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. 2023 Sep 20;8(39):36401–36411. doi: 10.1021/acsomega.3c05293

Efficient Green Synthesis, Anticancer Activity, and Molecular Docking Studies of Indolemethanes Using a Bioglycerol-Based Carbon Sulfonic Acid Catalyst

Sailam Sri Gogula †,‡, Dasari Vijaya Prasanna ‡, Vishnu Thumma §, Sunil Misra ∥, Ch Abraham Lincoln †, P Muralidhar Reddy †,*, Anren Hu ⊥,*, B V Subbareddy ‡
PMCID: PMC10552104  PMID: 37810649

Abstract

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Indolemethane derivatives are significant molecules in the study of N-heterocyclic chemistry. Herein, we designed and developed a highly efficient green synthesis of indolemethane compounds using a recyclable biodegradable glycerol-based carbon solid acid catalyst under solvent-free conditions at room temperature for 5 min with excellent yields. The synthesized compounds were subjected to cytotoxic activity against prostate (DU145), hepatocellular carcinoma (HepG2), and melanoma (B16) cell lines. The highest cytotoxicity effects were found with 1k (1.09 μM) and 1c (2.02 μM) against DU145, followed by 1a, 1d, 1f, 1n, and 1m between 5.10 and 8.18 μM concentrations. The anticancer activity is validated using molecular docking simulations, and comparing binding energies with the standard drug doxorubicin suggests that the title compounds are well fitted into the active site pocket of the target molecules..

Introduction

Indolemethane (IM) derivatives also known as bisindolylmethanes (BIMs) or diindolylmethanes (DIMs) are diverse molecules and the most active chemicals in the study of N-heterocyclic chemistry.1–5 BIMs exhibit a wide range of biological characteristics, such as antimicrobial, antifungal, antibacterial, antiviral, anti-inflammatory, antioxidant, analgesic, and radical scavenging activities.6–10 They have considerable medicinal applications (Figure 1), and they are prevalent in natural compounds and are essential in the treatment of many malignancies, including breast,11 colon,12 prostate,13 and pancreatic cancer.14 Over the past several decades, their use in drug development has increased, making them a vital part of different protocols.15 Numerous methods use conventional catalysts, which are poisonous, expensive, dangerous, difficult to handle, thermally unstable, and non-reusable.16–19 Hence, researchers are creating methods for green synthesis using ecologically friendly reagents to reduce costs, dangers, waste, and energy. Green synthesis uses solvent-free conditions or solvents such as water, glycerol, and ethylene glycol and also uses unconventional processes like grinding, microwave irradiation, and ultrasound methods.20–22

Figure 1.

Figure 1

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Medicinally important indolemethane compounds.

Solid acid catalysts have been vital in the development of numerous techniques and catalysts used by researchers for organic conversions.23 In comparison to traditional homogeneous acid catalysts, heterogeneous solid acids have the benefit of being readily recovered and reused without losing effectiveness.24 Homogeneous liquid-phase mineral acids have been supplanted by carbon-based heterogeneous solid catalysts containing sulfonic acid due to their efficiency and reusability.25,26 These catalysts have faster reaction time, greater yield, and less pollution. We used the glycerol-based carbon sulfonic acid catalyst. It is a cost-efficient, eco-friendly, and potent catalyst in synthetic organic chemistry. It does not require column separation, catalyzes various reactions, and transforms organic functional groups. Prabhavathi et al.27,28 recommended using a sulfonic acid functionalized polycyclic fragrant carbon catalyst in order to recycle bioglycerol and glycerol pitch without losing much of its activity. This eco-friendly method has fast reaction rates, excellent yields, and little cleanup. Bio-glycerol-based carbon sulfonic acid is tested as an efficient catalyst for solvent-free synthesis of novel bisindolylmethane derivatives. Another potent and recyclable catalyst we used is bromodimethylsulfonyl bromide (BDMS), developed by Meerwein et al. in 1965. It catalyzes various brominating reactions and also transforms organic functional groups. Due to its inexpensive and safe handling, BDMS has gained extensive interest in organic synthesis.29–31

The significance of the indolemethane moiety attracted the attention of researchers, who used a variety of standard and unconventional techniques for the accomplishment. They employed different metal catalysts32–36 and nonconventional methods utilizing baker’s yeast,37 aromatic bromomethyl groups,38 meglumine-catalyzed,39 titanium(IV) salophen-catalyzed,40 sodium trifluoromethanesulfonate-mediated,41 and enzymatic approaches.42 Copper nanoparticles43 and the polyaniline sulfonic acid catalytic approach44 are the most recent notable reports. Although several methods are established, the majority of them suffer from any of the following disadvantages: long reaction times, unsatisfactory yields, use of organic solvents, and non-recyclability. A better catalytic approach is much needed to address these issues.

