Synthesis, identification and molecular docking studies of N-functionalized piperidine derivatives linked to 1,2,3-triazole ring

Article abstract of DOI:10.1080/00397911.2020.1776876

New derivatives of piperidine bearing a 1,2,3-triazole ring designed and synthesized smoothly over six steps from N-protected piperidone-4-one. These steps included reduction of the carbonyl group/tosylation of the resulting alcohol providing tosyl derivative in a good yield, followed by nucleophilic substitution and Cu-catalysed azide-alkyne cycloaddition. By removing the protecting group and functionalizing amine group via reductive amination gave the desired design in moderate to very good yields. Molecular modeling studies of these compounds predicted possible binding modes into the active site of dopamine receptor D2.

Full text of DOI:10.1080/00397911.2020.1776876

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis, identification and molecular docking
studies of N-functionalized piperidine derivatives
linked to 1,2,3-triazole ring
Rafid S. Dawood & Sudad A. Dayl
To cite this article: Rafid S. Dawood & Sudad A. Dayl (2020): Synthesis, identification and
molecular docking studies of N-functionalized piperidine derivatives linked to 1,2,3-triazole ring,
Synthetic Communications, DOI: 10.1080/00397911.2020.1776876
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https://doi.org/10.1080/00397911.2020.1776876
Synthesis, identification and molecular docking studies of
N-functionalized piperidine derivatives linked to 1,2,3-
triazole ring
Rafid S. Dawood
and Sudad A. Dayl
Department of Chemistry, College of Science, University of Baghdad, Baghdad, Iraq
ABSTRACT
ARTICLE HISTORY
Received 1 March 2020
New derivatives of piperidine bearing a 1,2,3-triazole ring designed
and synthesized smoothly over six steps from N-protected piperi-
done-4-one. These steps included reduction of the carbonyl group/
tosylation of the resulting alcohol providing tosyl derivative in a
good yield, followed by nucleophilic substitution and Cu-catalysed
azide-alkyne cycloaddition. By removing the protecting group and
functionalizing amine group via reductive amination gave the
desired design in moderate to very good yields. Molecular modeling
studies of these compounds predicted possible binding modes into
the active site of dopamine receptor D2.
KEYWORDS
DRD2 binding; ligand
docking; piperidine;
reductive amina-
tion; triazole
GRAPHICAL ABSTRACT
Introduction
Piperidine is a saturated six-membered heterocyclic ring bearing one nitrogen atom. It is
present in a variety of active synthetic pharmaceutical drugs. For example, paroxetine
shows a significant antidepressant activity and serotonin reuptake inhibitor. Clopidogrel
is used as a blood-clotting inhibitor, tadalafil as a PDE5 inhibitor and treatment of erectile
dysfunction. Methylphenidate shows a remarkable psychostimulant for treating ADHD,
and N-butyl-deoxyynojirimycin uses as a medication for Gaucher disease. Also, meflo-
quine is employed as a malarial drug.[1] Piperidine ring is also found in many alkaloid nat-
ural products such as (S)-coniine, (S)-anabasine, (–)-swainsonine and quinine (Figure 1).
CONTACT Rafid S. Dawood
rafid.s@sc.uobaghdad.edu.iq
Department of Chemistry, College of Science, University
of Baghdad, Al-Jadriya Campus, Baghdad 10071, Iraq.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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R. S. DAWOOD AND S. A. DAYL
(A)
(B)
Figure 1. Some compounds containing a piperidine ring in their structures. (A) Synthetic pharmaceut-
ical drugs. (B) Alkaloid natural products.
Also, compounds containing a triazole ring usually possess a wide range of biological
activities such as anti-herbicide,[2] anti-fungal,[3] anti-HIV activity,[4] anti-allergic[5] and
anti-influenza.[6] The interest in this work is combining two essential rings (the piperi-
dine and 1,2,3-triazole) to afford 6. Following this, product 6 will be functionalized with
substituted aromatic rings using a reductive amination reaction, to furnish a new selec-
tion of chemical compounds 8.
Dopamine receptors play a significant role in life functions including emotions, brain
reward system and affect movement. They are expressed in the central and periphery
nervous system.[7] Dopamine receptors types are D1, D2, D3, D4, and D5 with a spe-
cific function of each kind. Dopamine receptor D2 (DRD2) has a role in attention,
memory, sleep, learning and locomotion.[8] The two primary conditions that are target-
ing dopamine receptors are schizophrenia and Parkinson disease. Most of the antipsy-
chotic’s antagonists bind and block DRD2. Piperidine derivatives have been shown as a
dopaminergic stabilizer to treat Parkinson disease.[9,10] In this work, a set of piperidine
derivatives were synthesized to study their binding modes with DRD2.
Results and discussion
Chemistry
In our work, it was attempted to design and prepare new piperidine-linked triazoles
and benzyl derivatives 8a–f with different R groups that have different chemical

