Synthesis and in silico and in vivo anticonvulsant activities of substituted 2-phenyl indole derivatives

doi:10.21203/rs.3.rs-5185129/v1

In this study, a series of indole-based derivatives (2a to 2f) were synthesized, followed by a main base reaction from the starting material, phenylhydrazine, and substituted acetophenone in glacial acetic acid, and all the synthesized structures were characterized by IR, NMR, and mass spectrometry. The anticonvulsant activities of the synthesized derivatives were subsequently screened using a maximal electroshock model. Compounds 2b, 2c and 2e exhibited moderate activity against the extensor seizure phase compared with the standard drug phenytoin sodium. To determine the mechanism of action of the synthesized compounds, a docking study was performed against gamma-butyric acid (a GABAA receptor), and the AMPA-sensitive glutamate receptor was shown to have good binding interactions. 2b, 2c, and 2c exhibited good binding energies for AMPA. Among the six synthesized compounds, 2b, 2c, and 2e were found to possess optimum to excellent in silico ADME properties. Substituted 2-phenylindole derivatives also increase the therapeutic value of 2-phenylindole cores for the discovery of potent anticonvulsive agents. Thus, we observed that 2-phenylindole in combination with other heterocycles might be used as a lead compound for further study and for developing such compounds as suitable lead molecules with improved pharmacological profiles.

Medicinal Chemistry

Anticonvulsant

Indole

In silico

MES

ADME

An indole is an organic compound in which the benzene and pyrrole rings are fused at the 2nd and 3rd positions of the pyrrole ring. The indole ring is almost certainly the most ubiquitous heterocycle in nature and is a weak base with various biological activities. Indole heterocycles are of great interest among many naturally occurring compounds as well as pharmaceutical agents in the fields of anti-inflammatory, antidepressant, antihypertensive, antihyperlipidemic, antiosteoporosis and anti-HIV agents. The 2-phenylindole ring system is almost certainly the most versatile heterocyclic in nature.^1,2,3,4 Among the various indole derivatives, the 2-phenyl derivative is an effective scaffold for different activities. As they can bind to a wide range of highly excited receptors, substituted indoles have been described as confidential structures. In total, the fusion and functionalization of 2-phenylindoles has been a primary area of interest for organic chemists for more than 100 years, and many techniques are being used to research indoles. In some cases, the typical reaction of indole formation still makes it difficult to find particular substitution patterns; therefore, general methods viz. The Fischer indole reaction, the Madelung reaction, the Martinet reaction, the Bartoli reaction and the Reissert synthesis are the methods used for emergence.^{5, 6, 7} Fisher indole is a common method for the synthesis of compounds in which indole nuclei are formed during the heating of phenylhydrazones containing aldehydes, ketones and ketonyl acids.

Epilepsy is a long-term neural condition caused by repeated spontaneous seizures and other transient symptoms caused by excessive, synchronous, or aberrant brain neuronal activity.⁸

It affects more than 50 million people, i.e., approximately 1–2% of the population worldwide. Among every one thousand people, one died from sudden unexpected death in epilepsy (SUDEP). Epidemiologically, 80% of epileptic patients were found to come from developing areas.⁹

Although the pathophysiology of seizures is not completely understood, glutamate, the main excitatory neurotransmitter, causes seizures by being produced excessively and binding to its receptors, particularly NMDA and AMPA. On the other hand, inhibition of this pathway occurs when inhibitory interneurons release the gamma-aminobutyric acid (GABA). These seizures can be prevented by drugs that inhibit a glutamate receptor or increase GABA function.¹⁰

Molecules modified with indole fragments are resistant to metabolic degradation and chemical oxidants during biological transformation. Therefore, Indole tends to reduce the side effects of drugs to increase bioavailability and lipophilicity. Conformational analysis of synthesized drugs also suggested that any good antiepileptic drugs must have pharmacophoric features, e.g., an aryl hydrophobic region, a hydrogen bond donor/acceptor, an electron donor and a distal hydrophobic region, as shown in Fig. 1. Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the CNS. GABA is synthesized in the brain during the Krebs cycle. GABA acts by inhibiting and activating specific ionotropic or metabotropic receptors on both pre- and postsynaptic membranes. The importance of chemical drugs designed in this direction has increased due to their compatibility. Their models utilized small sets of in vivo ADME data. The pharmacokinetic profiles of the synthesized compounds, i.e., absorption, distribution, metabolism, and excretion (ADME), were predicted using the Swiss ADME model and the pKCSM online server. Computational methods and the prediction of many physiochemical and pharmacokinetic (absorption, distribution, metabolism, and excretion) properties of potential drugs are approaches for the drug development process to save time, effort, and money. The term “drug likeness” denotes the consistency of the relationship between structural characteristics and various molecular properties that determine drug discovery and production.^{11, 12}

Thus, this is the first report on the use of 2-phenyl indole derivatives as anticonvulsant drugs.

