Efficient One-Pot Synthesis of Indolhydroxy Derivatives Catalyzed by SnCl₂, DFT Calculations and Docking Study

Abstract

In this work we used an efficient and simple synthesis for the preparation of new indolhydroxy derivatives that has been performed by the reduction reaction of 2-nitrocinnamic acid or 2-nitrophenyl pyruvic acid with anhydrous stannous chloride (SnCl₂) as a metal catalyst in different alcoholic solvents. During this transformation there was the involvement of intramolecular elimination cyclization. In the case of the reduction of 2-nitrocinnamic acid we obtained hydroxyindole plus hydroxyquinoline, on the other hand, the reduction of 2-nitrophenyl pyruvic acid gives hydroxyindole only, the products were obtained in suitable yields. The structures of all the synthesized compounds were fully characterized by different spectroscopic techniques such as ¹H NMR, ¹³C NMR. In addition, the obtained products have been tested in silico against anti-human immunodeficiency virus type 1 (HIV-1) and SARS-CoV-2 virus. The outcomes of this work are very promising to develop more efficient antiviral compounds, indicating that these products may be a probable drugs for the SARS-CoV-2.

1 Introduction

The Indole moiety is a subunit frequently found in pharmaceuticals with important biological and potent pharmacological activities [1,2,3], including anti-inflammatory [4, 5], anti-cancer [6,7,8], and anti-HIV [9,10,11,12] antagonistic activity inhibitor of kinase protein [13, 14]. Indole derivatives have recently invaded several areas of pharmacology and can be found in photosensitive cells [15]. Various methods for Indole preparation have been reported [16] due to the importance of Indoles in the pharmaceutical industry [17]. However, in the present work, we are interested in the synthesis of new Indole derivatives from the reduction of 2-nitrocinnamic and 2-nitrophenylpyruvic acid by SnCl₂ in different alcoholic solvents. In the last ten years, the reduction of nitroindazoles has been performed in the presence of SnCl₂ as a catalyst for these multiple advantages [18,19,20,21,22,23,24]. It is a better reducing agent in organic transformations because of its greater selectivity leading to the efficient syntheses of different heterocyclic compounds based on the reduction of nitro derivatives, more the simplicity of operation, non-corrosive, low cost and ease of isolation. In parallel, we have realized a docking study about Indole (benzopyrrole) against anti-human immunodeficiency virus type 1 (HIV-1) and SARS-CoV-2 virus. Thus, we have tested our products into the active sites of the HIV-1 Protease (PDB ID: 1HSG) and the SARS-CoV-2 main protease (M^pro) (PDB ID: 6LU7) proteins. Discovery Studio Visualizer software and PyMol were applied for the visualization of the docked compound. Its H-bond interactions and possible binding mode of the indole molecules with their target proteins, aiming to explain their antiviral activities.

2 Results and Discussion

2.1 Synthesis

Based on the interest of our research group for the synthesis of nitrogenous compounds heterocycles [25] and following the work carried out on the reduction reactions of nitroheteroaryls, we are interested, in the present work in the synthesis of new derivatives of the indole from the reduction of 2-nitrocinnamic 1 and/or 2-nitrophenylpyruvic acid 4 by SnCl₂ in different alcoholic solvents (Scheme 1). The action of anhydrous tin chloride, in excess, in different alcoholic solvents on 2-nitrocinnamic acid 1 at the reflux of the alcohol, leads to a mixture of two products: hydroxyquinoline 3 and to new compounds of type 1-hydroxy-1H-indole-2-carboxylate 2a–f (Scheme 1). The yields of compounds 2a–f and 3 are listed in Table 1. Contrary to what was observed in the case of the reduction reaction of nitroindazoles by SnCl₂ in different alcoholic solvents and which allowed access alongside the corresponding amine to alkoxyaminoindazole derivatives, the reduction reaction of 2-nitrocinnamic acid 1 under the same conditions mentioned above results in a mixture of two products derived from indole and quinoline. This result shows that the nature of the structure plays a fundamental role in obtaining new heterocyclic systems.

