silico via formation of H-bonds. An acceptable ADME or phar-
macokinetic properties was predicted for 3g via the computational
ADME prediction of this compound in silico. Thus the overall out-
come of the in vitro and in silico studies suggested the compound
3g as an initial hit molecule for further pharmacological studies.
Finally, the current research efforts not only revealed the utility of
iodine and ultrasound for the rapid access of 2-substituted nico-
tinic acid ethyl ester derivatives but also highlighted the potential
of nicotinic acid ethyl ester based framework for the identification
of new inhibitors of SIRT1.
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.
Acknowledgement
The authors thank the management of GITAM University, Hy-
derabad, India for continuous support and encouragement. Authors
also than Dr. Rambabu Gundla of GITAM University 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.2021.131069.
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