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Figure 2. The design strategy for new piperidine-linked triazoles and benzyl derivatives 8a–f.
Scheme 1. Outline of the synthesis of amine intermediate 6 over five steps from ketone 1.
properties to study their binding with DRD2 using a molecular docking as described in
Figure 2 and Scheme 2.
The synthesis of 1-benzyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine derivatives 8a–f
was performed over six sequence steps starting from 1-benzylpiperidin-4-one 1. From
the literature, Denmark and Cresswell have prepared tosyl derivative 3 by nucleophilic
substitution of commercially available alcohol 2 with tosyl chloride.[11] While, in our
work, ketone 1 was used as a starting material for the preparation of 3 in two steps,
which included reduction of 3 with NaBH4 to furnish the corresponding alcohol crude
material 2 (Scheme 1). TLC and LCMS showed that there was a full conversion to alco-
hol 2. Tosylation of alcohol 2 was then achieved successfully, which gave the tosylate
alcohol 3 in good yield (72%). The product 3 can be considered more reactive than 2
toward nucleophilic substitution because of tosyl group is a better leaving group than
hydroxyl group. SN2 displacement of the OTs group at 3 with sodium azide was then
performed to provide 4 in 66% yield, which is better than the isolated yield from the lit-
erature procedure (48% vs. 66%).[12] The starting material 3 was consumed entirely
within 15 hours. The azide derivative 4 was confirmed by NMR spectroscopy via the

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R. S. DAWOOD AND S. A. DAYL
disappearance of the OTs group. FTIR showed an influential absorption band at
2129 cm–1, attributing to the stretch vibrations of the N3 bond of the azide group at 4.
The desired product 5 has previously prepared, but it was in a mixture with
undesired 1,5-triazole regioisomer 5a using thermal 1,3-dipolar cycloaddition reac-
tion.[13] In our work, Cu(I)-catalysed 1,3-dipolar cycloaddition reaction was used on 4
with phenylacetylene to afford 5 in good yield (71%). It was noted that there is just one
1
product formed (desired 1,4-regioisomer 5) in the crude material as judged by H NMR
spectroscopy. This is due to using CuI as a catalyst, which prevented the formation of
the undesired 1,5-triazole regioisomer 5a as reported in the literature.[14–17]
Furthermore, Funk and coworkers reported that the average chemical shift of C-5 for
triazole ring in the 1,4-regioisomers is further upfield (d ¼ 120 3 ppm) than C-4 in
1,5-regiosiomers (d ¼ 133 3 ppm) due to resonance factor.[18] From this, the structure
of the 1,4-regioisomer 5 was further supported by 13C and DEPT NMR experiments
(see the Supporting Information), which C-5 signal of the triazole moiety appears at
117.2 ppm (expected range). Following this, deprotection of benzyl group at 5 was
accomplished when treated 5 with H2 over Pd/C, which gave the corresponding amine
6 in excellent yield (91%), and the starting material 5 was consumed within 16 hours.
Reductive amination was then conducted between amine 6 and aldehydes 7a–f in the
presence of NaBH(OAc)3 and AcOH in DCE to provide the desired targets 8a–f in
yields ranging from 59 to 82% (Scheme 2). The 1H NMR spectra of 8a–f were
Scheme 2. Reductive amination of 6 with aromatic aldehydes 7a–f to access novel derivatives of
piperidine 8a–f.