Scheme 1

Reaction of reduction of (E)-3-(2-nitrophenyl) acrylic acid by SnCl₂ in different alcoholic solvents

Table 1 Yields for N-alkyl-6-nitroindazoles 2a–h and 3a–h hydroxyquinoline

All structures were determined by examination of their NMR data. Furthermore, the structures of product 2b are unambiguously confirmed through single-crystal X-ray crystallographic analysis (Fig. 1). Looking at the influence that the solvent on the reduction/cyclization yields in the presence of SnCl₂ in different alcoholic solvents, we observed that the rearrangement resulting from the reduction of nitrocinamic acid is complete, the overall yield of the final products oscillating between 87% and 98%. The yields of N-hydroxyindoles 2a–f are better compared to hydroxyquinoline 3. Compound 2f resulting from the reduction of nitrocinnamic acid in hydroxyalkyl is obtained in a better yield (60%).

Fig. 1

X-ray crystal structures of 2b

In the ¹H NMR spectrum of compounds 2a–f, we note more to the signals due to the protons of the alkoxy group, a signal at around 7.24–7.30 ppm attributable to the CH proton in position 3 of the indole and a signal at around 11.6–11.65 ppm of the proton of the hydroxy group OH. In the ¹³C NMR spectrum of the compounds 2a–f, we observe more to the signals due to the carbons of the alkoxy group, a signal around 109.2–110.0 ppm attributable to the CH carbon of the pyrrole.

A plausible mechanism for the formation of formation des N-hydroxyindoles 2a-f and l’hydroxyquinoline 3, Scheme 2. The initial step of the reduction reaction of compound 1 corresponds to the formation of esterified intermediate A. The latter evolves in two ways:

Scheme 2

Mechanism of reduction of (E)-3-(2-nitrophenyl) acrylic acid by SnCl₂ in alcohol

Way 1: A undergoes intramolecular cyclization, leading to the formation of intermediate B. The latter rearranges, and after aromatization leads to the expected products 2a-f.

Way 2: The nitro group of A changes to the amine group of intermediate C, the latter undergo intramolecular cyclization and leads to the expected product 3.

After this first interesting result of the synthesis of N-hydroxyindoles obtained for the first time via the reduction reaction of 2-nitrocinamic acid by SnCl₂ in different alcoholic solvents, we have opted to consider other conditions to improve the yield of the hydroxyl indole derivatives. Therefore, the treatment of 2-nitrocinamic acid 1 with different equivalents of SnCl₂ in methanol permits obtaining N-hydroxy indole 2a with varying yields (Table 2). The best yield is obtained with the use of three equivalents of SnCl₂. Beyond three equivalents of SnCl₂, product 3 is favoured.

Table 2 Yield of products 2a and 3 according to the number of SnCl₂ equivalents

We used the operating conditions mentioned above, this time in the presence of 2% HCl, the reduction reaction of nitrocinnamic acid with 3 equivalents of SnCl₂ led only to hydroxyquinoline 3 with a yield of 65% (Scheme 3).

Scheme 3

The reduction reaction of nitrocinnamic acid with 3 equivalents of SnCl₂ in the presence of 2% HCl

In the reaction conditions similar to those developed previously, we also envisioned the reduction reaction of 2-nitrophenylpyruvic acid 4 with three equivalents of SnCl₂ at the reflux of ethanol. These conditions made it possible to obtain N-hydroxy indole 2b with a yield of 60% (Scheme 4).