Results and Discussion

Chemistry

Despite the numerous approaches, we explored methods to address the aforementioned drawbacks in the synthesis of diindolylmethane derivatives under solvent-free, eco-friendly conditions utilizing simple, inexpensive, and easily available catalysts. Herein, we employed the bromodimethylsulfonyl bromide catalyst to produce BIM derivatives in a solvent-free environment with excellent yields. Initially, benzaldehyde was treated with indole to produce 3,3′-(phenylmethylene)bis(1H-indole) (1a) using a 5 mol % BDMS catalyst (Scheme 1). BDMS was optimized to give the best catalytic activity at 10 mol % (Table 1, entry 3); exceeding 10 mol %, the catalyst gave an insignificant increase in the yield of the product (Table 1, entries 4 and 5); however, the substrate conversion rate was reduced by employing a 5 mol % BDMS catalyst (Table 1, entry 1); when a solvent was employed, the conversion took substantially longer and produced lower yield (Table 1, entry 6–10). The synthesized product was isolated, characterized by 1H and 13C NMR and high-resolution mass spectrometry, then validated by crystallographic studies and matched to existing crystal data.

Scheme 1. BDMS-Catalyzed Synthesis of Turbomycin B.

Scheme 1

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Table 1. Optimization with the BDMS Catalyst.

entry BDMS (mol %) solvent time (minutes) yield (%)
1 5   5 55
2 10   5 70
3 10   10 95
4 15   20 85
5 20   60 90
6 10 CH3OH 120 50
7 10 CH2Cl2 120 40
8 10 CHCl3 60 60
9 10 C2H5CO2CH3 120 70
10 10 CH3CN 60 50
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In spite of succeeding in synthesizing BIMs using the BDMS catalyst, in view of previous reports which focused primarily on KHSO4–SiO2- catalyzed conversion,45 and few other catalyzed conversions also reported so far,46 we concentrated our efforts precisely on a highly efficient and eco-friendly approach. Despite the BDMS catalyst being effective, the bio-glycerol-based carbon acid catalyst has reduced conversion time, and recyclability has been improved with lower catalytic loadings. The application of a solid acid catalyst is vital in the conversion of organic functional groups. Carbon solid acid catalysts have efficient catalytic activity toward these transformations. Consequently, we provide a safe and highly effective green procedure using a biodegradable glycerol-based carbon sulfonic acid catalyst to produce bisindoles in excellent yield under solvent-free conditions.

The optimization of the biodegradable glycerol-based carbon sulfonic acid catalyst was evaluated at ambient temperature under solvent-free conditions with excellent yields in 5 min (Scheme 2). The reactants were treated with various solvents; subsequently, the catalytic activity was evaluated (Table 2). The outcomes of the optimization studies reveal that the bio-glycerol-based carbon sulfonic acid catalyst efficiently synthesized the BIM derivatives with 5 mol % catalytic loading.

Scheme 2. Bioglycerol-Based C–SO3H-Catalyzed Synthesis of Turbomycin B.

Scheme 2

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Table 2. Optimization of the Bioglycerol-Based Carbon Sulfonic Acid Catalyst.

entry catalyst (5 mol %) solvent time (minutes) yield (%)a
1 carbon–SO3H H2O 30 65
2 carbon–SO3H CH3OH 30 50
3 carbon–SO3H C2H5OH 10 95
4 carbon–SO3H   5 95
5 carbon–SO3H C2H5OH 5 90
6 carbon–SO3H C2H5OH: H2O 15 93
7b carbon–SO3H   10 70
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a

Isolated yield after the purification.

b

Catalyst (10 mol %).

We extended our study using an optimized protocol to assess the recyclability of the catalyst. It was discovered that the bio-glycerol-based carbon sulfonic acid catalyst could be used for four cycles without further activation with much less yield loss (Table 3) and that it could be recovered by simple filtration, washed with ethyl acetate, dried, and reused.

Table 3. Recyclability of the Bioglycerol-Based Carbon Sulfonic Acid Catalyst.

cycles yield (product)% recovery (catalyst)%
native 95 96
1 93 93
2 90 88
3 87 85
4 82 80
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The substrate scope was evaluated by employing various aldehydes and indoles (Scheme 3). Initially, we used substituted benzaldehydes and indoles to generate BIM derivatives in the presence of the biodegradable glycerol-based carbon sulfonic acid catalyst at room temperature under solvent-free conditions for 5 min to obtain quantitative yields.

Scheme 3. Synthesis of Bisindolylmethane Derivatives.

Scheme 3

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To evaluate the use of indole and benzaldehyde substituents, the procedure is as follows. Initially, benzaldehyde was treated with indole under the above-mentioned conditions to afford 3,3′-(phenylmethylene)bis(1H-indole) (1a). Later, p-tolualdehyde was treated with indole and 5-methoxy indole to generate 3,3′-(p-tolylmethylene)bis(1H-indole) (1b) and 3,3′-(p-tolylmethylene)bis(5-methoxy-1H-indole) (1c), respectively. Further, 4-methoxy benzaldehyde was treated with indole, 5-methoxy indole, 5-bromo indole, and 5-cyano indole to give 3,3′-((4-methoxyphenyl)methylene)bis(1H-indole) (1d), 3, 3′-((4-methoxyphenyl)methylene)bis(5-methoxy-1H-indole) (1e), 3,3′-((4-methoxyphenyl)methylene)bis(5-bromo-1H-indole) (1f), and 3,3′-((4-methoxyphenyl)methylene)bis(1H-indole-5-carbonitrile) (1g), respectively. Furthermore, 2,5-dimethoxy benzaldehyde, veratraldehyde, syringaldehyde, 4-bromo benzaldehyde, 4-nitro benzaldehyde, 1-naphthaldehyde, 9-anthraldehyde were treated with indole, veratraldehyde, 4-nitro benzaldehyde were treated with 2-phenyl indole to produce 3,3′-((2,5-dimethoxyphenyl)methylene)bis(H-indole) (1h), 3, 3′-((4-bromophenyl)methylene)bis(1H-indole) (1j), 3,3′-((3,4-dimethoxyphenyl)methylene)bis(1H-indole) (1t), 4-(di(1H-indol-3-yl)methyl)-2,6-dimethoxyphenol (1s), 3,3′-((4-nitrophenyl)methylene)bis(1H-indole) (1k), 3,3′-((naphthalen-1-yl)methylene)bis(1H-indole) (1m), 3,3′-((anthracen-9-yl)methylene)bis(1H-indole) (1n), 3,3′-((4-nitrophenyl)methylene)bis(2-phenyl-1H-indole) (1i), 3,3′-((4-nitrophenyl)methylene)bis(2-phenyl-1H-indole) (1l), respectively. It is observed that there are no remarkable changes in the yields of the products in the presence of the electron-activating groups and the electron-withdrawing groups.

