Quinoline Derivatives: Design and Synthesis as a Potential COVID-19 Protease Inhibitor

Mani R; Ranjith WAC

Research Article

Austin J Bioorg & Org Chem. 2023; 2(1): 1005.

Quinoline Derivatives: Design and Synthesis as a Potential COVID-19 Protease Inhibitor

Mani R* and Ranjith WAC

Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to be University), India

*Corresponding author: Rajeshekar Mani Centre for Molecular and Nanomedical Sciences, International Research Centre, Sathyabama Institute of Science and Technology (Deemed to be University), Chennai - 600 119, India

Received: November 21, 2022; Accepted: January 30, 2023; Published: February 06, 2023

Abstract

A multicomponent one-pot reaction involving Phenylacetylene, 4-Aminofluorescein and aromatic aldehydes using Cu (I) as a catalyst is described, which provides an efficient and practical route to synthesize quinoline in good yield. The compound was analyzed for its potential to act on 3C-like proteinase using in silico docking studies, 4b and 4c showed a docking score of -8.2 kcal/mol (2 hydrogen bonds) and -8.1 kcal/mol (2 hydrogen bonds) respectively for monomer of 3C-like protease, and -8.88 kcal/mol (3 hydrogen bonds) and -8.9 kcal/mol (4 hydrogen bonds) respectively for dimer of 3C-like protease. These provide an insight of using Quinolines as a potential drug to target COVID 19 protein target 3C-like protease.

Keywords: Aminofluorescein; Quinoline; One-Pot Reaction; Phenylacetylene; COVID 19

Introduction

An outbreak of a series of acute respiratory illness caused by a novel coronavirus, SARS-CoV-2, caused a global threat in 2020. The World Health Organization (WHO) named the disease “COVID-19” and declared it as a world health emergency pandemic. Quinolines play an important role in organic chemistry. They are important structural motifs that exist in numerous natural products are shown in (Figure 1) [1-3]. Quinolines are heterocyclic molecules composed off used benzene and pyridine rings. The quinolines can possess various biological activities, including antiproliferative [4], antiviral [5], antibacterial [6], antifungal [7], anti-infl ammatory [8], and antiparasitic [9]. Members of the quinoline family, such as chloroquine and hydroxychloroquine, have shown antiviral activity against several viruses, such as coronaviruses [5], human immunodeficiency virus [10], and respiratory syncytial virus [11]. Concerning Flavivirus, quinoline derivatives have proved active against the Hepatitis C virus [12], West Nile virus [13], Japanese Encephalitis virus [14], Zika virus [15], and dengue virus. It also found wide utility as efficient organo-catalysts and used as a ligand for the preparation of phosphorescent complexes. They are useful tools for the highly enantio selective syntheses of chiral molecules [16,17].

Figure 1: Structures of quinoline ring containing natural products.


    

    

    Figure 1: Structures of quinoline ring containing natural products.

Among these Multicomponent Reactions (MCRs) provides easy access to the preparation of quinoline derivatives, because Multicomponent Reactions (MCRs) have emerged as bond-forming efficient tools in medicinal chemistry [18,19]. All these procedures are through strong acid/metal-catalyzed sequential intermolecular addition of alkynes onto imines and subsequent intramolecular ring closure by arylation. The quinoline core in both biological and chemical fi elds, new direct approaches remain highly valuable to the contemporary collection of synthetic methods [20,21]. The study shows that most of the one-pot reaction involves amine, aldehyde, and acetylene moieties to synthesize quinoline derivatives [22]. In the context of our studies in the area of MCRs, we would like to report an efficient approach for the one-pot synthesis of quinolone and target the protein of COVID 19.

Experimental Section

General Methods

4-Aminofluorescein, Aldehydes, Phenylacetylene, Copper chloride and other solvents were obtained from SRL, Chennai, Tamil Nadu, India. Column chromatography was performed on Silica Gel (100-200 mesh). Melting points were measured on a Sigma micro melting point apparatus and are uncorrected. NMR spectra were recorded on Bruker DRX 300 MHz in CDCl₃ or DMSO-d₆ at the University of Madras (Chennai, Tamil Nadu, India). TMS was used as the internal standard (d = 0.00 ppm) and all the J values are given in hertz. Elemental analyses were performed using Perkin-Elmer 2400 elemental analyzer.

