Synthesis and molecular docking of indole and carbazole derivatives with potential pharmacological activity

Article abstract of DOI:10.1515/hc-2014-0006

Indole and carbazole derivatives were designed as non-competitive antagonists of the GluK2 receptor. The synthesized compounds were found to interact with the transduction domain of the receptor. The binding pocket is situated within one receptor subunit.

Full text of DOI:10.1515/hc-2014-0006

ꢁꢁꢁꢂ
ꢀHeterocycl. Commun. 2014; 20(2): 103–109
DOI 10.1515/hc-2014-0006ꢀ
Agnieszka A. Kaczor*, Kalevi Pihlaja, Jari Sinkkonen, Kirsti Wiinamäki, Christiane Kronbach,
Klaus Unverferth, Tomasz Wróbel, Tomasz Stachal and Dariusz Matosiuk
Synthesis and molecular docking of indole
and carbazole derivatives with potential
pharmacological activity
Abstract: Indole and carbazole derivatives were designed activities, including anti-HIV, anticancer, antibacterial,
as non-competitive antagonists of the GluK2 receptor. The and antifungal properties [7].
synthesized compounds were found to interact with the
Ionotropic glutamate receptors are interesting drug
transduction domain of the receptor. The binding pocket is targets for pharmacological intervention. Ligands of
situated within one receptor subunit.
kainate receptors are especially interesting because
antagonists of these receptors are potential antiseizure
Keywords: carbazole derivatives; GluK2 receptor; indole and neuroprotective agents. They are usually well toler-
derivatives; kainate receptors.
ated, similar to non-competitive antagonists of AMPA
receptors [8]. The study of non-competitive antagonists of
kainate receptors is difficult due to the fact that only three
series of such compounds have been reported to date
[9–11]. We have synthesized and studied 2,3,5-trisubsti-
tuted and 1,2,3,5-tetrasubstituted indole derivatives 1–7,
which belong to most active non-competitive antagonists
of the GluK1 receptor and are the first known such ligands
of the GluK2 receptor (Figure 1) [11–13]. We have also sug-
gested a binding site for these in the receptor transduction
domain [12, 13] owing to the construction of whole recep-
tor models [12–14]. Here, we present further modifica-
tions of structures 8–14 of the lead compound E099-25011
*Corresponding author: Agnieszka A. Kaczor, Faculty of Pharmacy
with Division of Medical Analytics, Department of Synthesis and
Chemical Technology of Pharmaceutical Substances with Computer
Modeling Lab, Medical University of Lublin, 4A Chodźki St., PL-20093
Lublin, Poland; and School of Pharmacy, University of Eastern
Finland, Yliopistonranta 1, P.O. Box 1627, FI-70211 Kuopio, Finland,
e-mail: agnieszka.kaczor@umlub.pl
Kalevi Pihlaja, Jari Sinkkonen and Kirsti Wiinamäki: Department
of Chemistry, University of Turku, Vatselankatu 2, FI-20014 Turku,
Finland
Christiane Kronbach and Klaus Unverferth: Biotie Therapie GmbH,
Meissner Str. 191, D-01445 Radebeul, Germany
Tomasz Wróbel, Tomasz Stachal and Dariusz Matosiuk: Faculty
of Pharmacy with Division of Medical Analytics, Department of
Synthesis and Chemical Technology of Pharmaceutical Substances
with Computer Modeling Lab, Medical University of Lublin, 4A
Chodźki St., PL-20093 Lublin, Poland
R3
R4
R2
N
R1
1
2
3
4
1
2
3
4
5
6
7
: R = Et, R = 4-OMePh, R = Me, R = OMe
Introduction
1
2
3
4
: R = H, R = 4-OMePh, R = Me, R = OMe
1
2
3
4
: R = 4-ClBn, R = 4-OMePh, R = Me, R = OMe
The indole system is an important component of many
natural biologically active compounds including trypto-
phan, serotonin and melatonin, and synthetic drugs, such
as fluvastatin, indomethacin, indapamide, indoramin,
pindolol, sumatriptan, and tropisetron. Many known
indole derivatives exhibit anticancer [1], antipsychotic,
analgesic, and antiviral activity [2, 3]. Some indole deriva-
tives act on ionotropic glutamate receptors [4–6]. Carba-
zole derivatives are also known for their pharmacological
1
2
3
4
: R = Et, R = Ph, R = H, R = OMe
1
2
3
4
: R = Et, R = 4-OMePh, R = Me, R = H
1
2
3
4
: R = Et, R = Ph, R = Me, R = OMe
: R = Et, R , R =
, R4 = OMe
1
2
3
Figure 1ꢀThe previously obtained indole-derived non-competitive
antagonists of the GluK2 receptor.