All the solvents and chemicals used were purchased from Loba Cheme Pvt. Ltd., Central Drug House and Thermo Fischer Scientific, India Pvt. IR, ¹H NMR and mass spectra were recorded by an Agilent Cary 630 FTIR, a Brucker Avance 400/AVIII HD 300 (FT-NMR) and Water Alliance.

2.1 Synthesis of 2-phenylindole

2.1.1 General procedure for the synthesis of 2-phenylindole

A combination of 2.0 g (0.0167 mol) of different acetophenone derivatives and 1.8 g (0.0167 mol) of different phenyl hydrazine derivatives with 6.0 ml of ethanol and 2–3 drops of glacial acetic acid will be added and warmed. The cold reaction mixture was filtered and washed with dilute HCl, followed by the addition of approximately 12 ml of cool rectified spirit. Recrystallization was performed with ethanol to obtain pure acetophenone phenylhydrazone.

Briefly, 2.8 g of crude phenylhydrazone was added to 12.85 g (0.143 mol) of polyphosphoric acid and maintained at 100-120⁰C for 10–20 minutes. Cold water (32.14–40.20 ml) was added, the mixture was stirred well to obtain a complete solution of polyphosphoric acid, which was filtered and washed with water. The crude solid was refluxed with 21.42 ml of rectified spirit; a little decolorizing charcoal was added, and the mixture was filtered and washed with 40 ml of hot rectified spirit to obtain 2-phenylindole. The reaction was monitored by TLC until the completion of the reaction. Compound purity was assessed by a recoated TLC plate, and n-hexane–ethyl acetate (9:1) was used as the developing solvent. The spots were subjected to UV light, and the melting point and spectral information (FT-IR, MS, ¹H and ¹³C-NMR) were applied to characterize all the synthesized compounds (2a to 2f).^{5,6, 13, 14,15,16,17} The recrystallized compound was purified by column chromatography on a silica gel 60–120 mesh (hexane/ethylacetate-90:20).

2.1.2 Synthesis of 2-(4-bromophenyl)-4chloro-1H-indole [2a]

FT-IR (cm ^− 1 )-NH stretching 3500 − 3100, C-H stretching 3000–3100, C = C and C-C stretching 1440–1625 and 1185–1600, N-H bending-1400-1410.

¹H NMR [DMSO-d6] δ (ppm): 6.77 (s, CH-indole, 1H), 6.81–7.55 (m, Ar-indole, 3H), 7.66–7.78 (m, Ar-CH, 4H), 11.36 (s, NH-indole, 1H).

¹³C NMR [300 MHz, DMSO-d6] δ (ppm): 136.047, 132.11, 132.66, 130.06, 129.812, 129.396, 128.816, 128.563, 127.262, 114.587

MS-ESI [M⁺]: 306.6 (70%)

2.1.3 Synthesis of 4-chloro-2(3,4-dimethoxyphenyl)-1H-indole [2b]

¹H NMR [DMSO-d6] δ (ppm): 3.83 (d, Ar-OCH₃, 6H), 6.77 (s, CH-indole, 1H), 6.81–7.55 (m, Ar-indole, 3H), 6.94–725 (m, Ar-CH, 3H), 11.36 (s, NH-indole, 1H)

¹³C NMR [300 MHz, DMSO-d6] δ (ppm): 137.6, 136.912, 100.003, 125.806, 126.7, 150.3, 149.811, 109.213, 130.233, 108.398, 120.111, 111.011, 122.812, 120.812, 56.121

FT-IR (cm^− 1) C-Cl (aromatic) 690, C-N stretching 1253.57, C = C (aromatic) 1464.96, C-C (aromatic) 1591.20, C-OCH₃ (aromatic) stretching 2836, C-H (aromatic) 3003.75, N-H (amine) stretching 3362.96.

