The indole system is an important component of many natural biologically active compounds including tryptophan, serotonin and melatonin, and synthetic drugs, such as fluvastatin, indomethacin, indapamide, indoramin, pindolol, sumatriptan, and tropisetron. Many known indole derivatives exhibit anticancer , antipsychotic, analgesic, and antiviral activity [2, 3]. Some indole derivatives act on ionotropic glutamate receptors [4–6]. Carbazole derivatives are also known for their pharmacological activities, including anti-HIV, anticancer, antibacterial, and antifungal properties .
Ionotropic glutamate receptors are interesting drug targets for pharmacological intervention. Ligands of kainate receptors are especially interesting because antagonists of these receptors are potential antiseizure and neuroprotective agents. They are usually well tolerated, similar to non-competitive antagonists of AMPA receptors . 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-trisubstituted 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 suggested a binding site for these in the receptor transduction domain [12, 13] owing to the construction of whole receptor models [12–14]. Here, we present further modifications of structures 8–14 of the lead compound E099-25011 (1). Its full systematic name is 1-ethyl-5-methoxy-2-(4-methoxyphenyl)-3-methylindole. The lead compound 1 was selected based on a search of internal databases of compounds in Elbion Institute, Radebul, Germany. This compound is an analog of zindoxifene, an antiestrogen, tumor-inhibiting agent . We have previously optimized compound 1 varying substituents in the indole system . The rationale towards compound 8 and 12 is bioisosteric replacement of phenyl ring with a 2-thienyl substituent. The rationale towards compound 9 and 13 is an attempt to design a derivative with the optimized interactions with the binding pocket, in particular, a bigger one and more rigid than in the previous series. We have also designed the simplified compounds 10 and 14 and the derivative 11 with a longer alkyl chain at the N1 atom. Furthermore, we show how these compounds may interact with the transduction domain of the previously constructed homology model of the GluK2 receptor .
Results and discussion
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 . 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  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 distribution of electrostatic potential in the studied derivatives 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].
Structural parameters of indole derivatives.
|Compound||Surface (Å2)||Ovality||Volume Å3)||Dipole moment, D|
Electronic parameters of indole derivatives.
|Compound||ELUMO (kJ/mol)||EHOMO (kJ/mol)||Charges|
The binding site for non-competitive GluK2 receptor antagonists was identified in the receptor transduction domain, that is, in the site which connects the ligand-binding domain and the transmembrane domain (Figure 2) . The interactions of compounds 11, 12, and 13 with the GluK2 receptor are presented in Figure 3A–F, respectively. 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 3. The ligand-receptor complexes were found to be stable in the short molecular dynamics run.
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 receptor subunit. The synthesized compounds are potential prototypic new drugs for the treatment of diseases with unbalanced glutamatergic transmission, such as neurodegenerative 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.
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 excitation and a 30° flip angle were employed. Recorded spectra were processed utilizing Bruker XWin NMR software 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 gradient selected NOESY spectra, hsqcetgpsisp.2 for 1H-13C HSQC spectra and hmbcgplpndqf for 1H-13C 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 V3.3X program package (Fisons Instruments, Manchester, UK) installed.
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. After cooling, the mixture was left 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.
Compound 2 was obtained in 79% yield as colorless crystalline needles; mp 148–150°C; spectral characteristics are given in .
Compound 8 was obtained in 69% yield as colorless crystalline needles; mp 100–102°C; 1H 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.
Compound 9 was obtained in 62% yield as colorless crystalline needles; mp 195–198°C; 1H 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.
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.
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. After 20 min, the ice bath was removed and stirring was continued for an additional 1.5 h at room temperature. After addition of water (2 mL) the mixture was filtered. The filtrate was cooled and combined with 20 mL of water. The resultant precipitate was filtered and crystallized from ethanol. Product 11 was washed 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 12–14
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 additional 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. After storing for 2 h in a refrigerator, the resulting precipitate was filtered, crystallized from ethanol, and washed with n-hexane.
Compound 12 was obtained in 77% yield as colorless needles; mp 92–94°C; 1H 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.
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.
Compound 14 was obtained in 33% yield as colorless needles; mp 50–53°C; 1H 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.
A homology model of the GluK2 receptor was constructed, as described previously . 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.184.108.40.206 , Gausian09 , and Discovery Studio 3.1. Molecular docking was performed with Glide from the Schrödinger Suite. Molecular dynamics of ligand-receptor complexes in POPC lipid bilayer was performed with Desmond v. 220.127.116.11 , as described previously . The following software was also used for visualization of the results: Chimera v.1.5.3 , VegaZZ v.18.104.22.168, Yasara Structure v.11.9.18 , and PyMol v.0.99 .
This paper was developed using the equipment purchased within the project ‘The equipment of innovative laboratories doing research on new medicines used in the therapy of civilization and neoplastic diseases’ within the Operational Program Development of Eastern Poland 2007–2013, Priority Axis I modern Economy, operations 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 Mathematical and Computational Modeling, Warsaw, Poland, grant number G30-18. Calculations with Desmond were carried out under resources of the CSC, Finland. We thank Dr. Urszula Kijkowska-Murak for her help in TLC analysis.
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