General Procedure for the Synthesis of Quinoline (4a-e)

To a solution of the aldehydes (1a-e, 1.0 mmol), 4-Aminofluorescein (2, 1.0 mmol), Phenylacetylene (3, 1.0 mmol) and dry THF (10 mL) were added copper chloride (0.3 mmol). After stirring at 80°C (oil bath temperature) for a given period of time, the reaction mixture was evaporated under reduced pressure and extracted by DCM-water. The DCM layer was dried over anhyd. Na₂SO₄ and concentrated to dryness. The product was further purifi ed by flash column chromatography.

Physicochemical and spectral data for 2-(4-chlorophenyl)-3',6'-dihydroxy-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9'-xanthen]-8-one (4a): A mixture of 4-Chlorobenzaldehyde (1a, 0.14 g, 1.0 mmol), 4-Aminofluorescein (2, 0.34 g, 1.0 mmol), Phenylacetylene (3, 0.10 g, 1.0 mmol) and CuCl (0.07 g, 0.3 mmol) in 10 mL of THF afforded compound 4a as an pale yellow solid (0.41 g, 73%); mp 152-154^oC; [a]_D³¹ + 58.8 (c 0.1, CHCl₃); ¹H NMR: (CDCl₃, 300 MHz): d 6.74 (d, 2H, J = 8.4 Hz, Ar-H), 6.77 (d, 1H, J = 8.4 Hz, Ar-H), 6.98 (t, 2H, J = 7.8 Hz, Ar-H), 7.08 (t, 2H, J = 9.9 Hz, Ar-H), 7.32 (t, 1H, J = 8.0 Hz, Ar-H), 7.58 (q, 4H, J = 7.5 Hz, Ar-H), 7.70 (d, 3H, J = 6.8 Hz, Ar-H), 8.09 (q, 1H, J = 8.5 Hz, Ar-H), 8.23 (s, 2H, Ar-OH), 8.25 (d, 2H, J = 7.8 Hz, Ar-H). 13C NMR: (CDCl₃, 75 MHz): d 82.8, 110.2, 116.4, 117.9, 118.4, 119.4, 124.2, 125.3, 125.6, 126.1, 128.4, 128.8, 128.9, 129.0, 130.2, 130.3, 130.4, 130.6, 133.9, 134.3, 135.4, 149.8, 150.2, 150.6, 150.8, 152.8, 164.5, 169.1, Anal. Calcd for C₃₅H₂₀ClNO₅: C, 73.75; H, 3.54; N, 2.46. Found: C, 73.76; H, 3.52; N, 2.44.

Physicochemical and spectral data for 2-(4-bromophenyl)-3',6'-dihydroxy-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9'-xanthen]-8-one (4b): A mixture of 4-Bromobenzaldehyde (1b, 0.18 g, 1.0 mmol), 4-Aminofluorescein (2, 0.34 g, 1.0 mmol), Phenylacetylene (3, 0.10 g, 1.0 mmol) and CuCl (0.07 g, 0.3 mmol) in 10 mL of THF afforded compound 4b as an pale yellow solid (0.43 g, 70%); [a]_D³¹ + 68.2 (c 0.1, CHCl₃); ¹H NMR: (CDCl₃, 300 MHz): d 6.72 (d, 2H, J = 7.2 Hz, Ar-H), 6.75 (d, 1H, J = 8.4 Hz, Ar-H), 6.95 (t, 2H, J = 7.2 Hz, Ar-H), 7.09 (t, 2H, J = 7.2 Hz, Ar-H), 7.35 (d, 1H, J = 7.4 Hz, Ar-H), 7.55 (q, 2H, J = 7.5 Hz, Ar-H), 7.62 (d, 2H, J = 7.5 Hz, Ar-H), 7.72 (d, 3H, J = 6.8 Hz, Ar-H), 8.12 (q, 1H, J = 7.5 Hz, Ar-H), 8.22 (s, 2H, Ar-OH), 8.28 (d, 2H, J = 7.5 Hz, Ar-H). ¹³C NMR: (CDCl₃, 75 MHz): d 82.6, 110.4, 116.6, 117.5, 118.2, 119.5, 124.4, 125.5, 125.8, 126.7, 128.2, 128.5, 128.8, 129.6, 130.1, 130.3, 130.5, 130.7, 133.5, 134.5, 135.4, 149.6, 150.4, 150.6, 150.8, 152.6, 164.6, 169.5, Anal. Calcd for C₃₅H₂₀BrNO₅: C, 68.42; H, 3.28; N, 2.28. Found: C, 68.44; H, 3.26; N, 2.26.