Scheme 4

The reduction reaction of 2-nitrophenylpyruvic acid with three equivalents of SnCl₂ at reflux of ethanol

2.2 Experimental Part

Melting points were determined using a Büchi-Tottoli apparatus.¹H and ¹³C NMR spectra were recorded in DMSO-d₆, and solution (unless otherwise specified) with tetramethylsilane (TMS) as an internal reference using a Bruker AC 300 (¹H) or 75 MHz (¹³C) instrument. The chemical shifts are given in ppm relative to tetramethylsilane (TMS) taken as an internal reference. The multiplicity of ¹³C NMR resources was assigned by distortionless enhancement by polarization transfer (DEPT) experiments. Column chromatography was carried out on SiO₂ (silica gel 60Merck 0.063–0.200 mm). Thin-layer chromatography (TLC) was carried out on SiO₂ (silica gel 60, F 254 Merck 0.063–0.200 mm), and the spots were located with UV light. Commercial reagents were used without further purification unless stated. The general procedure for the synthesis of compound 2a–f is as follows: under an inert atmosphere, (1.0 mmol) of 2-nitrocinnamic acid or (2-nitrophenylpyruvic acid) is added with SnCl₂ (3.0 mmol) in different alcoholic solvents (20 ml). The reaction mixture is brought to reflux for 6–8 h. After reduction, the solution was allowed to cool down. The pH was made slightly basic (pH 7–8) by the addition of 5% aqueous potassium bicarbonate before being extracted with ethyl acetate. The organic phase was washed with brine and dried over magnesium sulfate filtered and concentrated. The residue is eluted with ethyl acetate/hexane (10%/90%) through a column of silica gel.

Methyl 1-hydroxy-1H-indole-2-carboxylate 2a. White solid; mp 182–184 °C; ¹HNMR (DMSO-d₆): δ3.78 (s, 3H; CH₃O), 6.48 (d, 1H, J = 9.2 Hz, H-Ar), 7.13–7.23 (m, 3H, H-Ar), 7.26 (s, 1H, H-pyrrole), 7.84 (d, 1H, J = 9.2 Hz, H-Ar), 11.63 (s, 1H, OH). ¹³C NMR (DMSO-d₆): 55.90 (CH₃O), 109.80 (CH), 116.80 (CH), 119.90 (CH), 120.1 (C), 122.80 (CH), 133.80 (C), 140.30 (CH), 154.50 (C), 162.00 (CO).

Ethyle 1-hydroxy-1H-indole-2-carboxylate 2b. White solid; mp 175–177 °C. ¹HNMR (DMSO-d₆): δ1.33 (t, 3H, J = 7.20 Hz, CH₃),4.03 (q, 1H, J = 7.20 Hz, CH₂O), 6.48 (d, 1H, J = 9.60 Hz, H-Ar), 7.11–7.22 (m, 2H, H-Ar), 7.25 (s, 1H, H-pyrrole), 7.83 (d, 1H, J = 9.6 Hz, H-Ar), 11.63 (s, 1H, OH). ¹³C NMR(DMSO-d₆): 15.10 (CH₃), 63.80 (CH₂O), 110.50 (CH), 116.80 (CH), 120.10 (C), 120.30 (CH), 122.7 0(CH), 133.70 (C), 140.30 (CH), 153.80 (C), 162.00 (CO).

Propyle 1-hydroxy-1H-indole-2-carboxylate 2c. White solid; mp 170–172 °C. ¹HNMR(DMSO-d₆): 0.98 (t, 3H, J = 7.40 Hz, CH₃), 1.68–1.79 (m, 2H, CH₂), 3.94 (t, 1H, J = 6.50 Hz, CH₂O), 6.48 (d, 1H, J = 9.60 Hz, H-Ar), 7.12–7.25 (m, 3H, H-Ar), 7.82 (d, 1H, J = 9.60 Hz, H-Ar), 11.63 (s, 1H, OH). ¹³C NMR(DMSO-d₆): 10.90 (CH₃), 22.50 (CH₂), 69.80 (CH₂O), 110.50 (CH), 116.80 (CH), 120.10 (C), 120.40 (CH), 122.70 (CH), 133.7 0(C), 140.30 (CH), 153.90 (C), 162.00 (CO).

