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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 11  |  Issue : 5  |  Page : 206-210

Design and synthesis of pyrazole derivatives for in vitro screening to protect angiotensin-converting enzyme 2 human cells against COVID-19


1 Department of Medicinal Chemistry, Government Science College, VTU-RRC, Chitradurga, Karnataka, India
2 Department of Chemistry, Davangere University Campus, Davangere, Karnataka, India
3 Department of Food Technology, Davangere University Campus, Davangere, Karnataka, India

Date of Submission12-Aug-2020
Date of Decision28-Aug-2021
Date of Acceptance28-Aug-2021
Date of Web Publication30-Oct-2021

Correspondence Address:
Dr. Ganesh N Yallappa
Department of Medicinal Chemistry, Government Science College, VTU-RRC, Chitradurga - 577 501, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmrp.cmrp_10_20

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  Abstract 


Background: ACE2 is a receptor for Corona virus. COVID-19 (coronavirus) is a deadly virus which can enter the human body through 'angiotensin-converting enzyme 2' human cells, hardly damages the respiratory system. On severe infection on these cells make the lungs weaker, results difficulty in breathing and lead to death. We took this major issue as a challenge and planned to synthesize chemical molecules (compounds), particularly pyrazole derivatives, and found good results. We prepared a convenient laboratory and planned according to our work.
Aims and Objectives: Cinnamaldehydes prepared by Claisen condensation were made to react with hydrazine hydrate and phenylhydrazine derivatives to afford pyrazoles. Nano-TiO2 was influenced the reactions without using solvents. Green chemistry was employed by microwave irradiation. Comparitive studies with conventional method were done. The synthesised compounds were characterized by Fourier transform infrared (FT-IR), Proton NMR (1H NMR) and elemental analysis. Synthesised compounds were screened against COVID-19 as antiviral agents.
Materials and Methods: We reported microwave method for the green synthesis of chemical molecules so that the reactions maintained under microwave irradiation. All the reactions were carried in microwave oven. In-vitro studies by MTT-assay method of synthesized chemical molecules exhibited good potency in inhibiting ACE2 infected human cells.
Results: Microwave assisted reactions were completed in very short time compared to Conventional method. More compounds exhibited good inhibitory potency having cytotoxicity concentration (CC50) and effective concentration (EC50) values against COVID-19. Inhibition of ACE2 human cells infected from COVID-19 was determined by MTT method. Some compounds proved as good potent molecules by acting ACE2 human cells receptors against COVID-19.
Conclusion: We afforded the Pyrazole molecules by green synthesis proved that these can act as effective drugs for ACE2 infected cells against Covid-19. Microwave method is proved to be an efficient and convenient one for the green synthesis.

Keywords: Cinnamaldehydes, COVID-19, in vitro screening, microwave method, pyrazoles, TiO2 nano-catalyst


How to cite this article:
Yallappa GN, Prasad S R, Vaidya G. Design and synthesis of pyrazole derivatives for in vitro screening to protect angiotensin-converting enzyme 2 human cells against COVID-19. Curr Med Res Pract 2021;11:206-10

How to cite this URL:
Yallappa GN, Prasad S R, Vaidya G. Design and synthesis of pyrazole derivatives for in vitro screening to protect angiotensin-converting enzyme 2 human cells against COVID-19. Curr Med Res Pract [serial online] 2021 [cited 2021 Dec 8];11:206-10. Available from: http://www.cmrpjournal.org/text.asp?2021/11/5/206/329699




  Introduction Top


At present, COVID-19 (coronavirus) is a very dangerous virus causing infection to the respiratory system of human 'angiotensin-converting enzyme 2' (ACE2) cells and leading to death. This is a challenging task for the researchers to discover the medicine for this. Hence, we planned to synthesise heterocyclic compounds, particularly pyrazole derivatives, for possessing good pharmaceutical efficacy. Literature study tells us that these derivatives have shown excellent results by acting as antiviral agents. We attempted to test these molecules against COVID-19 in Cytxon laboratory and afforded good results.