MS-ESI [M⁺]: 288.37 (86%)

2.1.4 Synthesis of 4-bromo-2(3,4-dimethoxyphenyl)-1H-indole [2c]

C-Br (aromatic) 667.97 cm^− 1 C-N stretching 1348.57 cm^− 1 C = C (aromatic) 1462.61 cm^− 1 C-C (aromatic) 1609.20 cm^− 1 C-OCH₃ (aromatic) stretching 2841.57 cm^− 1 C-H (aromatic) 3012.75 cm^− 1 N-H (amine) stretching 3362.96 cm^− 1

¹H NMR [DMSO-d6] δ (ppm): 3.83 (d, Ar-OCH₃, 6H), 6.77 (s, CH-indole, 1H), 6.88 (s, CH-indole, 1H), 6.94–7.25 (m, Ar-CH, 3H), 7.50–761 (d, Ar- CH-Indole, 2H), 11.36 (s, NH- Indole, 1H)

¹³C NMR [300 MHz, DMSO-d6] δ (ppm): 137.712, 137.612, 100.003, 130.406, 112.671, 150.3, 149.811, 110.113, 130.233, 108.398, 120.111, 111.011, 122.412, 120.812, 56.12

MS-ESI [M⁺]: 332.31 (62%)

2.1.5 Synthesis of 4-chloro-2(3-nitrophenyl)-1H-indole [2d]

C-Cl (aromatic) 771.97 cm^− 1 C-N stretching 1348.57 cm^− 1 C = C (aromatic) 1462.61 cm^− 1 C-C (aromatic) 1609.20 cm^− 1 C-NO₂ (aromatic) stretching 1517.45 cm^− 1 C-H (aromatic) 2918.04 cm^− 1 N-H (amine) stretching 3364.96 cm^− 1

¹H NMR [DMSO-d6] δ (ppm): 6.77 (s, CH-indole, 1H), 6.81–7.55 (m, CH-indole, 3H), 7.77–8.65 (m, Ar-CH, 4H), 11.36 (s, NH-indole, 1H).

¹³CNMR [300 MHz, DMSO-d6] δ (ppm): 137.731, 137.611, 133.939, 131.478, 130.506, 129.474, 128.824, 124.288, 122.414, 122.164, 119.562, 119.132, 113.110.

MS-ESI [M⁺]: 272.32 (75%)

2.1.6 Synthesis of 4-(4-bromo-1H-indole-2-yl) benzenamine [2e]

C-Br (aromatic) 771.97 cm^− 1 C-N stretching 1348.57 cm^− 1 C = C (aromatic) 1462.61 cm^− 1 C-C (aromatic) 1609.20 cm^− 1 C-NH₂ (aromatic) stretching 1517.45 cm^− 1 C-H (aromatic) 2918.04 cm^− 1 N-H (amine) stretching 3364.96 cm^− 1

¹H NMR [DMSO-d6] δ (ppm): 6.27 (s, NH_2, 2H), 6.58–7.54 (m, CH, 4H), 6.77 (s, CH-indole, 1H), 6.88–7.61 (m, Ar-CH-indole, 3H), 11.36 (s, NH-indole, 1H)

¹³C NMR [300 MHz, DMSO-d6] δ (ppm): 137.612, 137.711, 100.003, 130.41, 123.900, 112.911, 145.611, 110.100, 125.600, 115.111, 128.300, 123.2, 115.111, 122.400, 128.311

MS-ESI [M⁺]: 289.3 (100%)

2.1.7 Synthesis of 4-bromo-2-(3-nitrophenyl)-1H-indole [2f]

C-Br (aromatic) 586.37 cm^− 1 C-N stretching 1347.05 cm^− 1 C = C (aromatic) 1462.61 cm^− 1 C-C (aromatic) 1609.20 cm^− 1 C-NO₂ (aromatic) stretching 1524.03 cm^− 1 C-H (aromatic) 2996.64 cm^− 1 N-H (amine) stretching 3359.06 cm^− 1

¹H NMR [DMSO-d6] δ (ppm): 6.77 (s, CH-indole, 1H), 6.88–7.61 (m Ar-CH-indole, 3H), 7.77–8.65 (m, Ar-CH-, 4H), 11.36 (s, NH-indole, 1H).