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ꢁꢁꢁꢂ
104ꢀ ꢀA.A. Kaczor et al.: Synthesis and molecular docking of indole and carbazole derivatives
(1). Its full systematic name is 1-ethyl-5-methoxy-2-(4- The rationale towards compound 9 and 13 is an attempt
methoxyphenyl)-3-methylindole. The lead compound 1 to design a derivative with the optimized interactions with
was selected based on a search of internal databases of the binding pocket, in particular, a bigger one and more
compounds in Elbion Institute, Radebul, Germany. This rigid than in the previous series. We have also designed
compound is an analog of zindoxifene, an antiestrogen, the simplified compounds 10 and 14 and the derivative 11
tumor-inhibiting agent [15]. We have previously optimized with a longer alkyl chain at the N1 atom. Furthermore, we
compound 1 varying substituents in the indole system [10]. show how these compounds may interact with the trans-
The rationale towards compound 8 and 12 is bioisosteric duction domain of the previously constructed homology
replacement of phenyl ring with a 2-thienyl substituent. model of the GluK2 receptor [12].
R4
R3
R3
R2
R3
R4
R4
a
b
+
R2
R2
N
O
N
R1
H
NHNH2
2, 8, 10
11, 12, 14
a: EtOH/HCl, reflux
b: R1Br or (R1)2SO4, NaH, DMF
2: R1= Et, R2 = 4-OMePh, R3 = Me, R4 = OMe
8: R1= H, R2 = 2-thienyl, R3 = Me, R4 = OMe
10: R1 = H, R2 = Et, R3 = Me, R4 = OMe
11: R1 = Pr, R2 = 4-OMePh, R3 = Me, R4 = OMe
12: R1 = Et, R2 = 2-thienyl, R3 = Me, R4 = OMe
14: R1 = Et, R2 = Et, R3 = Me, R4 = OMe
Scheme 1
O
OMe
MeO
a
MeO
b
OMe
OMe
+
N
H
N
OMe
9
13
NHNH2
a: EtOH/HCl, reflux
b: EtBr, NaH, DMF
Scheme 2
Table 1ꢀStructural parameters of indole derivatives.
Table 2ꢀElectronic parameters of indole derivatives.