A simple and convenient method was followed for the synthesis of a series of pyrazoles. Different derivatives of cinnamaldehyde were made to react with hydrazine hydrate and different phenylhydrazines to afford pyrazoles.[1],[2],[3],[4] In this work, nano-TiO2 was used in all reactions without solvents. All reactions completed faster under microwave irradiation than conventional method.[5],[6] Structural elucidation of compounds was characterised by Fourier transform infrared (FT-IR), 1H NMR and elemental analysis. After literature study, pyrazoles exhibit excellent pharmaceutical applications by possessing various biological activities such as antibacterial, anti-inflammatory, antiviral, anticancer and anti-HIV.[7],[8],[9],[10] We planned to in vitro screening of the compounds against COVID-19. More compounds exhibited good inhibitory activity (CC50 and EC50 values) and confirmed that our compounds are having inhibitory potency against COVID-19.


  Materials and Methods Top


FT-IR spectrometer (Vertex series from Bruker), 1H NMR (400 MHz) and Thermo Fischer elemental analyser (BR422710716) were used. Biological activity against COVID-19 has been screened by Cytxon Biosolutions Pvt. Ltd., Hubli - 580 031, Karnataka, India.

General procedure for the synthesis of 2-substituted- 3-phenyl-1H-pyrazoles

0.01 M cinnamaldehydes (1) were made to react with 0.01 M of 0.5 g hydrazine hydrate (2) and 0.01 M phenylhydrazines (3). 0.1% M of nano-TiO2 was added to the reaction mixture. The reaction was run under microwave oven without solvents [Figure 1]. The solution was monitored by Thin Layer Chromatography and iodine chamber. After reaction completion, the crude compound along with nano-TiO2 was filtered off. It was separated by washing with hot water and recrystallised by ethanol.
Table 1: Reaction of 4a-j under microwave and conventional methods

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3-(2-methoxyphenyl)-1H-pyrazole (4a)

Orange solid, %yield = 87.00, m p: 146 °C, IR (KBr): 3412 cm−1 (N–H stretch), 3060 cm−1 (=C–H, stretch), 2867 cm−1 (–CH, stretch), 1175 cm−1 (C–O–C), 1212 cm−1 (C = N, stretch); 1H NMR (400 MHz, DMSO-d6): δ 2.5 (1H, d, CH = N, α to nitrogen), 3.3 (3H, s), 7.4 (1H, d, J = 2.5 Hz), 7.5 (1H, ddd, J = 8.2, 1.2, 0.5 Hz), 8.169-8.1 (1H, s, N–NH–CH).

Anal. Calcd. For C10H10N2O (174.00%): C, 68.97; N, 16.1; O, 9.19; H, 5.74; Found: C, 69.14; N, 15.89; O, 9.14; H, 5.83.

2-(1H-pyrazol-3-yl) phenol (4b)

Brown solid, %yield = 93.00, m p: 171°C, IR (KBr): 3432 cm−1 (N–H, stretch), 2919 cm−1 (–C–H, stretch), 1601 cm−1 (C = C, aromatic), 1180 cm−1 (C–OH, stretch); 1H NMR (400 MHz, DMSO-d6): δ 6.7 (1H, d, J = 2.5 Hz), 6.9 (1H, ddd, J = 8.2, 1.5, 1.4 Hz), 7.2 (1H, ddd, J = 7.6, 1.5, 1.5 Hz), 7.4 (1H, td, J = 1.4, 0.5 Hz), 7.7 (1H, ddd, J = 8.2, 7.6, 0.5 Hz), 8.1 (1H, d, J = 2.5 Hz), 9.6 (=N–NH).

Anal. Calcd. For C9H8N2O (160.00%): C, 67.50; N, 17.5; O, 10.00; H, 5.00; Found: C, 68.14; N, 17.59; O, 9.44; H, 4.83.