¹³C NMR [300 MHz, DMSO-d6] δ (ppm): 137.712, 137.612, 100.003, 130.41, 123.900, 112.911, 148.421, 110.100, 136.800, 103.511, 123.233, 122.4, 129.511, 122.711

MS-ESI [M⁺]: 318 (72%)

2.2a Molecular docking: To determine the probable binding poses of the synthesized compound against GABA and the AMPA receptor inhibitor. The molecular docking study was carried out by Schrödinger, USA. The X-ray crystal structures were obtained from the RCSB databank (1FTL and 4COF). The ligand structure was prepared by ChemDraw professional 16.0 in .sdf. The protein was imported into a Schrödinger virtual docker, and the crystal structure was prepared by removing water and optimizing the structure by missing amino acids. The binding site of the small molecule was described by selecting the reference ligands phenytoin and phenobarbitone.17, 18

2.2b In silico toxicity prediction

. pkCSM-pharmacokinetics was used to predict and optimize the ADME/Tox characteristics of small molecules using experimental data and graph-based signatures.

2.3 Anticonvulsant activity (in vivo) of maximal electroshock seizures (MES method)

The animals were randomly divided into eight groups, and each individual group consisted of five animals once the acclimatization period had been completed. Swiss albino mice were stimulated by corneal electrodes with an approximately 50 mA pulse of 50 Hz alternate current for 0.1 second. A 0.9% sodium chloride drop was injected into each eye before the rods were applied to avoid animal death. In mice, anticonvulsant activity was evaluated 1 h after oral administration of the test drug dissolved in a 0.5% CMC suspension at 100 mg/kg intervals. Anticonvulsant activity was measured by removal of tonic extensor spasm in the hind limbs. Phenytoin was used as a standard drug.

Swiss albino mice (25–35 g body weight) were used in Winter et al.'s study to examine the anticonvulsant properties of the synthesized compound (2a to 2f). The animals were randomly assigned to eight groups, each with five animals. Group I was the disease control group and was given 0.5 ml/mg/kg in a 0.5% solution of CMC. Group II was given phenytoin medication solution (1.0% in sterile water) via the intraperitoneal (i.p.) method while remaining standard. Moreover, compounds in groups III through VIII had an oral dosage of 100 mg kg-1 (suspended in 0.5% CMC). The mice were given an intraperitoneal injection of phenytoin solution after a one-hour period. The MES technique was used to induce seizures at 50 Hz for 0.2 seconds, and the various seizure stages were noted.¹⁸

2.4 Statistical analysis

The results are expressed as the mean ± SEM. GraphPad Prism 5 software was used to compare the data between the experimental groups using one-way ANOVA and Student’s t test. The import level was set at ***p ≤ 0.001, and Tukey's post hoc test was used.

3.1 Chemistry

The synthesis of 2-phenylindole derivatives was achieved through a 2-step process using standard techniques, including refluxing. First, we synthesized (E)-1-phenyl-2-(1-phenylethylidene) hydrazine using a previously reported procedure (Scheme 1). We then added polyphosphoric acid and refluxed it with ethanol to produce 2-phenylindole. This study revealed that temperature is an important parameter, so that the reaction does not proceed under intermediate conditions. In addition, the solvent also affects the course of the reaction. Yields are obtained better in the presence of highly polar solvents, viz. ethanol and methanol with high polarity where the solubility is strong. We evaluated the purity of the synthesized compounds using precoated TLC plates and subjected the spots to UV light. Spectral FT-IR, MASS, and ¹H NMR were used to characterize the synthesized compounds (2a to 2f), and the various physiochemical parameters, such as melting point, physical state, and solubility, are listed in Table S1.

Table 1 shows that substituted phenylhydrazine and acetophenone were converted to 2-phenyl indole derivatives under optimum conditions. For example, the substrates 4-chloro-phenylhydrazine 1a and 4-bromoacetophenone 1a were converted to 2-(4-bromophenyl)-4chloro-1H-indole 2a in 74.4% of the products within 3 hr (Table 1, entry 1). 4-Chlorophenylhydrazine (1a) and 3,4-dimethoxyacetophenone 1b were converted to 4-chloro-2(3,4-dimethoxyphenyl)-1H-indole 2b (79.36%) within 3 hr 30 min (Table 1, entry 2). 4-Bromo-phenylhydrazine (1b) and 3,4-dimethoxyacetophenone (1b) were converted to 4-bromo-2 (3,4-dimethoxyphenyl)-1H-indole (2c) with 73.68% yield within 3 hr20 min (Table 1, entry 3). 4-Chlorophenylhydrazine (1a) and 4-nitroacetophenone 1c (77.54%) were generated within 3 hr (Table 1, entry 4). 4-

Bromophenylhydrazine (1b) and 4-aminoacetophenone (1d) converted 4-(4-bromo-1H-indole-2-yl) benzamine to 50.74% within 2 h 50 min (Table 1, entry 5). 4-Bromophenylhydrazine (1b)

and 3-nitrophenylacetophenone (1f) converted 4-bromo-2-(3-nitrophenyl)-1H-indole 2f to 76.11% within 3 hr (Table 1, entry 6).