Butyle 1-hydroxy-1H-indole-2-carboxylate 2d. White solid; mp 160-162 °C. ¹HNMR (DMSO-d₆): 0.92 (t, 3H, J = 7.20 Hz, CH₃), 1.48–1.500(m, 2H, CH₂), 1.72–1.79 (m, 2H, CH₂), 3.96 (t, 1H, J = 6.90 Hz, CH₂O), 6.47 (d, 1H, J = 9.60 Hz, H-Ar), 7.10–7.24 (m, 3H, H-Ar), 7.84 (d, 1H, J = 9.6 Hz, H-Ar), 11.68 (s, 1H, OH). RMN ¹³C (DMSO-d₆): 14.10 (CH₃), 19.20 (CH₂), 31.20 (CH₂), 68.00 (CH₂O), 110.50 (CH), 116.80 (CH), 120.30 (CH), 120.40 (C), 122.70 (CH), 133.70 (C), 140.30 (CH), 154.10 (C), 162.10 (CO).

Isopropyle 1-hydroxy-1H-indole-2-carboxylate 2e. White solid; mp 150–152 °C. ¹HNMR (DMSO-d₆): 1.25 (d, 6H, J = 6.2 Hz, 2CH₃), 4.57 (m, 1H, O-CH), 6.47 (d, 1H, J = 9.6 Hz, H-Ar), 7.09–7.24 (m, 3H, H-Ar), 7.80 (d, 1H, J = 9.6 Hz, H-Ar), 11.68 (s, 1H, OH). RMN ¹³C (DMSO-d₆): 22.4 (2CH₃), 70.4 (CHO), 112.4 (CH), 116.8 (CH), 120.4 (C), 121.4 (CH), 122.6 (CH), 133.8 (C), 140.3 (CH), 152.7 (C), 162.1 (CO).

Allyl 1-hydroxy-1H-indole-2-carboxylate 2f. White solid; mp 195-197 °C. ¹HNMR (DMSO-d₆): 4.55–4.58 (m, 2H; CH₂O), 5.33–5.38 (m, 2H, =CH₂), 5.98–6.10 (m, 1H, =CH), 6.480 (d, 1H, J = 9.60 Hz, H-Ar), 7.12–7.22 (m, 3H, H-Ar), 7.81 (d, 1H, J = 9.60 Hz, H-Ar), 11.62 (s, 1H, OH). RMN ¹³C (DMSO-d₆): 69.10 (CH₂O), 103.70 (CH), 110.90 (CH), 117.90 (=CH₂), 120.20 (C), 120.40 (CH), 122.70 (CH), 134.10 (CH), 140.20 (CH), 153.60 (C), 162.10 (CO).

Quinolin-2-ol. White solid; mp 193-195 °C. ¹HNMR (DMSO-d₆): 6.48–6.57 (m, 1H; H-Ar), 7.15 (dd, 1H, Ar-H), 7.48 (d, 1H, Ar-H), 7.63 (d, 1H, Ar-H), 7.87 (d, 1H, –CH=), 11.75 (s, 1H, OH). RMN ¹³C (DMSO-d₆): 115.10 (CH), 119.10 (C), 121.70 (CH), 121.80 (CH), 127.80 (CH), 130.30 (CH), 138.80 (C), 140.10(CH), 161.90 (CO).

2.3 DFT Investigation

2.3.1 Calculation of the Global Reactivity Descriptors of 2b

All electron DFT geometry optimization, the spatial and electronic structure of the 2b were performed by DFT/RB3LYP/6-31+G(d,p) basis set implemented in Gaussian 9, Revision C.01 [26] Density Functional Theory electronic structure program by combining the results of Gauss View 6.0.16 programs [27]. Calculated quantum chemical descriptors (QCD) were performed to study the structural and electronic properties of 2b. The 3D minimized 2b spatial structure and atom counts are shown in Fig. 2.