Compoundꢁ Surfaceꢁ Ovalityꢁ Volumeꢁ
Dipole moment, D
Components Compoundꢁ
(Å2)
(Å3)ꢁ
ꢁ
Totalꢁ
ꢁ
ELUMO
ꢁ
EHOMO
ꢁ
Charges
Sꢁ Cl
(kJ/mol) (kJ/mol)ꢁ
μx ꢁ μy ꢁ
μz
Nꢁ O/C2ꢁ O/C5ꢁ
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
343.73ꢃ 1.6637ꢃ 324.86ꢃ 3.97ꢃ -1.99ꢃ 3.01ꢃ -1.65
1
ꢃ
ꢃ
ꢃ
ꢃ
ꢃ
335.30ꢃ -695.28ꢃ -0.271ꢃ -0.455ꢃ -0.447ꢃ
332.97ꢃ -695.48ꢃ -0.036ꢃ -0.458ꢃ -0.450ꢃ
300.76ꢃ -705.94ꢃ -0.272ꢃ
278.66ꢃ -664.30ꢃ -0.196ꢃ -0.457ꢃ -0.454ꢃ
358.05ꢃ -694.67ꢃ -0.162ꢃ –ꢃ -0.462ꢃ
–ꢃ
–ꢃ
–
–
–
–
–
11
12
13
14
360.60ꢃ 1.7081ꢃ 342.99ꢃ 3.96ꢃ -1.87ꢃ 2.55ꢃ -2.37 11
304.98ꢃ 1.5973ꢃ 285.59ꢃ 2.80ꢃ -1.31ꢃ 2.46ꢃ -0.30 12
339.50ꢃ 1.6325ꢃ 329.66ꢃ 4.11ꢃ -1.30ꢃ 3.88ꢃ -0.48 13
271.50ꢃ 1.5625ꢃ 251.16ꢃ 3.13ꢃ 1.91ꢃ 2.46ꢃ 0.29 14
–ꢃ -0.459ꢃ -0.011ꢃ
–ꢃ
–ꢃ
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A.A. Kaczor et al.: Synthesis and molecular docking of indole and carbazole derivativesꢀ
ꢀ105
Results and discussion
Figure 3. The ligand-receptor complexes were found to be
stable in the short molecular dynamics run.
Chemistry
Synthesis of compounds 8–14 is presented in Schemes 1
and 2. Compounds 2 and 8–10 were obtained by Fischer
indolization reaction. Alkylation was performed with
dipropyl sulfate to obtain compound 11 or ethyl bromide
to obtain compounds 12–14. The lead compound 1 and
derivatives 2, 8–10, and 13 were previously characterized
as antiestrogens [16–19]. Compounds 12 and 14 are new.
We have previously determined that compounds 1 and 2
are non-competitive antagonists of the GluK2 receptor.
The IC50 value of both compounds is in a micromolar range
of 0.7 μm and 2.5 μm for 1 and 2, respectively [11]. Thus,
we also hypothesize that compounds 11–14 have similar
pharmacological activity.
Structural and electronic parameters for compounds
1 and 11–14 are presented in Tables 1 and 2, respectively.
The data compared to our earlier studies [11] confirm
favorable properties of the investigated compounds. All
compounds are relatively polar and have comparable size
to a slightly smaller compound 14 (Table 1). The distri-
bution of electrostatic potential in the studied deriva-
tives reveals the high electron density on oxygen atoms,
with nearly identical values in all ligands. The values of
atomic charges on the nitrogen atoms vary more: from
-0.271 for the lead compound 1 to -0.036 for compound 11
(Table 2). The significant difference between HOMO and
LUMO values (Table 2) indicates that the compounds are
nucleophilic and may participate as acceptors (through
oxygen atoms) in hydrogen bonds with the binding
pocket residues, which is in agreement with our earlier
studies [11–13].
Conclusions
Indole and carbazole derivatives, which are potential
non-competitive antagonists of the GluK2 receptor, were
synthesized and characterized. Molecular docking and
molecular dynamics of the ligand-receptor complexes
are consistent with the location of the binding site in
the receptor transduction domain within one recep-
tor subunit. The synthesized compounds are potential
prototypic new drugs for the treatment of diseases with
unbalanced glutamatergic transmission, such as neuro-
degenerative diseases (Parkinson’s disease, Alzheimer’s
disease, Huntington’s disease) and epilepsy. It should
be noted that the assumed non-competitive method of
receptor blocking is favorable for the drug profile and
may reduce side effects.
Ligand-receptor interactions
The binding site for non-competitive GluK2 receptor antag-
onists was identified in the receptor transduction domain,
that is, in the site which connects the ligand-binding
domain and the transmembrane domain (Figure 2) [20].