Physicochemical and spectral data for 2-(4-fluorophenyl)-3',6'-dihydroxy-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9'-xanthen]-8-one (4c): A mixture of 4-Fluorobenzaldehyde (1c, 0.12 g, 1.0 mmol), 4-Aminofluorescein (2, 0.34 g, 1.0 mmol), Phenylacetylene (3, 0.10 g, 1.0 mmol) and CuCl (0.07 g, 0.3 mmol) in 10 mL of THF afforded compound 4c as an pale yellow solid (0.37 g, 67%); [a]_D³¹ + 65.7 (c 0.1, CHCl₃); ¹H NMR: (CDCl₃, 300 MHz): d 6.73 (d, 2H, J = 8.4 Hz, Ar-H), 6.78 (d, 2H, J = 8.4 Hz, Ar-H), 6.96 (d, 2H, J = 7.5 Hz, Ar-H), 7.09 (t, 2H, J = 7.5 Hz, Ar-H), 7.32 (d, 1H, J = 8.0 Hz, Ar-H), 7.58 (d, 4H, J = 7.2 Hz, Ar-H), 7.70 (d, 2H, J = 7.6 Hz, Ar-H), 8.08 (d, 1H, J = 8.2 Hz, Ar-H), 8.23 (s, 2H, Ar-OH), 8.25 (d, 2H, J = 7.2 Hz, Ar-H). ¹³C NMR: (CDCl₃, 75 MHz): d 82.5, 110.3, 116.6, 117.6, 118.4, 119.5, 124.5, 125.3, 125.8, 126.5, 128.3, 128.8, 128.9, 129.6, 130.1, 130.3, 130.4, 130.8, 133.8, 134.3, 135.6, 149.6, 150.2, 150.6, 150.8, 152.8, 164.6, 169.2. Anal. Calcd for C₃₅H₂₀FNO₅: C, 75.94; H, 3.64; N, 2.53. Found: C, 75.92; H, 3.66; N, 2.54.

3.2.4 Physicochemical and spectral data for 3',6'-dihydroxy-2-(4-iodophenyl)-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9'-xanthen]-8-one (4d): A mixture of 4-Iodobenzaldehyde (1d, 0.23 g, 1.0 mmol), 4-Aminofluorescein (2, 0.34 g, 1.0 mmol), Phenylacetylene (3, 0.10 g, 1.0 mmol) and CuCl (0.07 g, 0.3 mmol) in 10 mL of THF afforded compound 4d as an pale yellow solid (0.45 g, 68%); [a]_D³¹ + 56.8 (c 0.1, CHCl₃); ¹H NMR: (CDCl₃, 300 MHz): d 6.75 (d, 2H, J = 8.4 Hz, Ar-H), 6.78 (d, 1H, J = 8.4 Hz, Ar-H), 6.96 (d, 2H, J = 7.8 Hz, Ar-H), 7.08 (d, 2H, J = 7.8 Hz, Ar-H), 7.32 (t, 2H, J = 8.0 Hz, Ar-H), 7.62 (q, 3H, J = 7.5 Hz, Ar-H), 7.74 (d, 3H, J = 7.2 Hz, Ar-H), 8.11 (q, 1H, J = 8.2 Hz, Ar-H), 8.25 (s, 2H, Ar-OH), 8.28 (d, 2H, J = 7.8 Hz, Ar-H). ¹³C NMR: (CDCl₃, 75 MHz): d 82.8, 110.5, 116.5, 117.8, 118.5, 119.6, 124.4, 125.1, 125.6, 126.5, 128.3, 128.8, 128.9, 129.5, 130.2, 130.3, 130.4, 130.6, 133.6, 134.6, 135.6, 149.7, 150.2, 150.6, 150.8, 152.7, 164.5, 169.3. Anal. Calcd for C₃₅H₂₀INO₅: C, 63.55; H, 3.05; N, 2.12. Found: C, 63.55; H, 3.05; N, 2.12.