3.2 Anticonvulsant activity

The anticonvulsant activities of six new compounds, i.e., the 2-phenylindole scaffold, were evaluated. Epilepsy is one of the most challenging neurological problems in society.

The MES seizure model was used to conduct an initial assessment of every synthesized compound. The anticonvulsant efficacy of all the substances was good. Compounds 2b, 2c, and 2e showed the highest level of activity against the MES test at a dose of 100 mg/kg. Maximum inhibition of the extensor phase was observed with phenytoin, which was used as a standard. Therefore, all the synthesized compounds were evaluated for their anticonvulsant activity. The in vivo anticonvulsant effect of the new 2-phenylindole was explored using an MES model. The mice were intraperitoneally injected with standard phenytoin solution after a one-hour period via maximal electroshock seizures (MESs) induced at 50 Hz for 0.2 seconds. and noted the various seizure stages. The most potent compounds were found to be 2b, 2c, and 2e, as shown in Fig. 2.

2b, 2c and 2e were found to have maximum potential, while 2d and 2f were found to be less potent against phenytoin sodium at significant ***(p = 0.001) when the maximal electroshock-induced seizure (MES) method was used for pharmacological evaluation.

The structural relationship of the synthesized compound showed that the substitution of methoxy, nitro and amino groups on the distal aryl ring had the most potent activity, as shown in Fig. 1. Substitution of the phenyl ring at R₂ and R₃ with methoxy, nitro and amino groups results in potent activity because the electron-donating group forms a hydrogen bond with the target protein, and the lipophilicity of the distal aryl groups increases, which is required for activity. The presence of other aryl groups and indoles is involved in the formation of hydrophobic bonds, as shown in Fig. 1.^{19, 20, 21}

3.3 In silico docking study

A docking study was conducted to determine the different binding interactions of synthetic compounds of well-known antiepileptic drugs against targets, such as GABA and the AMPA receptor. The comparative analysis of different targets also contributed to the development of tested drugs as anticonvulsants. All the synthetic compounds showed in vivo anticonvulsant activity and were selected for molecular docking studies. The binding energies of the synthesized compounds are shown for the selected targets in Table 2. All the active compounds had binding energies against 1FTL ranging from − 5.139 to -5.879 kcal/mol, which are comparable to those of the standard drugs phenytoin (-6.049 kcal/mol) and phenobarbitone (-6.491 kcal/mol). However, interactions between the synthesized compound and other targets are not substantial. Figure 3 shows that the methoxy groups in compounds 2b and 2c form one hydrogen bond with the amino acid residue glu A::13 and serine A:142. 2b and 2c also form halogen bonds with the amino acid residue THR A:143 and 147 and pi-pi stacking with the amino acid residue Tyr A:61. The nitro groups in compounds 2d and 2f exhibited one hydrogen bond with the amino acid residues TYR A:220 and TYR A:220. All the above data confirmed good interactions between the tested compounds and their targets. All the above information showed that the synthesized compounds have good antiepileptic properties and that they act through AMPA (1FTL), the standard drug. Hence, it has been concluded that this is a possible mechanism of action of anticonvulsant activity.

Table 2

Binding energies of synthesized compound (2a-2f) against GABA_A and AMPA receptor
S.N.	Compounds	Binding energies (Kcal/mol)	Amino-acid residue
		AMPA (1FTL)
1.	2a	-5.139	TYR A:61, THR A:174
2.	2b	-5.749	TYR A:61, THR A:143, GLU A:13
3.	2c	-5.699	TYR A:61, THR A:174, SER A:174
4.	2d	-5.351	ARG A:96, TYR A:220
5.	2e	-5.879	TYR A:61, THR A:174
6.	2f	-5.749	TYR A:220, ARG A:96
7.	Phenytoin	-6.049
8.	Phenobarbitone	-6.491