The scope was extended by using hetero aromatic aldehydes, such as 2-furaldehyde treated with indole, 5-bromo indole, and 2-phenyl indole, and thiophene-2-carboxaldehyde with 2-methylindole to generate 3,3′-((furan-2-yl)methylene)bis(1H-indole) (1o), 3,3′-((furan-2-yl)methylene)bis(5-bromo-1H-indole) (1p), 3,3′-((furan-2-yl)methylene)bis(2-phenyl-1H-indole) (1q), 3,3′-((thiophene-2-yl)methylene)bis(2-methyl-1H-indole) (1r), respectively (Scheme 4). All the synthesized indolemethane derivatives (1a–t) are represented in Figure 2 with the yields of the compounds.

Scheme 4. Bisindole Synthesis Using Heteroaromatic Aldehydes.

Scheme 4

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Figure 2.

Figure 2

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Substrate scope.

Plausible Mechanism

Figure 3 depicts a possible pathway for the synthesis of diindolylmethanes. Initially, a carbon solid acid catalyst reacts with benzaldehyde to form intermediate IX, then the first mole of indole reacts with IX to form intermediate X, and finally, it eliminates the water molecule to produce benzylidene intermediate XI. Later, it combines with the second mole of indole to form the diindolylmethane molecule (1a).

Figure 3.

Figure 3

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Plausible mechanism.

Cytotoxicity

The cytotoxicity of the synthesized compounds (1a–t) was assessed using the MTT assay47 against human prostate cancer cell lines DU-145, hepatocellular carcinoma cell lines HepG2, and melanoma cancer cell lines B-16 by employing doxorubicin as a standard reference. The results showed that all of the test compounds were found to have good anticancer activity against all three cell lines (Table 4). Compound 1k was found to have potent activity against the DU-145 cell line with an IC50 value of 1.09 ± 0.92 μM. In addition, compounds 1a, 1c, 1d, 1f, and 1n showed good activity against DU-145 cells with IC50 values of 5.24 ± 0.67, 2.02 ± 0.74, 5.10 ± 0.26, 5.58 ± 0.17, and 6.87 ± 1.06 μM, respectively. The activity of compounds 1g, 1j, and 1m was noteworthy against DU-145 cells with IC50 values of 8.13 ± 0.77, 9.46 ± 1.23, and 8.18 ± 0.74 μM, respectively, whereas all other compounds displayed good to moderate activity against the prostate cancer cell line. In HepG2 cells, all the compounds (1a–t) showed potent cytotoxic effects with IC50 values ranging between 4.23 and 11.9 μM, among which compounds 1a, 1d, and 1f demonstrated highest activity with IC50 values of 4.62 ± 0.03, 4.93 ± 1.04, and 4.23 ± 1.09 μM, respectively. Similarly, in the B16 cell line, the activity of compounds 1a, 1d to 1h, 1j, 1m, 1s, and 1t was very good, with IC50 values ranging between 4.40 and 9.90 μM, whereas the rest of the compounds showed moderate activity. The activity of these compounds may be attributed to the presence of indole nuclei and different substituents present on them, and further, the structures varied with different substituents such as substituted phenyl rings, naphthalene, anthracene, furans, and thiophene attached to the chiral carbon. The toxicity of all of the compounds (1a–t) was tested against the normal cell line CHO–K1. Although all these compounds showed good cytotoxicity against all the tested cancer cells, they also showed moderate toxicity toward normal cells with IC50 ranging between 6.13 and 31.39 μM. Hence, it is inferred that all these compounds are more toxic to cancer cells compared to normal cells. It is known that chemotherapies are mostly toxic in nature. However, they are being used to increase the life expectancy of cancer patients.