Fig. 2

3D-Minimized structure of 2b

In this work, the SD (standard deviation) was operated in comparative studies between the minimized structure DFT method (bond length (in Å), bond angles and dihedral (in degrees)) in the isolated form and experimental results (X-ray data) for 2b [28,29,30,31]. The average percentage change in link lengths between DFT data and X-ray data is 1% Å. The average percentage change in bond angles is 2% °. The average percentage change for the dihedrals is 1.7% °. Note that the link distances, link angles and dihedral angles calculated by the DFT/RB3LYP/6-31+G(d,p)/H₂O basis set are slightly high than the experimental (X-ray) observation. Indeed, theoretical calculations were made on a molecule in the aqueous phase, but the experimental data were obtained in the crystalline state. The crystal and ground state minimized structural descriptors of link distances, link angles and dihedral angles of 2b are collected in Table 3.

Table 3 Distances, angles and dihedral angles of 2b

The HOMO(TD-HOMO)/LUMO(TD-LUMO) orbital’s and MEPs of 2b using $\text{DFT}/RB3LYP/6-31+\text{G(d,p)}$ a basis set in the aqueous phase. DFT studies (local and global reactivity) covered geometry minimization. Frontier molecular orbitals the: HOMO (bonding orbital)–LUMO (anti-bonding orbital) energies and molecular electrostatic potential (MEPs) [32] is shown in Fig. 3.

Fig. 3

The The HOMO (TD-HOMO). LUMO(TD-LUMO) plots of title 2b molecule

The frontier molecular orbital (HOMO/LUMO) determine how the molecule interacts with other species. The HOMO (total density-HOMO) orbitals exhibited the predominance of the electron density character of the two characters (Sigma (σ) and Pi (π) bonds)) over the entire backbone of the compound. except for oxygen (–O₁₅ and –O₁₆) and carbon (C₁₄, C₁₇ and C₁₈) atoms which exhibited of the electron density distribution (Sigma (σ) and Pi (π) bonds). On the other hand, the electron density distribution on the LUMO (total density-LUMO) orbitals showed a mixture of the two characters (Sigma (σ) and Pi (π) bonds) but the ethyl (–CH₂–CH₃) group did not show any type of electron density distribution.

2.3.2 Calculation of the Global Reactivity Descriptors of 2b.

The E_HOMO energy is found to be −5.04518 kcal/mol and the E_LUMO energy is found to be −1.67417 kcal/mol. Hence, the energy difference between E_HOMO and E_LUMO (energy gap ΔE_g) is + 3.37111 kcal/mol. The mostly small energy difference between HOMO and LUMO lead to the ease of transporting electrons from HOMO level to LUMO level. With a small gap, the molecule is more polarized and is known as a soft molecule [33]. The bond gap plays a critical role in determining the molecular electrical transport properties and enables us to determine the chemical reactivity and kinetic stability of the single molecule. A molecule with a lower ΔE_g energy is associated with a high chemical reactivity and low kinetic stability. The lower ΔE_g energy explains the charge transfer interactions taking place within the molecule, which was recently, used to prove the bio-activity from intramolecular charge transfer because it is an electron conductivity measure [34]. For the charged molecule, its value depends on the orientation and the choice of the origin of the molecule. This dipole moment value is among the descriptors useful for estimating the biological activity of molecule [33]. The relationships between biological activity and dipole (µ) moment value are studied in 2b compound. The µ value of 2b is again calculated using the DFT/RB3LYP/6-31+G(d,p) basis set. The µ value reflects the molecular charge distribution and is given as +3.80339D, which reflects the high stability of 2b. The calculated (E_HOMO. E_LUMO. ΔE_g) values for these global reactivity descriptors using the $\text{DFT}/RB3LYP/6-31 + \text{G(d, p)}$ basis set are displayed in Table 4.