3.4 In silico toxicity study

There are many free computer programs available that can predict the potential toxicity of a compound using in silico methods. These tools include the LAZAR and pkCSM tools, which were used for the subsequent analyses. The LAZAR and pkCSM tools for predicting complex toxicological endpoints, such as reproductive toxicity, carcinogenicity, long-term toxicity, AMES toxicity, and hepatotoxicity, were used. This generates several drug-related chemical structural characteristics, such as certain toxicity parameters and drug homology. The open-source pkCSM-pharmacokinetics online tool uses experimental data and graph-based signs to predict and optimize the ADME/Tox features of small particles. The results that are predicted are grated and color-coded. Red indicates potential harm, and green indicates drug-conforming behavior.¹⁸

In silico prediction of the pharmacokinetics of the synthesized compounds (L-a to L-f) was performed with free Swiss-ADME and pkCSM software, and the results are summarized in Tables 2 to 3. Additionally, the LAZAR and pkCSM tools accurately predicted complex toxicologic endpoints, such as reproductive toxicity, carcinogenicity, continuing toxicity, AMES toxicity, and hepatotoxicity, and the results are shown in Table S2. Furthermore, in silico prediction of the pharmacokinetic properties of the synthesized compounds (2a to 2f) was based on substructure pattern identification and predicted with the help of various computational tools, such as the Swiss-ADME and pkCSM online servers. The relevant ADMET attributes calculated and the results summarized in STables 2 to 3 showed that all the prepared derivatives, particularly the most active candidates 2b, 2c, and 2e, were found to possess optimum to excellent in silico ADME properties. None of the compounds violated Lipinski’s rule of five, indicating optimal or good CNS-related parameters; therefore, these compounds exhibit commendable BBB penetration, excellent human oral absorption, and oral bioavailability.

This showed an average to good performance for most of the synthesized derivatives; in particular, the more active derivatives were found to be completely free from potential toxicity risks. Therefore, most of the predicted ADMET properties fell within the acceptable range for drug candidacy, thus minimizing the risk of failure for such compounds in later stages of drug discovery and development.

The study showed that 2-phenylindole in combination with other heterocycles might be useful as a lead compound for identifying potent anticonvulsive agents. The potency of the newly synthesized compounds was determined based on their reduction in convulsive effects at different time intervals by using the maximal electroshock-induced seizure (MES) method in 3 mice, which differed significantly from that of the standard phenytoin sodium drug.

Substituted 2-phenylindole derivatives also increase the therapeutic value of 2-phenylindole cores for the discovery of potent anticonvulsive agents. Thus, we observed that 2-phenylindole in combination with other heterocycles might be used as a lead compound for further studies on developing such compounds as suitable lead molecules with improved pharmacological profiles.

Conflict of interest

The authors have no conflicts of interest.

Acknowledgment

The authors are thankful to the Hygia Institute of Pharmaceutical Education and Research, Lucknow, for providing facilities for animal activity and for providing IR, NMR, and mass spectrometry from CDRI and Lucknow.

Animals were approved by IAEC, Hygia Institute of Pharmaceutical Education and Research, Lucknow.( HIPER/IAEC/122/03/2023)