Table 4. Cytotoxicity of 1a–ta,b.

test compound DU145 HepG2 B16 CHO–K1
1a 5.24 ± 0.67 4.62 ± 0.03 9.88 ± 1.19 29.32 ± 0.40
1b 15.04 ± 1.02 7.18 ± 1.89 13.39 ± 1.01 31.39 ± 0.05
1c 2.02 ± 0.74 5.47 ± 0.56 36.03 ± 1.09 16.24 ± 0.93
1d 5.10 ± 0.26 4.93 ± 1.04 5.31 ± 0.07 18.63 ± 0.48
1e 11.99 ± 0.46 8.27 ± 1.03 8.89 ± 0.26 16.82 ± 0.66
1f 5.58 ± 0.17 4.23 ± 1.09 4.40 ± 0.35 6.13 ± 1.19
1g 8.13 ± 0.77 6.33 ± 1.8 9.82 ± 0.52 46.55 ± 0.59
1h 16.79 ± 0.65 6.23 ± 1.6 8.17 ± 0.37 11.60 ± 1.27
1i 10.28 ± 0.87 7.43 ± 1.6 15.93 ± 0.25 13.53 ± 0.73
1j 9.46 ± 1.23 5.24 ± 0.1 9.90 ± 1.61 6.38 ± 0.55
1k 1.09 ± 0.92 5.28 ± 0.24 29.24 ± 2.38 26.8 ± 1.29
1l 91.35 ± 0.81 9.73 ± 1.4 23.30 ± 0.65 24.23 ± 0.68
1m 8.18 ± 0.74 7.54 ± 1.19 9.49 ± 1.97 16.5 ± 0.88
1n 6.87 ± 1.06 11.9 ± 0.10 13.6 ± 0.92 12.36 ± 1.38
1o 60.81 ± 1.24 5.87 ± 0.30 16.14 ± 0.79 10.12 ± 0.75
1p 19.36 ± 0.88 11.39 ± 1.37 19.65 ± 0.87 30.49 ± 1.73
1q 39.52 ± 1.02 5.00 ± 0.01 23.5 ± 7.0 9.18 ± 1.58
1r 21.23 ± 2.01 5.82 ± 0.5 15.68 ± 2.10 30.46 ± 0.33
1s 22.62 ± 0.98 7.01 ± 0.53 7.02 ± 0.32 15.84 ± 0.52
1t 12.21 ± 0.96 8.12 ± 0.87 8.14 ± 1.45 15.21 ± 0.35
standard (doxorubicin) 0.7 ± 0.13 0.6 ± 0.12 0.8 ± 0.12  
standard (Mitomycin C)       13.3 ± 0.68
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a

IC50 values (μM) (mean ± S.D.).

b

DU 145 -Prostate cancer cell lines; HepG2-Liver hepato cellular carcinoma cells; B16 -Melanoma cancer cell lines; CHO–K1-Chinese hamster ovary cells (normal).

Molecular Docking

To validate the anticancer activity of the title compounds, the crystal structures of the androgen receptor (AR) (PDB ID: 5T8E),48 proprotein convertase subtilisin/kexin type 9 (PCSK9) (PDB ID: 3GCW),49 and suppressor of cytokine signaling 6 (Socs6)50 were retrieved from the protein data bank (www.rcsb.org). Molecular docking simulations were performed in the active site pocket of receptors with all the ligand molecules 1a–t and compared binding energies with standard reference doxorubicin.

Molecular Docking against the AR

Modification of the AR causes prostate cancer, which is why targeting AR is a viable strategy to combat early-stage cancer.51–53 The docking scores of all molecules 1a–t are comparable to the doxorubicin score. The binding energies and binding interactions of all molecules with the AR (PDB ID: 5T8E) are presented in Table S1. The best active compound 1k scored a binding energy value of −8.8 kcal/mol, which was higher than that of doxorubicin, which scored −8.3 kcal/mol. It demonstrated two H-bond interactions with Arg752 and Asn756 with bond distances of 2.25 and 2.80 Å, respectively. And hydrophobic interactions were displayed with Glu681, Pro682, Val684, and Ala748 of the AR, whereas doxorubicin indicated H-bond interactions with Glu678, Trp751, Thr755, Pro682, Val684, Val685, Ala748, Arg752, Asn756, Pro801, Phe804, and Leu805 with the AR (Figure 4).

Figure 4.

Figure 4

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Docking pose of (a) compound 1k and (b) doxorubicin, and binding interactions of (c) compound 1k and (d) doxorubicin in the cavity of the AR.

Molecular Docking against Proprotein Convertase Subtilisin/Kexin Type 9

PCSK2 is a serine protease enzyme mostly produced by the liver cell, and it can potentially be used as a drug target.54 All the novel synthesized compounds 1a–t were docked into the active site pocket of PCSK2 (PDB ID: 3GCW) along with doxorubicin. The docking scores of compounds range from −7.6 to −11.1 kcal/mol, whereas doxorubicin scored −8.8 kcal/mol against PCSK9, as presented in Table S2. The best active compound 1f scored a binding energy value of −9.6 kcal/mol and indicated key interactions with Ser329, Cys358, and Trp461 and hydrophobic interactions with Ala330, Pro331, Arg357, Cys358, Leu436, Pro438, Arg458, Thr459, Val460, Trp461, Arg476, and Ala478 of PCSK9. The standard compound doxorubicin showed H-bond interactions with Pro331, Arg357, Asp360, Arg412, Arg458, Ala463, and Arg476 and hydrophobic interactions with Pro331, Glu332, Arg357, Cys358, Asp360, Arg412, Ser462, Ala463, Ile474, and Arg476 of PCSK9 (Figure 5).

Figure 5.

Figure 5

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Docking pose of (a) compound 1f and (b) doxorubicin, and binding interactions of (c) compound 1f and (d) doxorubicin in the cavity of PCSK2.