Table 4 The obtained docking parameters of the (2a–2f) indole derivatives

2.3.3 Calculation of the Local Reactivity Descriptors of 2b

The mapping of 3D-MEPs gives an overview of the charge density of 2b (Fig. 4). The greatest negative electrostatic potential is concentrated around the $\rangle {\text{N}}_{{{24}}} - {\text{O}}_{{{25}}} - {\text{H}}$. $\rangle {\text{C}}_{{{14}}} - {\text{O}}_{{{15}}}$. $\rangle {\text{C}}_{{{14}}} - {\text{O}}_{{{16}}}$ and $\rangle {\text{C}}_{{{17}}} - {\text{O}}_{{{16}}}$ groups and aromatic rings (red legend). As exposed in Fig. 3, this suggests that these (Sigma (σ) character of electron density distribution) groups and aromatic (Pi (π) character of electron density) ring are rich in electrons (correspond to their electron-withdrawing effect) and is most susceptible to electrophilic active centers. Regions with groups show a positive electrostatic potential (blue legend). which implies that they are deficient in electrons and are sensitive to nucleophilic active centers. The 3D-charge distributions on 2b indicate that the molecule active (N₂₄, O₂₅, O₁₆ and O₁₅) centres correspond to reactivity concerning electrophilic attack when the molecule loses electrons. On the other hand, the other centers correspond to reactivity concerning nucleophilic active centers.

Fig. 4

3D-Molecular electrostatic potential(MEPs) surface of 2b

From Fig. 4. the 2b MEPs presence with colors scaled between −3.6610^–2 (deepest red) and + 3.6610^–2 (deepest blue). whereas the intermediary colors indicate the intermediary electrostatic potentials. The maximum negative electrostatic potential (electro-negativity) appears around the (=N₂₄, –O₂₅, –O₁₆ and –O₁₅) atoms, which indicates the nucleophilic center reaction of the 2b compound. On the other hand, the maximum positive electrostatic potential appears around the hydrogen atoms of the aromatic ring and some carbon atoms, which indicate the electrophilic site reaction of the 2b. Applying the same ideas as before, the definitions for Fukui (local reactivity Fig. 5) Indices are [34]:

Fig. 5

The bar graph of Fukui (local reactivity) indices for nucleophilic f ⁻ and electrophilic f⁺ active centres for 2b

Nucleophilic (f⁺) Fukui Function: $f_{x}^{ + } = \rho_{N + 1} (x) - \rho_{N} (x)$

Electrophilic (f⁻) Fukui Function: $f_{x}^{ - } = \rho_{N} (x) - \rho_{N - 1} (x)$

where $\rho_{N + 1} (x)$. $\rho_{N} (x)$ and $\rho_{N - 1} (x)$ are the electronic densities at point x for a system with N + 1, N, and N − 1 electrons. respectively.

The Fukui functions (electrophilic and nucleophilic regions) were calculated by the DFT/RB3LYP/6-31+G(d,p)/H₂O method to predict the chemical reactivity of the 2b.

The nucleophilic active centre will be where the f⁻ value is maximal. In turn, the electrophilic active centre was controlled by the f⁺ value. Therefore, the most favoured electrophilic active centres are C₁₄, C_7, O_25, O₁₆ and O₁₅, and since the nucleophile index provides important values in N₂₄. Thus. for nucleophilic centre actives. The most reactive centres of 2b are the rest of the carbons (C₁, C₂, C₁₇, C₁₈, C₅, …) atoms. this result is agreed with MEPs.