2-(1H-pyrazol-3-yl)-aniline (4c)

Yellow solid, % yield = 91.00, m p: 14903°C, IR (KBr): 3432 cm−1 (N–H, stretch), 3251 cm−1 (NH2, stretch), 3098 cm−1 (=C–H, stretch), 1422 cm−1 (C = C, aromatic); 1H NMR (400 MHz, DMSO-d6): δ 3.7 (2H, NH2), 2.0 (–CH = N, stretch), 6.8 (1H, d, J = 2.5 Hz), 7.04 (1H, td, J = 8.1, 1.1 Hz), 7.1 (1H, ddd, J = 8.3, 8.1, 1.4 Hz), 7.4 (1H, ddd, J = 8.3, 1.1, 0.5 Hz), 7.5 (2H, 7.48 (d, J = 2.5 Hz), 7.8 (ddd, J = 8.1, 1.4, 0.5 Hz), 8.6 (=CH–NH).

Anal. Calcd. For C9H9N3 (159.00%): C, 67.92; N, 26.42; H, 5.66; Found: C, 68.12; N, 26.79; H, 5.09.

2-(1H-pyrazol-3-yl)-benzonitrile (4d)

Yellow solid, %yield = 82.00, m p: 168°C, IR (KBr): 3390 cm−1 (N–H, stretch), 2191 cm−1 (CN, stretch), 1597 cm−1 (C = C, aromatic). 1H NMR (400 MHz, DMSO-d6): δ 2.5 (–CH = N), 7.5 (1H, d, J = 2.4 Hz), 7.5 (2H, 7.58 (ddd, J = 8.4, 7.6, 1.6 Hz), 7.8 (d, J = 2.4 Hz)), 7.89 (1H, ddd, J = 7.6, 1.6, 0.5 Hz), 7.9 (2H, 7.76 (ddd, J = 7.6, 7.6, 1.2 Hz), 7.7 (ddd, J = 8.4, 1.2, 0.5 Hz), 8.7 (s, =CH–NH).

Anal. Calcd. For C10H9N3 (171.00%): C, 70.17; N, 24.56; H, 5.26; Found: C, 71.12; N, 24.69; H, 4.19.

3-(2-nitrophenyl)-1H-pyrazole (4e)

Brown solid, %yield = 81.00, m p: 164°C, IR (KBr): 3439 cm−1 (N–H, stretch), 3081 cm−1 (=C–H), 1630 cm−1(), 1596 cm−1 (NO2). 1H NMR (400 MHz, DMSO-d6): δ 2.5 (=CH–N), 7.18 (1H, d, J = 2.1 Hz), 7.3 (1H, ddd, J = 8.5, 8.1, 1.6 Hz), 7.4 (1H, d, J = 2.1 Hz), 7.6 (2H, 7.77 (ddd, J = 8.1, 7.5, 1.6 Hz), 7.8 (ddd, J = 7.5, 1.6, 0.5 Hz)), 8.4 (1H, ddd, J = 8.5, 1.6, 0.5 Hz), 9.7 (1H, =CH–NH).

Anal. Calcd. For C9H7N3O2 (189.00%): C, 57.14; N, 22.23; O, 16.93, H, 3.70; Found: C, 58.02; N, 21.89; O, 16.97; H, 3.2.

Methyl 2-(1H-pyrazol-3-yl)-benzoate (4f)

Yellow solid, %yield = 79.00. m p: 192°C, IR (KBr): 3333 cm−1 (N–H, stretch), 2921 cm−1 (–C–H, stretch), 1732 cm−1 (C = O, ester). 1H NMR (400 MHz, DMSO-d6): δ 3.8 (3H, CH3), 6.8 (1H, d, J = 2.4 Hz), 7.0 (1H, ddd, J = 8.2, 7.7, 1.4 Hz), 7.1 (1H, d, J = 2.4 Hz), 7.4 (2H, 7.77 (ddd, J = 7.7, 7.6, 1.3 Hz), 7.8 (ddd, J = 7.6, 1.4, 0.4 Hz)), 7.86 (1H, ddd, J = 8.2, 1.3, 0.4 Hz), 8.6 (s, =CH–NH).

Anal. Calcd. For C11H10N2O2 (202.00%): C, 65.34; N, 13.86; O, 15.84; H, 4.96; Found: C, 66.02; N, 14.29; O, 15.27; H, 4.33.