Physicochemical and spectral data for 3',6'-dihydroxy-4-phenyl-2-(p-tolyl)-8H-spiro[furo[3,4-g]quinoline-6,9'-xanthen]-8-one (4e): A mixture of 4-Methylbenzaldehyde (1e, 0.12 g, 1.0 mmol), 4-Aminofluorescein (2, 0.34 g, 1.0 mmol), Phenylacetylene (3, 0.10 g, 1.0 mmol) and CuCl (0.07 g, 0.3 mmol) in 10 mL of THF afforded compound 4e as an pale yellow solid (0.36 g, 66%); [a]_D³¹ + 62.8 (c 0.1, CHCl₃); ¹H NMR: (CDCl₃, 300 MHz): d 2.34 (s, 3H, -CH₃), 6.75 (d, 2H, J = 8.4 Hz, Ar-H), 6.77 (d, 1H, J = 8.4 Hz, Ar-H), 6.96 (d, 2H, J = 7.8 Hz, Ar-H), 7.08 (t, 2H, J = 7.8 Hz, Ar-H), 7.38 (t, 2H, J = 8.0 Hz, Ar-H), 7.56 (q, 3H, J = 7.5 Hz, Ar-H), 7.72 (d, 3H, J = 6.8 Hz, Ar-H), 8.08 (d, 1H, J = 8.5 Hz, Ar-H), 8.23 (s, 2H, Ar-OH), 8.28 (d, 2H, J = 7.8 Hz, Ar-H). ¹³C NMR: (CDCl₃, 75 MHz): d 20.1, 82.5, 110.4, 116.7, 117.9, 118.6, 119.6, 124.5, 125.7, 125.7, 126.1, 128.2, 128.8, 128.9, 129.3, 130.2, 130.3, 130.4, 130.9, 133.2, 134.1, 135.4, 149.6, 150.2, 150.6, 150.8, 152.5, 164.2, 169.2. Anal. Calcd for C₃₆H₂₃NO₅: C, 78.68; H, 4.22; N, 2.55. Found: C, 78.66; H, 4.24; N, 2.53.

Ligand-Based Target Prediction and Molecular Docking Studies

The 3D structure of the molecule is drawn using the Discovery Studio software and was subjected to target protein prediction studies using D3 Similarity in the D3Targets-2019-nCoV server [23]. The Server uses two-dimensional and three-dimensional similarity of known molecular structure to predict target proteins for the desire/ query compounds. Further docking was performed using the D3Docking server which used Autodock Vina [24] to study the efficiency of the molecule for interaction with the 3C-like protease of COVID 19. K36 and O6K were used as control for the study.

Results and Discussion

Synthesis of Quinolines

Aldehydes (1a-e) and 4-Aminofluorescein (2) reacts with phenylacetylene (3) in the presence of CuCl as a catalyst in THF solvent and results in 66-73% yield of the respective quinoline (4a-e) as shown in (Scheme 1). The ¹H NMR spectra of the quinoline exhibit signals for the aromatic ring of the quinoline core structure in the region of 8.22-6.98 ppm. However, the aromatic carbons in the ¹³C NMR spectrum corresponding to the quinoline core structure resonate in the region of 158.1-110.2 ppm, which provides evidence for the quinoline over the possible fluorescein-amine. All these observations provide clear support for the formation of the 2,4-disubstituted quinoline. Structure of reaction time and product yields are given in (Table 1).

Scheme 1: Synthesis of quinolines.


    

    

    Scheme 1: Synthesis of quinolines.

Table 1: Structure of reaction time and product yields.






Table 1: Structure of reaction time and product yields.

The fi rst A³ coupling approach for quinoline synthesis was described by Rajasekar et al. in the presence of catalyst CuCl in 2014 [24]. The A³ coupled product propargylamine 5 underwent a Cu-mediated allenyl isomerization (6), followed by a intramolecular cyclization and dehydrogenative oxidation to accomplish quinoline 4a-e are shown in (Scheme 2).

Scheme 2: First A³ coupling approach for quinoline synthesis.


    

    

    Scheme 2: First A³ coupling approach for quinoline synthesis.

Target Prediction using D3 Similarity

D3Similarity is based on the two-dimensional and three-dimensional similarity of molecular structure. The target proteins are predicted based on the active compounds already available from experimental studies, followed by virtual screening via 2D and 3D similarities. The compounds showed a similarity index of 20.74 to CBMicro_032111 which is an inhibitor of 3C-like protease (Table 2). COVID 19 protein targets were primaried in the present study and the docking were performed.

Table 2: COVID 19 protein Target prediction of compounds using 3D similarity search.