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characterized by the absence of N–H proton of 6, and the presence of additional ali-
phatic, aromatic protons and carbon atoms of substituted benzyl group. It was observed
that using aromatic aldehydes bearing electron-withdrawing groups giving the corre-
sponding tertiary amines in better yield than those bearing electron-donating groups in
their structures. For example, the aldehyde 6a affording the desired product 8a in 69%
yield. The decreased yield was obtained when aldehyde 6b was used, which gave 8b in
65%. The imine analogues of aldehydes 7a and 7b were consumed completely within 5
and 7 hours, respectively (monitored by TLC and HRMS). The use of aldehyde bearing
strong donating group (hydroxyl) on the aromatic ring 7c provided the corresponding
tertiary amine 8c in a lower yield (59%) than aldehydes bearing moderate electron-
donating groups (methyl 7a and methoxy 7b). The imine analogues of aldehyde 7c
could not be consumed completely within 24 hours. This is explained by the presence of
an electron-donating group, which deactivates the carbonyl group of the aldehydes
toward the nucleophilic addition by amine 6.
On the other hand, the reductive amination was tolerant with halogen substituents, such
as, chloro and bromo groups on the aromatic ring of aldehydes. This gave the desired ter-
tiary amines in good yields (75% for 8d and 79% for 8e). As expected, the use of aromatic
aldehydes bearing a strong electron-withdrawing group in their structures will encourage
the reductive amination due to increasing the electrophilicity that leading to activate the
nucleophilic addition by amine 6. For example, the use of p-nitrobenzaldehyde 7f afforded
the desired product 8f in very good yield (82%) (Scheme 2).
Molecular docking study
Molecular docking was performed with the crystal structure of D2 dopamine receptor
bound to risperidone (6CM4) using AutoDock 4.2.6[19] to predict binding modes, orien-
tation and affinities of the synthesized compounds 8a–f. Estimated inhibition constant
(Ki, nM), docking scores (estimated free energy of binding DGꢀ, kcal/mol; binding
energy includes hydrogen bonding, p–p interactions, Van der Waals forces, etc.) and
possible binding residues of the docking compounds were compared as shown in
Table 1. All the docked compounds were occupied the orthosteric site of DRD2 with
different orientations. Results from docking scores predicted that compound 8f has the
lowest binding energy in comparison to the other compounds and that is due to the
introducing NO2 group that reduces the final intermolecular energy, vdW, Hbond and
dissolve energy comparing to other compounds.
Possible binding residues of the compounds 8a–f using the lowest energy from
the largest cluster were compared. Best solutions of the compounds 8a–f are pre-
dicted to interact with similar binding residues D114, C118, S197, W386, F390 and
T412. In comparison to the crystal structure of DRD2 with risperidone bound, the
residues D114, C118, S197, W386, F390 and T412 were found to interact with ris-
peridone. Moreover, Wang et al. found that D114, W386 and T412 reduced risperi-
done binding affinity by more than tenfold[20] that suggests these residues are
essential in binding DRD2 inhibitors. Furthermore, compound 8f showed a possible
hydrogen bond between one of the nitro group oxygen and sidechain of T412 (dis-
tance: 1.9 Å). Compound 8b predicted to have one hydrogen bond between OCH3

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R. S. DAWOOD AND S. A. DAYL
Table 1. Docking scores (estimated free energy of binding DGꢀ, kcal/mol) and the estimated inhib-
ition constant (Ki, nM) of the synthesized compounds 8a–f with D2 dopamine receptor (6CM4).
Estimated free energy of
Estimated inhibition
constant, Ki (nM)
Compounds
Interacting residues
binding DGꢀ (kcal/mol)
8a
V91, L94, F110, D114, V115, C118, T119,
A122, I184, F189, S193, S197, F198,
F382, W386, F389, F390, T412,
W413, W416
ꢁ10.78
12.44
8b
D114, V115, C118, T119, A122, F189,
S193, S197, F198, F382, W386, F389,
F390, H393, Y408, T412
D114, V115, C118, T119, A122, I184,
S193, S197, F198, F382, W386, F389,
F390, H393, Y408, T412, Y416
V91, L94, W100, F110, D114, C118, T119,
I184, S197, W386, F390, F398, T412,
W413, Y416
V91, L94, W100, F110, D114, C118, T119,
I184, S197, W386, F390, F398, T412,
W413, Y416
D114, V115, C118, A122, F189, S193,
S197, F198, F382, W386, F389, F390,
H393, Y408, T412
ꢁ10.50
ꢁ10.28
ꢁ11.11
ꢁ10.89
ꢁ11.20
19.98
29.17
7.17
8c
8d
8e
10.46
6.2
8f
Risperidone
W100, F110, D114, V115, C118, T119,
A122, S193, S197, F198, F382, W386,
F390, F389, Y408, T412, Y416
Figure 3. Docking pose of the compound 8f at the DRD2 crystal structure. (a) and (b) Panels show
an extracellular sideview and top of DRD2 crystal structure in gray cartoon representation, respect-
ively. Red and green sticks represent risperidone and compound 8f, respectively. (c) DRD2 sidechain
residues at 4 Å cut-off from compound 8f are shown as red sticks. Compound 8f is colored with
white, blue and red that represent carbon, nitrogen and oxygen atoms, respectively.