Molecular Docking against the Suppressor of Cytokine Signaling 6

The suppressor of cytokine signaling (Socs6) (PDB ID: 2VFI) is an attractive drug target for the inhibition of melanoma cancer cells.55,56 All the ligands 1a–t were docked into the active site pocket of Socs6, and the binding energies of compounds ranged from −6.9 to −10.1 kcal/mol, and the doxorubicin score was −8.9 kcal/mol, as presented in Table S3. The best active compound 1f scored a binding energy value of −8.2 kcal/mol, and it exhibited only hydrophobic interactions such as pi–pi stacking, pi-cation, and other alkyl interactions with Leu429, Thr431, Tyr442, Arg474, and Arg476 of Socs6, whereas doxorubicin scored −8.9 kcal/mol which showed H-bond interaction with Arg474, Arg476, Arg391, Phe422, His430, Arg432, Tyr443, Phe470, Cys471, and Arg474 of Socs6 (Figure 6).

Figure 6.

Figure 6

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Docking pose of (a) compound 1f and (b) doxorubicin and binding interactions of (c) compound 1f and (d) doxorubicin in the cavity of Socs6.

Conclusions

In conclusion, we have developed highly efficient green protocols to synthesize indolemethane derivatives utilizing both bromodimethylsulfonyl bromide and bio-glycerol-based carbon sulfonic acid catalysts under solvent-free conditions with substituted benzaldehydes and indoles at room temperature in a short time. The biodegradable glycerol-based carbon sulfonic acid-catalyzed method was found to be more effective. The synthesized compounds exhibit excellent anticancer activity against DU145, HepG2, and B16 cell lines. The highest cytotoxicity effects were found with 1k (1.09 μM) against DU145 followed by 1c, 1f, 1n, and 1m between 2.02 and 8.18 μM concentrations. In HepG2 cells, all of the compounds (1a–t) showed potent cytotoxic effects with IC50 from 4.23 to 11.9 μM. Similarly, the compounds 1d–h, 1j, 1m, 1s, and 1t exhibited excellent to promising anticancer activity for the B16 cell line. These substances are more effective in preventing cancer cells than normal cells and are being used for improving the lifespan of cancer patients. The docking studies and binding interactions suggest that drugs are well fitted into the active site pocket of the target molecules, which supports the experimental evidence obtained from in vitro testing.

Experimental Section

Experimental Procedure for the Synthesis of Indolemethane Derivatives (1a–t)

Method 1

In a round-bottom flask, the mixture of benzaldehyde (1 mmol), indole (2 mmol), and bromodimethylsulfonyl bromide (10 mol %) was taken and stirred for 10 min. The completion of the reaction was monitored by TLC, and the reaction mixture was quenched with NaHCO3, extracted with ethyl acetate and water, and the ethyl acetate layer dried over Na2SO4 and concentrated to get corresponding indolemethane derivatives without further purification.

Method 2

In a round-bottom flask, the mixture of benzaldehyde (1 mmol), indole (2 mmol), and carbon sulfonic acid (5 mol %) was added and stirred for 5 min. The completion of the reaction was monitored by TLC, and the reaction mixture was filtered, and then the crude product was recrystallized with water then hexane to get the desired compounds without further purification.

3,3′-(Phenylmethylene)bis(1H-indole) (1a)

Red solid; (0.29 g, 98% yield); mp 124–125 °C; 1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 7.6 Hz, 2H), 7.29 (dt, J = 7.2, 1.9 Hz, 2H), 7.25 (m, 4H), 7.20–7.15 (m, 2H), 7.14–7.09 (m, 1H), 7.07 (m, 2H), 6.92 (m, 2H), 6.54 (dd, J = 7.3, 0.9 Hz, 2H), 5.79 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 144.1, 136.7, 128.8, 128.3, 127.1, 126.2, 123.7, 121.9, 120.0, 119.7, 119.2, 111.1, 40.2. Mass (ESI+): 321 [M – H]. HRMS (ESI+): m/z Calc. Mass for C23H17N2, [M – H]: 321.13838; found, 321.13863.

3,3-(p-Tolylmethylene)bis(1H-indole) (1b)

Orange–red solid; (0.26 g, 94% yield); mp 101–103 °C; 1H NMR (400 MHz, CDCl3): δ 7.81 (s, 2H), 7.31 (d, J = 7.8 Hz, 2H), 7.24 (s, 1H), 7.19–7.13 (m, 3H), 7.07 (t, J = 7.5 Hz, 2H), 6.99 (d, J = 7.7 Hz, 2H), 6.91 (t, J = 7.5 Hz,2H), 6.56 (d, J = 7.3 Hz, 2H), 5.76 (s, 1H), 2.24 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 141.0, 136.6, 128.9, 128.5, 127.0, 123.5, 121.8, 119.9, 119.1, 111.0, 39.8, 21.1. HRMS (ESI+): m/z calc. mass for C24H19N2, [M-H]: 335.15354; found, 335.15428.

3,3′-(p-Tolylmethylene)bis(5-methoxy-1H-indole) (1c)

Orange solid; (0.32 g, 98% yield); mp 195–198 °C; 1H NMR (400 MHz, CDCl3): δ 7.80 (s, 2H), 7.25–7.21 (m, 4H), 7.08 (d, J = 7.8 Hz, 2H), 6.83–6.78 (m, 4H), 6.65 (d, J = 7.0 Hz, 2H), 5.73 (s, 1H) 3.68(s, 6H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.7, 140.9, 135.5, 131.9, 128.9, 128.6, 128.0, 127.6, 124.4, 119.6, 111.8, 111.6, 102.1, 55.9, 39.9, 21.1. HRMS (ESI+): m/z calc. mass for C26H23O2N2, [M – H]: 395.17506; found, 395.17540.