  

    Compound

    Pubchem CID

    Mol ID

    Similarity

    3D Similarity

    2D Similarity

    Target Name

  

  

    4a

    2867165

    CBMicro_032111

    20.74

    69.64

    29.77

    virus:    3C-like protease

  

  

    4b

    2867165

    CBMicro_032111

    20.98

    69.48

    30.19

    virus: 3C-like protease

  

  

    4c

    70673796

    CHEMBL2235440

    20.82

    61.8

    33.69

    virus: 3C-like protease

  

  

    4d

    2867165

    CBMicro_032111

    20.74

    69.64

    29.77

    virus: 3C-like protease

  

  

    4e

    70673796

    CHEMBL2235440

    21.57

    61.98

    0.348

    virus: 3C-like protease

  

  

    4a

    66839793

    2-(3,4-Dihydroxyphenyl)-6-(3,7-dimethylocta-2,6-dienyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one

    22.01

    61.98

    0.3221

    virus: Papain-like protease

  

  

    4b

    66839793

    2-(3,4-Dihydroxyphenyl)-6-(3,7-dimethylocta-2,6-dienyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one

    22.01

    68.34

    0.3221

    virus: Papain-like protease

  

  

    4c

    66839793

    2-(3,4-Dihydroxyphenyl)-6-(3,7-dimethylocta-2,6-dienyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one

    22.71

    68.35

    0.3209

    virus: Papain-like protease

  

  

    4d

    66839793

    2-(3,4-Dihydroxyphenyl)-6-(3,7-dimethylocta-2,6-dienyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one

    21.91

    70.76

    0.3209

    virus: Papain-like protease

  

  

    4e

    66839793

    2-(3,4-Dihydroxyphenyl)-6-(3,7-dimethylocta-2,6-dienyl)-5,7-dihydroxy-2,3-dihydrochromen-4-one

    22.63

    68.26

    0.332

    virus: Papain-like protease






Table 2: COVID 19 protein Target prediction of compounds using 3D similarity search.

Docking and Interaction of Synthesized Componds against 3C-like Protease

Docking studies were carried out between the protein and the ligand in D3Docking server. The docking studies were performed against the dimer and monomer of 3C-like protease. CYS A:145, HIS A:163, HIS A:164, GLU A:166, HIS A:41, MET A:49, TYR A:54, PHE A:140, LEU A:141, ASN A:142, GLY A:143, SER A:144, MET A:165, HIS A:172, ASP A:187, GLN A:189 are the active site amino acid of the monomer of 3C-like protease, similarly THR A:26, HIS A:41, MET A:49, PHE A:140, LEU A:141, ASN A:142, GLY A:143, SER A:144, CYS A:145, HIS A:163, HIS A:164, MET A:165, GLU A:166, HIS A:172, ASP A:187, GLN A:189 are the active site residues of dimer of 3C-like protease. The docking score for 4b and 4c of -8.2 kcal/mol and -8.1 kcal/mol respectively for monomer of 3C-like protease, and -8.88 kcal/mol and -8.9 kcal/mol respectively for dimer of 3C-like protease (Table 3). The molecular interactions shows 4b and 4c has 2 hydrogen bonds each comparitivly less when compared to K36 (8) and O6K (5) for 3C-like protease monomer (Figure 2). The in teraction of 4b and 4c with 3C-like protease dimer also showed 3 and 4 hydrogen bonds when compared to K36 and O6K which showed 6 hydrogen bond. Similar hydrophobic interactions were observed in all the interactions (Figure 3).

Figure 2: Number of interactions (Hydrogen bond, Hydrophobic interaction, Pi-staking and salt bridges) present in the 3C-like protease and ligand complex.


    

    

    Figure 2: Number of interactions (Hydrogen bond, Hydrophobic interaction, Pi-staking and salt bridges) present in the 3C-like protease and ligand complex.

Figure 3: Molecular docking and interaction of 3C Like protease and 2-(4-chlorophenyl)-3’,6’-dihydroxy-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9’-xanthen]-8-one (4). (A) Aminoacid interaction in the active site between Dimer 3C like protease and synthesized molecule. (B) Aminoacid interaction in the active site between Monomer 3C like protease and synthesized molecule.


    

    

    Figure 3: Molecular docking and interaction of 3C Like protease and 2-(4-chlorophenyl)-3’,6’-dihydroxy-4-phenyl-8H-spiro[furo[3,4-g]quinoline-6,9’-xanthen]-8-one (4). (A) Aminoacid interaction in the active site between Dimer 3C like protease and synthesized molecule. (B) Aminoacid interaction in the active site between Monomer 3C like protease and synthesized molecule.