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Figure 4. Docking solutions for compounds 8a–e in the active site of DRD2 showing 2 D ligand-
receptor interactions.
group and sidechain of T412 (distance: 1.9 Å). In addition, sidechain of D114 is
close to 1,2,3-triazole ring of the docked compounds which rise the possibility of a
salt-bridge interaction. It is worth to mention that D114 is part of salt-bridge inter-
action with the tertiary amine of risperidone,[20] see Figure 3 for docking pose of
compound 8f. Interaction of compounds 8a–e with the binding site of DRD2 is
illustrated in Figure 4.
Conclusion
A series of novel 1-benzyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine derivatives 8a–f
were prepared successfully in yields ranging from 59 to 82%. Molecular docking showed
that the prepared compounds could fit in the active site of the DRD2 receptor. Best binding
modes of the docked compounds suggested the following binding residues (D114, C118,
S197, W386, F390 and T412) that might be important as a useful template for further devel-
opment of the DRD2 that could be used to improve the efficiency of DRD2 inhibitors

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R. S. DAWOOD AND S. A. DAYL
Experimental section
Chemistry
General procedure for reductive amination to synthesize 1-benzyl-4-(4-phenyl-1H-
1,2,3-triazol-1-yl)piperidine derivatives 8a–f
The crude material of amine 6 (350 mg, 1.5 mmol, 1.0 eq.) was dissolved in DCE
(20 mL) in a 100 mL round bottom flask. Aromatic aldehydes 7a–f (2.25 mmol, 1.5 eq.)
and acetic acid (215 mL, 3.75 mmol, 2.5 eq.) were then added and the resulting mixture
stirred at room temperature for 2 hours. A solution of sodium triacetoxyborohydride
(381 mg, 1.8 mmol, 1.2 eq.) in DCE (10 mL) was added dropwise. The reaction mixture
was stirred overnight (14 hours) at room temperature then washed with 1.0 M HCl
(2 ꢂ 15 mL). The aqueous phase was basified using saturated aqueous NaHCO3 (15 mL)
solution then extracted with ethyl acetate (2 ꢂ 15 mL), washed with water (2 ꢂ 15 mL),
and the combined extracts, dried over anhydrous MgSO4, filtered and solvent removed
in vacuo. Flash column chromatography (petroleum ether/ethyl acetate) provided the
desired products 8a-f.
1-(4-Methylbenzyl)-4-(4-phenyl-1H-1,2,3-triazol-1-yl)piperidine (8a)
General procedure of reductive amination was followed to provide 8a as a yellow oil
(344 mg, 1 mmol, 69%); IR ꢀmax(CHCl3)/cm-1 ¼ 3115 (C–Halkene), 3071, 3056, 3022
1
(C–Haro), 2971, 2952, 2849 (C–Hali), 1648 (C ¼ C); H NMR (400 MHz, CDCl3) dH
¼
7.67–7.61 (2H, m), 7.51–7.44 (2H, m), 7.34–7.27 (5H, m), 6.06 (1H, s), 3.47 (2H, s),
3.41–3.37 (1H, m), 2.69–2.64 (2H, m), 2.39 (3H, s), 2.32–2.27 (2H, m), 1.85–1.75 (4H,
m); 13C NMR (100 MHz, CDCl3) dC ¼ 148.1, 144.6, 138.3, 134.4, 133.0, 129.2, 128.3,
127.2, 126.2, 117.1, 62.4, 57.2, 51.2, 30.2, 21.0; HRMS (ESI) m/z, calculated for
[C21H25N4þ] [M þ H]þ 333.2074, found 333.2076.
Molecular docking study
ChemDraw was used to draw, set charges and run energy minimization of the com-
pounds 8a–f and the output files were saved mol2 format. Crystal structure of DRD2
bound to Risperidone (PDB ID: 6CM4; resolution: 2.8 Å) was retrieved from protein
data bank.[21] Ligand docking of compounds 8a-f into the crystal structure of DRD2
was carried out using AutoDock 4.2.6.[19] Each of these compounds in the PDBQT for-
mat was docked separately into the active site of DRD2. All calculations for protein-lig-
and docking were carried out using default settings. A grid box with the dimensions of
X: ꢁ16.098, Y: 9.428 and Z: ꢁ15.288 A˚ with a default grid spacing was used. The best
conformation was selected with the lowest docked energy from the largest cluster. The
interactions between docked compounds and DRD2 receptor were analyzed.
The entire experimental section can be found in the through the “Supplementary
Content” section of this article’s webpage, including spectral data and scanned spectra
(1H and 13C NMR) of all compounds.