2.4 Molecular Docking

Indole (benzopyrrole) is one of the most widely distributed heterocyclic ring systems consisting of fused six-membered benzene and five-membered pyrrole rings. Indole containing compounds are well known to exhibit a variety of pharmacological activities such as anti-inflammatory [35], antioxidant [36], antiviral [37], antibacterial [38, 39], and anticancer [39], On the other hand, 2.3-dioxindole an oxidized form of Indole, is reported to exhibit a variety of biological activities like antibacterial, antimicrobial [41] and anti-human immunodeficiency virus type 1 (HIV-1) activities [42]. The structures of 1-hydroxy-1H-indole-2-carboxylate derivatives (2a–2f) evaluated were optimized using the Gaussian 9, software program [26]. The three-dimension crystal structures of the target proteins before docking were obtained from Protein Data Bank (see http//www.rcsb.org/pdb). The molecular docking study carried out with Autodock 4.2 program along with the graphical interface Auto Dock Tools (ADT) version 1.5.6 [43] was used to evaluate the potential of the (2a–2f) derivatives to docked into the active sites of the HIV-1 Protease (PDB ID: 1HSG) and the SARS-CoV-2 main protease (M^pro) of Coronavirus disease 2019 (PDB ID: 6LU7) proteins. Discovery Studio Visualizer software was applied to visually verify the docked compound and its H-bond interactions [44]. PyMol [45] was used to show the possible binding mode of the indole molecules with their target proteins, aiming to explain their anti-HIV-1 and antiviral activities. The water molecules were removed from the 1HSG and 6LU7 proteins. Polar hydrogen atoms and then Kollman and Gasteiger atom charges were added to the (2a–2f) derivatives by Auto dock Tools (ADT) before subjecting to docking analysis.

Auto Dock binding energy (kcal/mol). inhibition constants (μM), and interactions of all the docked compounds with protein residues were listed in Table 5. 1HSG crystal structure of the HIV-1 Protease bound with binding energy − 4.72, − 4.75, − 4.68, − 4.98, − 4.97, − 4.61 kcal/mol for 2a, 2b, 2c, 2d, 2e and 2f respectively. The trend of the human immunodeficiency virus type 1 activity of all the indole derivatives is as follows: 2d > 2e > 2b > 2a > 2c > 2f. Interaction of anti-HIV-1 protein shows the existence of many interactions which are as follows: two conventional hydrogen bonds and one Pi-Alkyl bond was found in 1HSG interacting with amino acids (1.9–2.4 Å, ARG57; 1.7–1.9, GLU35 and 3.3–3.6, PRO79) with the inhibition constant (228.19–420.98 M$\mu$). respectively, The antiviral activity of the (2a–2f) indole derivatives obeyed the order 2b > 2a > 2f > 2c > 2e > 2d. Several interactions between COVID-19 main protease (PDB ID: 6LU7) and (2a–2f) indole derived compounds are as follows: the conventional hydrogen bond interaction between indole ring and THR111 residue is observed within the bond distance 3.3–3.8 Ǻ and Pi-Alkyl interactions between PHE294, PRO293, VAL104 residues and hydrogen atom of CH₃ group at 3.4–4.7 Ǻ. It can be observed in Figs. 6 and 7 that hydrogen and oxygen atoms in the (2a–2f) indole derivatives are responsible for forming hydrogen bonds with 1HSG and 6LU7 protein residues.

Table 5 The E_HOMO, E_LUMO, ΔE_g as well as other global reactivity descriptors of 2b

Fig. 6

2D diagrams of the (2a–2f) indole derivatives docked into the binding site of the anti-HIV-1 and antiviral proteins

Fig. 7

3D diagrams of the (2a–2f) indole derivatives docked into the binding site of the anti-HIV-1 and antiviral proteins

3 Conclusion

In conclusion, we have developed a new rapid and efficient synthesis strategy allowing access to various derivatives of N-hydroxyindole and hydroxyquinoline. Our strategy involves the condensation reaction intramolecular reductive in different alcoholic solvents of 2-nitrocinnamic acid and 2-nitrophenylpyruvic acid. This reduction reaction with stannous chloride (SnCl₂) gave good yields with a short reaction time and easy processing. This method represents a new strategy for obtaining new derivatives of substituted indole, which promises a wide application of organic, biological and pharmacological products. Finally, this reduction made it possible to isolate the substituted indole by a judicious choice of the metal catalyst with better yields, which enriches the database of the literature. The docking results about our Indole products show an interesting potential of them against anti-human immunodeficiency virus type 1 (HIV-1) and SARS-CoV-2 virus.