3,3-((4-Methoxyphenyl)methylene)bis(1H-indole) (1d)

Orange–red solid; (0.24 g, 95% yield); mp 193–195 °C; 1H NMR (400 MHz, CDCl3): δ 7.90 (s, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.1 Hz, 2H), 7.25–7.21 (m, 2H), 7.13 (dd, J = 7.7, 1.6 Hz, 2H), 7.10–7.06 (m, 1H), 7.00–6.95 (m, 2H), 6.82–6.77 (m, 2H), 6.61 (s, 2H), 5.82 (d, J = 6.4 Hz, 1H), 3.76 (d, J = 7.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 157.8, 136.6, 136.2, 129.5, 127.0, 123.5, 121.8, 119.9, 119.1, 113.9, 113.5, 110.9, 55.2, 39.4. Mass (ESI+): 351 [M – H]. HRMS (ESI+): m/z calc. mass for C24H19ON2, [M – H]: 351.14839; found, 351.14919.

3,3-((4-Methoxyphenyl)methylene)bis(5-methoxy-1H-indole) (1e)

Reddish-brown solid; (0.29 g, 96% yield); mp 211–214 °C; 1H NMR (400 MHz, CDCl3): δ 7.88 (s, 2H), 7.37–7.34 (m, 1H), 7.23 (s, 1H), 6.91–6.82 (m, 8H), 6.31 (dd, J = 7.1, 1.9 Hz, 1H), 6.07 (s, 1H), 5.83 (s, 1H), 3.72 (s, 9H). 13C NMR (100 MHz, CDCl3): δ 156.9, 153.8, 141.2, 131.6, 127.1, 123.7, 116.8, 112.0, 111.7, 110.1, 107.9, 106.6, 101.5, 55.9, 34.2. Mass (ESI+): 411 [M – H].

3,3-((4-Methoxyphenyl)methylene)bis(5-bromo-1H-indole) (1f)

Dark-red solid; (0.36 g, 98% yield); mp 219–221 °C; 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 2H), 7.48 (d, J = 7.9 Hz, 2H), 7.19 (dd, J = 7.3, 2.0 Hz, 6H), 6.83 (d, J = 7.6 Hz, 2H), 6.62 (s, 2H), 5.69 (s, 1H), 3.79 (s,3H). 13C NMR (100 MHz, CDCl3): δ 158.2, 135.3, 129.5, 128.7, 125.0, 124.7, 122.3, 119.4, 113.8, 112.6, 55.3, 39.1. HRMS (ESI+): m/z calc. mass for C24H17ON2Br2, [M – H]: 506.96994; found, 506.97021.

3,3′-((4-Methoxyphenyl)methylene)bis(1H-indole-5-carbonitrile) (1g)

Brownish-orange solid; (0.27 g, 92% yield); mp 109–111 °C; 1H NMR (500 MHz, CDCl3): δ 8.00 (s, 2H), 7.47 (s, 2H), 7.26–7.16 (m, 6H), 6.82 (dd, J = 6.7, 1.9 Hz, 2H), 6.61 (d, J = 7.8 Hz, 2H), 5.68 (s, 1H), 3.78 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 157.9, 136.7, 136.3, 131.3, 129.6, 127.1, 123.6, 122.5, 121.9, 121.1, 120.0, 119.2, 114.9, 113.6, 111.1, 55.2, 39.4. HRMS (ESI+): m/z calc. mass for C26H17ON4, [M – H]: 401.13922; found, 401.13969.

3,3-((2,5-Dimethoxyphenyl)methylene)bis(1H-indole) (1h)

Dark-red solid; (0.21 g, 92% yield); mp 195–197 °C; 1H NMR (400 MHz, CDCl3): δ 7.90–7.81 (m, 2H), 7.27–7.19 (m, 3H), 7.08–6.97 (m, 6H), 6.82–6.73 (m, 4H), 6.38–6.35 (m, 1H) 3.62–3.57 (S, 3H), 3.47–3.43 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 164.5, 161.7, 149.5, 137.6, 130.0, 129.7, 129.0, 128.8, 128.3, 123.9, 123.5, 123.0, 117.2, 114.8, 67.6, 40.0. HRMS (ESI+): m/z calc. mass for C25H22O2N2, [M – H]: 381.15979; found, 381.15975.

3,3′-((3,4-Dimethoxyphenyl)methylene)bis(2-phenyl-1H-indole) (1i)

Red solid; (0.30 g, 94% yield); mp 236–239 °C; 1H NMR (400 MHz, CDCl3): δ 8.03 (s, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.18 (dt, J = 7.0, 1.2 Hz, 10H), 7.08 (s, 2H), 7.01(d, J = 7.8 Hz, 2H), 6.89–6.79 (m, 4H), 6.75 (d, J = 7.6 Hz, 1H), 6.04(s, 1H), 3.87 (s, 3H), 3.61 (s, 3H). 13C NMR(100 MHz, CDCl3): δ 135.9, 135.3, 133.1, 128.9, 128.3, 127.4, 121.8, 121.5, 119.6, 115.9, 112.8, 110.6, 77.4, 77.0, 76.7, 55.8, 39.8. Mass (ESI+): 533 [M – H]. HRMS (ESI+): m/z calc. mass for C37H29O2N2, [M – H]: 533.22208; found, 533.22235.