The interactions of compounds 11, 12, and 13 with the
GluK2 receptor are presented in Figure 3A–F, respec-
tively. The methoxy group at C5 of compound 11 forms
a hydrogen bond with the main chain of Gly756. In the
case of compound 13, one methoxy group is involved in
the hydrogen bond with the main chain of Leu755. Other
residues present in the binding pocket are also shown in
Figure 2ꢀModel of the GluK2 receptor [12].
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106ꢀ ꢀA.A. Kaczor et al.: Synthesis and molecular docking of indole and carbazole derivatives
Figure 3ꢀInteractions of compounds 11 (A, B), 12 (C, D), and 13 (E, F) with the binding pocket of the GluK2 receptor.
excitation and a 30° flip angle were employed. Recorded spectra
Experimental
were processed utilizing Bruker XWin NMR sofware applying
1 Hz exponential weighing for 13C proton-decoupled spectra. The
originally installed Bruker cosygpmfqf pulse program was used for
gradient selected DQF-COSY spectra, as was noesygpph for gradi-
Chemistry
13
ent selected NOESY spectra, hsqcetgpsisp.2 for 1H- C HSQC spectra
NMR spectra were recorded on a Bruker Avance 500 (500 MHz for
1H NMR and 125 MHz for 13C NMR) fitted with a BBO Z gradient probe.
CDCl3 was used as a solvent at 25°C with non-spinning sample and
TMS as the internal standard. During acquisition, single-pulse
1
13
and hmbcgplpndqf for H- C HMBC. The electron ionization (EI)
mass spectra were acquired on a VG ZABSpec mass spectrometer
(VG Analytical, Division of Fisons, Manchester, UK) with the Opus
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A.A. Kaczor et al.: Synthesis and molecular docking of indole and carbazole derivativesꢀ
ꢀ107
V3.3X program package (Fisons Instruments, Manchester, UK) was filtered and crystallized from ethanol. Product 11 was washed
installed.
several times with n-hexane.
Derivative 11 was obtained in 71% yield as colorless needles; mp
104–106°C; 1H NMR: δ 7.29 (d, 1H, J ꢀ= ꢀ 8 Hz), 7.23 (d, 1H, J ꢀ= ꢀ 8 Hz), 7.02
(d, 1H, J ꢀ= ꢀ 2 Hz), 7.01 (d, 1H, J ꢀ= ꢀ 8 Hz), 6.87 (dd, 2H, J1 ꢀ= ꢀ 2 Hz, J2 ꢀ= ꢀ 8 Hz),
3.93 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H), 2.19 (s, 3H), 1.61 (m, 4H), 0.73
(t, 3H, J ꢀ= ꢀ 7 Hz); 13C NMR: δ 159.2, 153.8, 138.1, 131.7, 131.5, 128.7, 124.9,
113.8, 111.3, 110.4, 108.0, 100.7, 56.0, 55.3, 45.6, 23.4, 11.4, 9.3. HR-MS.
Calcd for C20H23NO2: m/z 309.1729; found: m/z 309.1728. Anal. Calcd
for C20H23NO2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.68; H, 7.45; N, 4.56.
RF A, 0.600; B, 0.429.
General procedure for synthesis of 2 and
8–10
Ethanol (10 mL) saturated with HCl was added to a mixture of 0.05
mol of ketone and 0.05 mol of arylhydrazine hydrochloride in 100 mL
of anhydrous ethanol. The mixture was stirred under mild reflux for
4 h. Afer cooling, the mixture was lef overnight and the resulting
precipitate was filtered and crystallized from ethanol followed by
repeated washing with n-hexane. The obtained product was kept in
the dark in a fridge due to its tendency to photooxidation.
General procedure for synthesis of 12–14
5-Methoxy-2-(4-methoxyphenyl)-3-methylindole (2) Compound 2
was obtained in 79% yield as colorless crystalline needles; mp 148–
150°C; spectral characteristics are given in [11].