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Disclosure statement
The authors declare no conflict of interest.
Funding
This work was financially supported by the Ministry of Higher Education and Scientific Research
– Iraq (MOHESR) (Rafid S. Dawood), and Higher Committee for Education Development in
Iraq (HCED) (Sudad A. Dayl).
ORCID
Rafid S. Dawood
Sudad A. Dayl
http://orcid.org/0000-0002-7412-0019
http://orcid.org/0000-0001-9947-7244
References
[1] Kim, Y. R.; Hall, D. G. Optimization and Multigram Scalability of a Catalytic
Enantioselective Borylative Migration for the Synthesis of Functionalized Chiral
Piperidines. Org. Biomol. Chem. 2016, 14, 4739–4748. DOI: 10.1039/c6ob00685j.
[2] Simmons, K. A.; Dixson, J. A.; Hailing, B. P.; Plummer, E. L.; Plummer, M. J.; Tymonko,
J. M.; Schmidt, R. J.; Wyle, M. J.; Webster, C. A.; Baver, W. A.; et al. Synthesis and
Activity Optimization of Herbicidal Substituted 4-Aryl-1,2,4-Triazole-5(1H)-Thiones.
J. Agric. Food Chem. 1992, 40, 297–305. DOI: 10.1021/jf00014a027.
[3] Cao, X.; Li, F.; Hu, M.; Lu, W.; Yu, G. A.; Sheng, H. L. Chiral gamma-aryl-1H-1,2,4-tri-
azole Derivatives as Highly Potential Antifungal Agents: Design, Synthesis, Structure, and
In Vitro Fungicidal Activities. J. Agric. Food Chem. 2008, 56, 11367–11375. DOI: 10.1021/
jf8026843.
ꢀ
ꢀ
[4] Alvarez, R.; Velazquez, S.; San-Felix, A.; Aquaro, S.; De Clercq, E.; Perno, C. F.; Karlsson,
A.; Balzarini, J.; Camarasa, M. J. 1,2,3-Triazole-[20,50-bis-O-(Tert-Butyldimethylsilyl)-beta-
D-Ribofuranosyl]-30-Spiro-500-(400-Amino-100,200-Oxathiole 200,200-Dioxide) (TSAO) Analogues:
Synthesis and Anti-HIV-1 Activity. J. Med. Chem. 1994, 37, 4185–4194. DOI: 10.1021/
jm00050a015.
[5] Buckle, D. R.; Outred, D. J.; Rockell, C. J. M.; Smith, H.; Spicer, B. A. Studies on
v-Triazoles. 7. Antiallergic 9-oxo-1H,9H-benzopyrano[2,3-d]-v-triazoles. J. Med. Chem.
1983, 26, 251–254. DOI: 10.1021/jm00356a025.
[6] Cheng, H.; Wan, J.; Lin, M. I.; Liu, Y.; Lu, X.; Liu, J.; Xu, Y.; Chen, J.; Tu, Z.; Cheng,
Y. S. E.; Ding, K. Design, Synthesis, and In Vitro Biological Evaluation of 1H-1,2,3-tri-
azole-4-carboxamide Derivatives as New Anti-influenza A Agents Targeting Virus
Nucleoprotein. J. Med. Chem. 2012, 55, 2144–2153. DOI: 10.1021/jm2013503.
[7] Bhatia, A.; Saadabadi, A. 2019 Biochemistry, Dopamine Receptors. StatPearls Publishing.
[8] Mishra, A.; Singh, S.; Shukla, S. Physiological and Functional Basis of Dopamine
Receptors and Their Role in Neurogenesis: Possible Implication for Parkinson’s Disease. J.
Exp. Neurosci. 2018, 12, 117906951877982–117906951877988. DOI: 10.1177/
1179069518779829.
[9] Mattsson, C.; Andreasson, T.; Waters, N.; Sonesson, C. Systematic In Vivo Screening of a
Series of 1-Propyl-4-Arylpiperidines Against Dopaminergic and Serotonergic Properties in
Rat Brain: A Scaffold-Jumping Approach. J. Med. Chem. 2012, 55, 9735–9750. DOI: 10.
1021/jm300975f.
[10] De Yebenes, J. G.; Landwehrmeyer, B.; Squitieri, F.; Reilmann, R.; Rosser, A.; Barker,
R. A.; Saft, C.; Magnet, M. K.; Sword, A.; Rembratt, Å.; Tedroff, J. Pridopidine for the