3,3-((4-Bromophenyl)methylene)bis(1H-indole) (1j)

Pink solid; (0.2 g, 92% yield); mp 102–104 °C; 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 2H), 7.43 (d, J = 7.7 Hz, 2H), 7.29–7.21 (m, 7H), 7.12 (d, J = 7.3 Hz,2H), 6.61 (d, J = 7.3 Hz, 2H), 5.75 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 147.9, 141.8, 135.4, 129.8, 128.5, 125.2, 124.8, 122.1, 121.8, 120.9, 120.6, 118.6, 112.8, 39.3. HRMS (ESI+): m/z calc. mass for C23H16N2Br, [M – H]: 399.04841; found, 399.04914.

3,3′((4-Nitrophenyl)methylene)bis(1H-indole) (1k)

Yellow–orange solid; (0.23 g, 98% yield); mp 222–223 °C; 1H NMR (400 MHz, CDCl3): δ 8.13 (d, J = 7.5 Hz, 2H), 8.01 (s, 2H), 7.50 (d, J = 7.4 Hz, 2H), 7.38 (d, J = 7.1 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 7.19 (t, J = 7.6 Hz, 2H) 7.03 (t, J = 7.4 Hz, 2H), 6.68 (d, J = 7.2 Hz,2H), 5.98 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 151.9, 136.7, 129.6, 123.7, 122.4, 119.6, 118.2, 111.3, 40.2. HRMS (ESI+): m/z calc. mass for C23H16O2N3, [M – H]: 366.12318; found, 366.12369.

3,3-((4-Nitrophenyl)methylene)bis(2-phenyl-1H-indole) (1l)

Yellow–orange solid; (0.33 g, 98% yield); mp 256–259 °C; 1H NMR (400 MHz, CDCl3): δ 7.97 (s, 2H), 7.73 (d, J = 7.4 Hz, 1H), 7.64(d, J = 7.4 Hz, 1H), 7.43–7.33 (m, 9H), 7.25–7.15 (m, 6H), 7.06–7.00 (m, 3H), 6.68 (s, 2H), 5.87 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 143.1, 139.9, 133.7, 132.9, 131.5, 131.3, 131.0, 130.5, 126.9, 123.6, 122.1, 119.8, 119.4, 119.1, 115.2, 111.1, 39.7. HRMS (ESI+): m/z calc. mass for C35H24O2N3, [M – H]: 518.18577; found, 518.18630.

3,3′-(Naphthalen-1-ylmethylene)bis(1H-indole) (1m)

Yellow–orange solid; (0.22 g, 96% yield); mp 165–166 °C; 1H NMR (400 MHz, CDCl3): δ 10.47 (s, 2H), 8.13 (d, J = 7.3 Hz, 1H), 7.86 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.39–7.27 (m, 4H), 7.20 (d, J = 6.9 Hz, 3H), 6.97 (t, J = 7.4 Hz, 2H), 6.78 (t, J = 7.4 Hz, 2H), 6.57 (s, 2H), 6.54 (s, 1H). 13C NMR (125 MHz, CDCl3): δ 145.3, 141.8, 138.7, 136.5, 133.5, 131.7, 131.0, 130.8, 130.8, 129.9, 129.4, 128.9, 126.0, 123.9, 123.4, 122.9, 116.6, 40.5. Mass (ESI+): 371 [M – H]. HRMS (ESI+): m/z calc. mass for C27H19N2, [M – H]: 371.15403; found, 371.15428.

3,3′-(Anthracen-9-ylmethylene)bis(1H-indole) (1n)

Dark-pink solid; (0.19 g, 95% yield); mp 188–190 °C; 1H NMR (400 MHz, CDCl3): δ 8.64 (d, J = 7.4 Hz, 2H), 8.45 (s, 1H), 8.00 (d, J = 7.2 Hz, 2H), 7.91 (s, 2H), 7.35 (dd, J = 7.2, 1.6 Hz, 6H), 7.11 (dd, J = 7.0, 1.2 Hz, 5H), 6.87 (s, 2H), 6.80 (s, 2H). 13C NMR (100 MHz, CDCl3): δ 136.6, 135.1, 131.9, 129.1, 127.2, 124.7, 123.9, 121.8, 120.0, 119.2, 119.0, 111.0, 35.1. HRMS (ESI+): m/z calc. mass for C31H21N2, [M – H]: 421.16875; found, 421.16993.

3,3′-(Furan-2-ylmethylene)bis(1H-indole) (1o)

Pinkish-red solid; (0.31 g, 96% yield); mp 311–314 °C; 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 2H), 7.47 (d, J = 7.5 Hz, 2H), 7.33 (d, J = 7.6 Hz, 3H), 7.19–7.12 (m, 2H), 7.06–6.9 (m, 2H), 6.85 (s, 2H), 6.28 (dd, J = 7.0, 1.8 Hz, 1H), 6.04 (d, J = 7.1 Hz,1H), 5.93 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 157.0, 141.2, 136.5, 126.7, 123.0, 122.0, 119.6, 119.3, 117.1, 111.0, 110.1, 106.5, 34.0. HRMS (ESI+): m/z calc. mass for C21H15ON2, [M – H]: 311.11705; found, 311.1178.