A solution of indole derivative 8–10 (0.01 mol) in anhydrous DMF
(30 mL) and cooled to 0°C and treated with sodium hydride (0.8 g) as
a 50% oil suspension. The mixture was stirred for 30 min at 0°C and
then treated dropwise with a solution of alkyl halide (0.012 mol) in
anhydrous DMF (20 mL) and stirred at room temperature for an addi-
tional 3 h. Then it was filtered and 10–15 mL of water was added to the
filtrate. Resin-like substance separated and an additional 25–30 mL of
water was added until a solution was formed. Afer storing for 2 h in
a refrigerator, the resulting precipitate was filtered, crystallized from
ethanol, and washed with n-hexane.
5-Methoxy-3-methyl-2-(2-thienyl)indole (8) Compound
8 was
obtained in 69% yield as colorless crystalline needles; mp 100–
1
102°C; H NMR: δ 10.82 (s, 1H), 7.47 (dd, 1H, J ꢀ= ꢀ 1.2 Hz and 5.3 Hz),
7.25 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.19 (dd, 1H, J ꢀ= ꢀ 3.6 Hz and 5.3 Hz), 7.11 (dd,
1H, J ꢀ= ꢀ 1.2 Hz and 3.6 Hz), 7.04 (d, 1H, J ꢀ= ꢀ 2.4 Hz), 6.93 (dd, 1H, J ꢀ= ꢀ
2.4 Hz and 8.8 Hz), 3.78 (s, 3H), 2.29 (s, 3H); 13C NMR: δ 157.1, 140.3,
132.5, 117.4, 111.9, 83.0, 78.3, 78.2, 76.1, 67.8, 67.5, 54.0, 36.0, 9.4; HR-MS.
Calcd for C14H13NOS: m/z 243.3282; found: m/z 243.3278. Anal. Calcd
for C14H13NOS: C, 69.10; H, 5.38; N, 5.76; S, 13.18. Found: C, 69.16; H,
5.42; N, 5.74; S, 13.14. RF A, 0.400; B, 0.457.
1-Ethyl-5-methoxy-3-methyl-2-(2-thienyl)indole (12) Compound
12 was obtained in 77% yield as colorless needles; mp 92–94°C; H
1
NMR: δ 7.46 (dd, 1H, J1 ꢀ= ꢀ 1.2 Hz, J2 ꢀ= ꢀ 5.3 Hz), 7.23 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.17
(dd, 1H, J1 ꢀ= ꢀ 3.6 Hz, J2 ꢀ= ꢀ 5.3 Hz), 7.09 (dd, 1H, J1 ꢀ= ꢀ 1.2 Hz, J2 ꢀ= ꢀ 3.6 Hz),
7.02 (d, 1H, J ꢀ= ꢀ 2.4 Hz), 6.91 (dd, 1H, J1 ꢀ= ꢀ 2.4 Hz, J2 ꢀ= ꢀ 8.8 Hz), 4.11 (q, 2H,
J ꢀ= ꢀ 7.1 Hz), 3.88 (s, 3H), 2.28 (s, 3H), 1.27 (t, 3H, J ꢀ= ꢀ 7.1 Hz); 13C NMR:
δ 153.9, 132.9, 131.5, 129.9, 128.7, 128.4, 127.2, 126.9, 112.5, 110.8, 110.3,
100.8, 56.0, 38.8, 15.7, 9.6. HR-MS. Calcd for C16H17NOS: m/z 271.1031;
found: m/z 271.1033. Anal. Calcd for C16H17NOS: C, 70.81; H, 6.31; N,
5.16; S, 11.81. Found: C, 70.75; H, 6.28; N, 5.18; S, 11.85. RF A, 0.595; B,
0.675.