10
R. S. DAWOOD AND S. A. DAYL
Treatment of Motor Function in Patients with Huntington’s Disease (MermaiHD): A
Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Neurol. 2011, 10,
1049–1057. DOI: 10.1016/S1474-4422(11)70233-2.
[11] Denmark, S. E.; Cresswell, A. J. Iron-catalyzed Cross-coupling of Unactivated Secondary
Alkyl Thio Ethers and Sulfones with Aryl Grignard Reagents. J. Org. Chem. 2013, 78,
12593–12628. DOI: 10.1021/jo402246h.
[12] Ritschel, J.; Sasse, F.; Maier, M. E. Synthesis of a Benzolactone Collection Using Click
Chemistry. Eur. J. Org. Chem. 2007, 2007, 78–87. DOI: 10.1002/ejoc.200600681.
[13] Moore, K. W.; Bonner, K.; Jones, E. A.; Emms, F.; Leeson, P. D.; Marwood, R.; Patel, S.;
Patel, S.; Rowley, M.; Thomas, S.; Carling, R. W. 4-N-Linked-Heterocyclic Piperidine
Derivatives with High Affinity and Selectivity for Human Dopamine D4 Receptors.
Bioorg. Med. Chem. Lett. 1999, 9, 1285–1290. DOI: 10.1016/S0960-894X(99)00169-9.
[14] Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. A Stepwise Huisgen
Cycloaddition Process: copper(I)-Catalyzed Regioselective “Ligation” of Azides and
Terminal Alkynes. Angew. Chem. Int. Ed. 2002, 41, 2596–2599. DOI: 10.1002/1521-
3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4.
[15] Struthers, H.; Mindt, T. L.; Schibli, R. Metal Chelating Systems Synthesized Using the
Copper(I) catalyzed Azide-Alkyne Cycloaddition. Dalton Trans. 2010, 39, 675–696. DOI:
10.1039/b912608b.
[16] Liang, L.; Astruc, D. The Copper(I)-Catalyzed Alkyne-Azide Cycloaddition (CuAAC)
“Click” Reaction and Its Applications. An Overview. Coord. Chem. Rev. 2011, 255,
2933–2945. DOI: 10.1016/j.ccr.2011.06.028.
[17] Slimi, R.; Kalhor-Monfared, S.; Plancq, B.; Girard, C. A-21ꢃCuI as a Catalyst for Huisgen’s
Reaction: About Iodination as a Side-Reaction. Tetrahedron Lett. 2015, 56, 4339–4344.
DOI: 10.1016/j.tetlet.2015.05.079.
[18] Creary, X.; Anderson, A.; Brophy, C.; Crowell, F.; Funk, Z. Method for Assigning
Structure of 1,2,3-Triazoles. J. Org. Chem. 2012, 77, 8756–8761. DOI: 10.1021/jo301265t.
[19] Morris, G. M.; Huey, R.; Lindstrom, W.; Sanner, M. F.; Belew, R. K.; Goodsell, D. S.;
Olson, A. J. AutoDock4 and AutoDockTools4: Automated Docking with Selective
Receptor Flexibility. J. Comput. Chem. 2009, 30, 2785–2791. DOI: 10.1002/jcc.21256.
[20] Wang, S.; Che, T.; Levit, A.; Shoichet, B. K.; Wacker, D.; Roth, B. L. Structure of the D2
Dopamine Receptor Bound to the Atypical Antipsychotic Drug Risperidone. Nature 2018,
555, 269–273. DOI: 10.1038/nature25758.
[21] Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.;
Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28,
235–242. DOI: 10.1093/nar/28.1.235.