Table 3: Hydrogen bond and hydrophobic interaction between compounds and 3C-like protease.








  

    Compound 

    3C-like    protease monomer

    3C-like    protease dimer

    3C-like    protease monomer (Interactions)

    3C-like    protease dimer (Interactions)

  

  

    4a

    -6.6

    -6.8

    Hydrophobic 41A HIS 3.28


      Hydrophobic 47A GLU 3.97


      Hydrophobic 141A LEU 3.81


      Hydrophobic 166A GLU 3.9


      Hydrophobic 187A ASP 3.71


      p-Stacking 41A HIS .86

    Hydrophobic 25A THR 2.82


      Hydrophobic 27A LEU 3.47


      Hydrophobic 166A GLU 3.92


      Hydrophobic 168A PRO 2.94


      Hydrogen Bond 1B SER 2.89


      Hydrogen Bond 47A GLU 2.95


      Hydrogen Bond 166A GLU 2.25


      Hydrogen Bond 166A GLU 1.8


      Hydrogen Bond 189A GLN 2.71

  

  

    4b

    -8.2

    -8.8

    Hydrophobic 140A PHE 3.81


      Hydrophobic 141A LEU 3.87


      Hydrophobic 166A GLU 3.3


      Hydrogen Bond 189A GLN 2.64


      Hydrogen Bond 192A GLN 3.19

    Hydrophobic 140A PHE 3.8


      Hydrophobic 165A MET 3.87


      Hydrophobic 166A GLU 3.46


      Hydrogen Bond 188A ARG 1.7


      Hydrogen Bond 189A GLN 2.61


      Hydrogen Bond 192A GLN 2.75

  

  

    4c

    -8.1

    -8.9

    Hydrophobic 41A HIS 3.55


      Hydrophobic 47A GLU 3.31


      Hydrophobic 167A LEU 3.36


      Hydrophobic 168A PRO 3.76


      Hydrophobic 192A GLN 3.36


      Hydrogen Bond 47AGLU 2.31


      Hydrogen Bond 166A GLU 3.24

    Hydrophobic 140A PHE .75


      Hydrophobic 165A MET 3.83


      Hydrophobic 166A GLU 3.42


      Hydrogen Bond 186A VAL 2.07


      Hydrogen Bond 188A ARG 2.4


      Hydrogen Bond 189A GLN 2.67


      Hydrogen Bond 192A GLN 2.68

  

  

    4d

    -8.1

    -5.8

    Hydrophobic 140A PHE 3.8


      Hydrophobic 166A GLU 3.35

    Hydrophobic 47A GLU 3.32


      Hydrophobic 168A PRO 3.27


      Hydrogen Bond 1B SER 2.02


      Hydrogen Bond 47A  GLU 3.16


      Hydrogen Bond 142A ASN 3.07

  

  

    4e

    -7.4

    -7.9

    Hydrophobic 41A HIS 3.57


      Hydrophobic 47A GLU 3.27


      Hydrophobic 167A LEU 3.56


      Hydrophobic 168A PRO 3.64


      Hydrophobic 192A GLN 3.37


      Hydrogen Bond 47A GLU 2.39

    Hydrophobic 41A HIS 3.79


      Hydrophobic 47A GLU 3.34


      Hydrophobic 192A GLN 3.49


      Hydrogen Bond 1B SER 2


      Hydrogen Bond 1B SER 2.34


      Hydrogen Bond 47A GLU 2.73

  

  

    CBMicro_


      032111 (Control)

    -7

    -7.2

    Hydrophobic 47A GLU 3.17


      Hydrophobic 165A MET 3.92


      Hydrophobic 166A GLU 3.68


      Hydrophobic 189A GLN 3.88


      Hydrophobic 192A GLN 3.95


      Hydrogen Bond 189A GLN 3.08


      Hydrogen Bond 192A GLN 2.4


      Salt Bridges 41A HIS 5.3

    Hydrophobic 47A GLU 3.16


      Hydrophobic 140A PHE 3.9


      Hydrophobic 166A GLU 3.68


      Hydrophobic 189A GLN 3.86


      Hydrophobic 192A GLN 3.92


      Hydrogen Bond 189A GLN 3.11


      Hydrogen Bond 192A GLN 2.39

  