3,8-Dimethoxy-5,6-dihydronaphto[1,2-b]indole (9) Compound 9
was obtained in 62% yield as colorless crystalline needles; mp 195–
1
198°C; H NMR: δ 8.03 (br, s, 1H), 7.25 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 7.25 (d, 1H,
J ꢀ= ꢀ 8.5 Hz), 6.97 (d, 1H, J ꢀ= ꢀ 2.4 Hz), 6.80 (dd, 1H, J1 ꢀ= ꢀ 2.3 Hz, J2 ꢀ= ꢀ 8.5
Hz), 6.79 (dd, 1H, J1 ꢀ= ꢀ 2.4 Hz, J2 ꢀ= ꢀ 8.8 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.04
(br, t, 2H, J ꢀ= ꢀ 7.5 Hz), 2.93 (br, t, 2H, J ꢀ= ꢀ 7.5 Hz); 13C NMR: δ 158.6, 154.3,
138.4, 134.1, 131.9, 128.0, 122.1, 120.9, 114.8, 111.6, 111.6, 111.4, 110.7,
100.4, 55.9, 55.3, 30.0, 19.7. HR-MS. Calcd for C18H17NO2: m/z 279.1259;
found: m/z 279.1258. Anal. Calcd for C18H17NO2: C, 77.40; H, 5.84; N,
5.01. Found: C, 77.49; H, 5.82; N, 5.04. RF A, 0.345; B, 0.228.
11-Ethyl-3,8-dimethoxy-5,6-dihydronaphto[1,2-b]indoleꢀ(13)
Derivative 13 was obtained in 60% yield as a colorless crystalline
(needles) solid, mp 185–187°C; 1H NMR: δ 7.45 (d, 1H, J ꢀ= ꢀ 8.5 Hz), 7.24
(d, 1H, J ꢀ= ꢀ 8.8 Hz), 6.99 (d, 1H, J ꢀ= ꢀ 7.4 Hz), 6.91 (d, 1H, J ꢀ= ꢀ 2.6 Hz), 6.85
(dd, 1H, J1 ꢀ= ꢀ 2.4 Hz, J2 ꢀ= ꢀ 8.8 Hz), 6.83 (dd, 1H, J1 ꢀ= ꢀ 2.6 Hz, J2 ꢀ= ꢀ 8.5 Hz),
4.38 (q, 2H, J ꢀ= ꢀ 7.2 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 2.94 (m, 2H), 2.86 (m,
2H), 1.51 (t, 3H, J ꢀ= ꢀ 7.2 Hz); 13C NMR: δ 158.0, 154.1, 140.3, 134.8, 133.3,
126.5, 123.1, 122.7, 115.1, 111.8, 111.5, 111.3, 110.0, 100.3, 55.9, 55.3, 39.7,
31.3, 20.1, 15.7. HR-MS. Calcd for C20H21NO2: m/z 307.1572; found: m/z
307.1582. Anal. Calcd for C20H21NO2: C, 78.14; H, 6.89; N, 4.56. Found:
C, 78.10; H, 6.85; N, 4.61. RF A, 0.470; B, 0.443.
2-Ethyl-5-methoxy-3-methylindole (10) Compound 10 was
obtained in 59% yield as colorless crystalline needles; mp 70–72°C.
1H NMR: δ 10.75 (s, 1H), 7.08 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 6.84 (d, 1H, J ꢀ= ꢀ 2.4
Hz), 6.58 (dd, 1H, J1 ꢀ= ꢀ 2.4 Hz, J2 ꢀ= ꢀ 8.8 Hz), 3.76 (s, 1H), 2.64 (q, 1H,
J ꢀ= ꢀ 7.2 Hz), 2.29 (s, 1H), 1.41 (t, 1H, J ꢀ= ꢀ 7.2 Hz); 13C NMR: δ 151.4, 135.8,
130.3, 102.5, 98.9, 97.4, 88.3, 81.8, 79.3, 66.7, 62.9, 35.9. HR-MS: Calcd
for C12H15NO: m/z 189.2584; found: m/z 189.2580. Anal. Calcd for
C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 76.21; H, 7.95; N, 7.44. RF
A, 0.266; B, 0.239.