3,3′-(Furan-2-ylmethylene)bis(5-bromo-1H-indole) (1p)

Blackish-brown solid; (0.46 g, 96%); mp 331–334 °C; 1H NMR (400 MHz, CDCl3): δ 8.06 (s, 2H), 7.58–7.52(m, 2H), 7.38 (dd, J = 7.8, 0.9 Hz, 1H), 7.24 (dd, J = 7.2, 1.6 Hz, 4H), 6.88 (dd, J = 7.5, 1.6 Hz, 2H), 6.33 (dd, J = 7.2, 1.9 Hz, 1H), 6.05–5.98 (m, 1H), 5.81 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 162.9, 140.2, 137.0, 128.9, 126.8, 124.6, 122.0, 116.8, 27.8. HRMS (ESI+): m/z calc. mass for C21H13ON2Br2, [M – H]: 466.93835; found, 466.93891.

3,3′-(Furan-2-ylmethylene)bis(2-phenyl-1H-indole) (1q)

Purple–pink solid; (0.45 g, 95% yield); mp 319–323 °C; 1H NMR (400 MHz, CDCl3): δ 7.92 (s, 2H), 7.30 (s, 1H), 7.22 (d, J = 7.0 Hz, 2H), 7.15–7.06 (m, 10H), 7.02(t, J = 7.1 Hz, 4H), 6.82 (t, J = 7.6 Hz, 2H), 6.30–6.24 (m, 1H), 6.03–5.94 (m, 2H). 13C NMR (100 MHz, CDCl3 + DMSO-d6): δ 162.9, 140.2, 137.0, 128.9, 126.8, 124.6, 122.0, 116.8, 27.8. Mass (ESI+): 487 [M + Na]. HRMS (ESI+): m/z calc. mass for C33H24ON2, [M] 464.18778; found, 464.18831.

3,3′-(Thiophen-2-ylmethylene)bis(2-methyl-1H-indole) (1r)

Green solid; (0.30 g, 96% yield); mp 148–151 °C; 1H NMR (400 MHz, DMSO-d6): δ 10.77 (s, 4H), 7.32 (d, J = 7.2 Hz, 4H), 7.20 (d, J = 7.9 Hz, 5H), 6.91 (dd, J = 7.2, 1.4 Hz, 11H), 6.76–6.66 (m, 7H), 6.10 (s, 2H), 2.14 (s, 14H). 13C NMR (100 MHz, CDCl3): δ 135.1, 132.1, 129.8, 128.4, 123.4, 121.0, 119.4, 119.0, 111.9, 110.4, 110.2, 39.4, 12.5. Mass (ESI+): 355 [M – H]. HRMS (ESI+): m/z calc. mass for C23H19N2S, [M – H]: 355.12623; found, 355.12635.

4-(Di(1H-indol-3-yl)methyl)-2,6-dimethoxyphenol (1s)

Dark red; (0.25 g, 98% yield); mp 115–116 °C; 1H NMR (500 MHz, CDCl3): δ 7.92 (s, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 7.19 (s, 2H), 6.96–6.90 (m, 2H), 6.60 (s, 2H), 6.52 (s, 2H), 5.74 (s, 1H), 3.70–3.64 (m, 6H). 13C NMR (125 MHz, CDCl3): δ 152.05, 135.10, 132.17, 129.86, 123.45, 121.28, 121.04, 119.46, 119.05, 112.51, 111.87, 110.48, 110.29, 39.44, 25.11. HRMS (ESI+): m/z calc. mass for C25H22O3N2, [M – H]: 397.15423.

3,3′-((3,4-Dimethoxyphenyl)methylene)bis(1H-indole) (1t)

Orange–red solid; (0.21 g, 95% yield); mp 208–209 °C; 1H NMR (400 MHz, CDCl3): δ 8.10 (dd, J = 7.6, 1.7 Hz 2H), 7.85 (s,2H), 7.42 (d, J = 7.8 Hz, 2H), 7.28 (s, 1H), 7.07 (m, 3H), 6.88 (dt, J = 7.2, 1.5 Hz, 5H), 6.05 (s, 1H), 2.08 (s, 6H).

Acknowledgments

The authors express their gratitude to the Head, Dean, and Principal of the Department of Chemistry at the University College of Science, Osmania University, Hyderabad, as well as the Director of CSIR-IICT, Hyderabad, for providing laboratory facilities. P.M.R. acknowledges financial support from TSCOST under Project Relate Grants (File No. 03/TSCOST/DST-PRG/2021-22, Dt: 31.12.2021). P.M.R. also extends thanks to the UGC-UPE FAR & DST-PURSE PROGRAMME (2017-22) at Osmania University, Hyderabad, for their financial support. Anren Hu would like to express their gratitude to the Ministry of Science and Technology, Taiwan, for providing financial support for this research under contract numbers NSTC 112-2113-M-320-001 and MOST 111-2113-M-320-001. Additionally, they extend their thanks to Tzu-Chi University and Tzu Chi Hospital for their financial support of this work.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c05293.

  • General information, experimental procedures, docking experimental tables, and characterization spectra of 1a–t (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c05293_si_001.pdf (3.5MB, pdf)

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