  

    CHEMBL


      2235440 (Control)

    -8

    -8

    Hydrophobic 25A THR 3.76


      Hydrophobic 27A LEU 3.83


      Hydrophobic 140A PHE 3.56


      Hydrophobic 165A MET 3.45


      Hydrophobic 166A GLU 3.44


      Hydrogen Bond 142A ASN 2.26


      Hydrogen Bond 143A GLY 2.61


      Hydrogen Bond 189A GLN 2.48

    Hydrophobic 25A THR 3.76


      Hydrophobic 27A LEU 3.94


      Hydrophobic 140A PHE 3.65


      Hydrophobic 166A GLU 3.62


      Hydrogen Bond 142A ASN 2.23


      Hydrogen Bond 143A GLY 2.75


      Hydrogen Bond 189A GLN 2.57


      Hydrogen Bond 190A THR 3.15

  

  

    K36 (Control)

    -6.8

    -7.2

    Hydrophobic 166A GLU 3.8


      Hydrophobic 168A PRO 3.84


      Hydrogen Bond 166A GLU 2.05


      Hydrogen Bond 166A GLU 2.36


      Hydrogen Bond 166A GLU 2.23


      Hydrogen Bond 188A ARG 2.45


      Hydrogen Bond 189A GLN 2.7


      Hydrogen Bond 190A THR 2.17


      Hydrogen Bond 190A THR 3.28


      Hydrogen Bond 192A GLN 2.32

    Hydrogen Bond 166A GLU 2.6


      Hydrogen Bond166A GLU 2.14


      Hydrogen Bond 189A GLN 2.15


      Hydrogen Bond 190A THR 2.22


      Hydrogen Bond 190A THR 2.56


      Hydrogen Bond 192A GLN 2.34

  

  

    O6K (Control)

    -6.9

    -7.3

    Hydrophobic 27A LEU 3.82


      Hydrophobic 166A GLU 3.71


      Hydrophobic 168A PRO 3.39


      Hydrogen Bond 47A GLU 2.17


      Hydrogen Bond 187A ASP 3.2


      Hydrogen Bond 189A GLN 2.42


      Hydrogen Bond 189A GLN 2.14


      Hydrogen Bond 192A GLN 3.49

    Hydrophobic 25A THR 3.68


      Hydrophobic 27A LEU 3.64


      Hydrophobic 47A GLU 3.83


      Hydrophobic 168A PRO 3.43


      Hydrophobic 189A GLN 3.85


      Hydrogen Bond 143A GLY 2.99


      Hydrogen Bond 166A GLU 3.06


      Hydrogen Bond 187A ASP 3.19


      Hydrogen Bond 189A GLN 2.18


      Hydrogen Bond 190A THR 2.33


      Hydrogen Bond 192A GLN 2.3


      Salt Bridges 47A GLU 5.04






Table 3: Hydrogen bond and hydrophobic interaction between compounds and 3C-like protease.

Conclusions

In conclusion, we have reported the synthesis of a novel class of quinoline. The most noteworthy aspect of this research is the development of an efficient and general route for the synthesis of the quinoline through a one-pot synthesis from aminofluorescein, benzaldehyde and phenylacetylene. This methodology of a one-pot three-component reaction in the synthesis of quinoline with substitution at the C-2 and C-4 positions appears attractive for the combinatorial synthesis of a quinoline library. Quinolines are potential antiviral molecules and in the present study, an attempt to fi nd its potential against COVID 19 is been assed using in silico docking studies. This resulted in identifying the synthesized compound to be a potential inhibitor molecule against the 3C like protease both as monomer and dimer. Further in vitro and in vivo studies can help in fi nding the efficacy of the synthesized molecule as a potential antiviral agent.

Acknowledgement

M. R. acknowledges fi nancial support from the DBT, New Delhi. The authors thank ‘Sathyabama Institute of Science and Technology, Chennai, Tamilnadu, India’ for providing infrastructure and instrumentation support to execute the research work.

References

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Citation: Mani R, Ranjith WAC. Quinoline Derivatives: Design and Synthesis as a Potential COVID-19 Protease Inhibitor. Austin J Bioorg & Org Chem. 2023; 2(1): 1005.

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S. No	R	Time (h)	Yield (%)
1	Cl (4a)	8	73
2	Br (4b)	8	70
3	F (4c)	8	67
4	I (4d)	8	68
5	Me (4e)	8	66