5-Methoxy-2-(4-methoxyphenyl)-3-methyl-1-propylindole (11) A
chilled mixture of 0.4 g of sodium hydride as a 50% oil suspension
in 10 mL of anhydrous DMF was treated dropwise with a solution of 2
(1 mmol) in 10 mL of anhydrous DMF. The mixture was stirred at 0°C
for 45 min, followed by addition of 1 mmol of alkyl sulfate in 5 mL
of anhydrous DMF. Afer 20 min, the ice bath was removed and stir-
ring was continued for an additional 1.5 h at room temperature. Afer
addition of water (2 mL) the mixture was filtered. The filtrate was
cooled and combined with 20 mL of water. The resultant precipitate
1,2-Diethyl-5-methoxy-3-methylindole (14) Compound 14 was
1
obtained in 33% yield as colorless needles; mp 50–53°C; H NMR: δ
7.05 (d, 1H, J ꢀ= ꢀ 8.8 Hz), 6.81 (d, 1H, J ꢀ= ꢀ 2.4 Hz), 6.53 (dd, 1H, J1 ꢀ= ꢀ 2.4 Hz,
J2 ꢀ= ꢀ 8.8 Hz), 4.01 (q, 2H, J ꢀ= ꢀ 7 Hz), 3.70 (s, 3H), 2.61 (q, 2H, J ꢀ= ꢀ 7 Hz),
2.24 (s, 3H), 1.42 (t, 3H, J ꢀ= ꢀ 7 Hz), 1.15 (t, 3H, J ꢀ= ꢀ 7 Hz); 13C NMR: δ 160.9,
156.9, 149.3, 149.3, 136.0, 107.5, 77.0, 73.7, 59.5, 49.6, 49.3, 43.7, 33.1, 22.7.
HR-MS. Calcd for C14H19NO: m/z 217.3122; found: m/z 217.3123. Anal.
Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.44. Found: C, 77.32; H, 8.85;
N, 6.49. RF A, 0.318; B, 0.287.
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108ꢀ ꢀA.A. Kaczor et al.: Synthesis and molecular docking of indole and carbazole derivatives
Molecular modeling
used in the therapy of civilization and neoplastic diseases’
within the Operational Program Development of Eastern
Poland 2007–2013, Priority Axis I modern Economy, opera-
tions I.3 Innovation promotion. The research was partially
performed during the postdoctoral fellowship of A.A.K. at
University of Eastern Finland, Kuopio, Finland under a Marie
Curie fellowship. Computations were performed under a
computational grant by the Interdisciplinary Centre for Math-
ematical and Computational Modeling, Warsaw, Poland,
grant number G30-18. Calculations with Desmond were car-
A homology model of the GluK2 receptor was constructed, as described
previously [12]. Input conformations of the studied compounds were
obtained by applying the LigPrep protocol from the Schrödinger Suite.
To sample different protonation states of ligands in physiological pH,
the Epik module was used. Structural and electronic parameters of
the ligands were calculated with VegaZZ v.2.4.0.25 [21], Gausian09
[22], and Discovery Studio 3.1. Molecular docking was performed with
Glide from the Schrödinger Suite. Molecular dynamics of ligand-recep-
tor complexes in POPC lipid bilayer was performed with Desmond v.
3.0.3.1 [23], as described previously [12]. The following sofware was
also used for visualization of the results: Chimera v.1.5.3 [24], VegaZZ ried out under resources of the CSC, Finland. We thank Dr.
v.2.4.0.25, Yasara Structure v.11.9.18 [25], and PyMol v.0.99 [26].
Urszula Kijkowska-Murak for her help in TLC analysis.
Acknowledgments: This paper was developed using the
equipment purchased within the project ‘The equipment of
innovative laboratories doing research on new medicines Received January 19, 2014; accepted March 3, 2014
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