Vitaku E, Smith D T and Ardarson J T 2014 Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among US FDA Approved Pharmaceuticals: Mini Perspective J. Med. Chem. 57 10257–10274. DOI: 10.1021/jm501100b.
Sharma V, Kumar P, Pathak D 2010 Biological Importance of the Indole Nucleus in Recent Years: A Comprehensive Review J. Heterocycl. Chem. 47 491–502.
Sundberg R J 1970 The Chemistry of Indoles Academic Press, New York.
4. Evans BE, Rittle KE, Bock MG, Dipardo RM, Whitter WL, Gould NP, Lundell GF, Homnick CF and Veber DF 1988 Methods for drug discovery: development of potent, selective, orally effective cholecystokinin anatagonists J. Med. Chem. 31(12) 2235:2246.
Gribble G W 2000 Recent developments in indole ring synthesis. J Chem Soc. Perkin trans 1 1 1045-1075.
Haag BA, Zhang Z, Li G, J. S Knochel, P 2010 Fischer Indole Synthesis with Organo zinc Reagents. Angew Chem. Int. Ed. 49 9513–9516. DOI: 10.1002/anie.201005319.
Inman M, Carbone A and Moody C J 2012 Two-Step Route to Indoles and Analogs from Haloarenes: A Variation on the Fischer Indole Synthesis J. Org. Chem. 77 1217–1232. DOI: 10.1021/jo201866c.
Fiest KM, Birbeck GL, Jacoby A and Jette N 2014 Stigma in epilepsy. Curr. Neurol. Neurosci. Rep. 14 444.
Engel J, Pedley T and Aicardi J 2008 Epilepsy: a comprehensive textbook, Philadelphia (2^nd ed.) (Lippincott Williams & Wilkins) p.1-13.
Yu Y, Li W and Jiang J 2022 TRPC channels as emerging targets for seizure disorders. Trends in pharmacol. sci. 40(9) 787-798.
Sweidan K, Sabbah D A, Bardaweel S, Dush K A, Sheikha G A and Mubarak M S 2016 Computer-Aided Design, Synthesis, and Biological Evaluation of New Indole- Carboxamide Derivatives as PI3Ka/EGFR Inhibitors. Bioorg. Med. Chem. Lett. 26 2685–2690. DOI: 10.1016/j.bmcl.2016.04.011
Villa D, Xavier F, Durán-Iturbide NA and Ávila-Zárraga JG 2021 Synthesis, molecular docking, and in silico ADME/Tox profiling studies of new 1-aryl-5-(3-azidopropyl) indol-4-ones: Potential inhibitors of SARS CoV-2 main protease Bioorg chem. 106 104497.
Fischer E and Liebigs J 1886 Synthese von Indole derivaten, Justus Liebigs Ann. Chem. 236 116–126. DOI: 10.1002/jlac.18862360106.
Humphrey GR and Kuethe JT 2006 Practical Methodologies for the Synthesis of Indoles. Chem. Rev. 106 2875–2911. DOI: 10.1021/cr0505270.
Wagaw S, Yang BH and Buchwald SL 1999 A Palladium-Catalyzed Method for the ,Preparation of Indoles via the Fischer Indole Synthesis J. Am. Chem. Soc. 121 10251–10263. DOI: 10.1021/ja992077x.
Xu DQ, Wu J, Luo SP, Zhang JX, Wu JY, Du XH and Xu ZY 2009 Fischer Indole Synthesis Catalyzed by Novel SO₃H-Functionalized Ionic Liquids in Water Green Chem. 11 1239–1246. DOI: 10.1039/b901010f.
Inman M and Moody CJ 2013 Indole Synthesis–Something Old, Something New. Chem Sci. 4 29–41. DOI: 10.1039/C2SC21185H
Krall RL, Penry JK, White BG and Kupferberg HJ 1978 Antiepileptic Drug Development:II. Anticonvulsant Drug Screening, Epilepsia 19 409. https://doi.org/10.1111/j.1528-1157.1978.tb04507.x
Kamal M, Jawaid T, Dar U A and Shah S A 2021 Amide as a Potential Pharmacophore for Drug Designing of Novel Anticonvulsant Compounds Chem. Biol. Potent Nat. Prod. Synth. Compd. 319−342.
Sahu M, Siddiqui N, Naim MJ, Alam O, Yar MS, Sharma V and Wakode S 2017 Design, synthesis, and docking study of pyrimidine−triazine hybrids for GABA estimation in animal epilepsy models Arch. Pharm. 350 1700146.
Lal S, J Snape T. 2012 2-Arylindoles: A Privileged Molecular Scaffold with Potent, Broad-Ranging Pharmacological Activity. Cmc. 19 4828–4837. DOI: 10.2174/092986712803341449.
Singh H, Kumar R, Mazumder A, Yadav RK, Chauhan B, Datt V, Shabana K, Abdullah M 2022 Design, synthesis, in vivo and in silico evaluation of novel benzothiazole-hydrazone derivatives as new antiepileptic agents. Med. Chem. Res. 31 1431−1447.

Table 1 is available in the Supplementary Files section.

Scheme 1 is available in the Supplementary Files section.

The authors declare no competing interests.

Supplementaryfile.docx
Synthesis and in silico and in vivo anticonvulsant activities of substituted 2-phenyl indole derivatives
Scheme1.png
Scheme 1 Synthesis of 2-phenylindole via the Fischer indole method
Table1Synthesisofvarious2.docx

Synthesis and in silico and in vivo anticonvulsant activities of substituted 2-phenyl indole derivatives

Status:

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Abstract

Figures

1. Introduction

2. Experimental