1-[2-(1H-pyrazol-3-yl) phenyl]-ethanone (4g)

Yellow solid, %yield = 83.00, m p: 138°C, IR (KBr): 3372 cm−1 (–NH, stretch), 3147 cm−1 (=CH, stretch), 2942 cm−1 (–CH, stretch), 1718 cm−1 (C = O, stretch), 1605 cm−1 = C, r, weak), 1438 cm−1 (CH3, bend); 1H NMR (400 MHz, DMSO-d6): δ 3.7 (3H, s), 2.3 (=CH–N), 6.8 (1H, d, J = 2.4 Hz), 7.0 (1H, ddd, J = 7.9, 7.7, 1.5 Hz), 7.5 (2H, 7.64 (d, J = 2.4 Hz), 7.6 (ddd, J = 7.9, 1.3, 0.4), 7.4 (2H, 7.76 (td, J = 7.7, 1.3 Hz), 7.8 (ddd, J = 7.7, 1.5, 0.4 Hz, 8.6 (=CH–NH).

Anal. Calcd. For C11H10N2O (186.00%): C, 70.97; N, 15.05; O, 8.60; H, 5.37; Found: C, 71.46; N, 15.55; O, 7.78; H, 5.21.

(4-nitro-1-phenyl)-3-phenyl-pyrazole (4h)

Brown solid, %yield = 82.00, m p: 168°C, IR (KBr): 3439 cm−1 (N–H, stretch), 3081 cm−1 (=C–H), 1630 cm−1(), 1596 cm−1 (NO2). 1H NMR (400 MHz, DMSO-d6): δ 2.5 (=CH–N), 7.1 (1H, d, J = 2.1 Hz), 7.3 (1H, ddd, J = 8.5, 8.1, 1.6 Hz), 7.4 (1H, d, J = 2.1 Hz), 7.6 (2H, 7.77 (ddd, J = 8.1, 7.5, 1.6 Hz), 7.8 (ddd, J = 7.5, 1.6, 0.5 Hz)), 8.4 (1H, ddd, J = 8.5, 1.6, 0.5 Hz), 9.7 (1H, =CH–NH).

(4-fluoro-1-phenyl)-3-phenyl-pyrazole (4i)

Brown solid, % yield 79.00, m p: 192°C, IR (KBr): 3412 cm−1 (N–H stretch), 3060 cm−1 (=C–H, stretch), 2867 cm−1 (–CH, stretch), 1175 cm−1 (C–O–C), 1212 cm−1 (C = N, stretch); 1H NMR (400 MHz, DMSO-d6): δ 2.5 (1H, d, CH = N, α to nitrogen), 3.3 (3H, s), 7.4 (1H, d, J = 2.5 Hz), 7.5 (1H, ddd, J = 8.2, 1.2, 0.5 Hz), 7.5 (2H, 7.14 (td, J = 8.2, 1.5 Hz), 7.6 (ddd, J = 8.2, 8.0, 1.2 Hz)), 7.61 (2H, 7.52 (d, J = 2.5 Hz), 7.64 (ddd, J = 8.0, 1.5, 0.5 Hz), 8.1 (1H, s, N–NH–CH).

(4-methoxy-1-phenyl)-3-phenyl-pyrazole (4j)

Yellow solid, %yield = 81.00. m p: 192°C, IR (KBr): 3333 cm−1 (N–H, stretch), 2921 cm−1 (–C–H, stretch), 1732 cm−1 (C = O, ester). 1H NMR (400 MHz, DMSO-d6): δ 3.8 (3H, CH3), 6.8 (1H, d, J = 2.4 Hz), 7.0 (1H, ddd, J = 8.2, 7.7, 1.4 Hz), 7.1 (1H, d, J = 2.4 Hz), 7.4 (2H, 7.77 (ddd, J = 7.7, 7.6, 1.3 Hz), 7.8 (ddd, J = 7.6, 1.4, 0.4 Hz)), 7.86 (1H, ddd, J = 8.2, 1.3, 0.4 Hz), 8.6 (s, =CH–NH).


  Results and Discussions Top


The cells were trypsinised and aspirated into a 5-ml centrifuge tube. Cell pellet was obtained by centrifugation at 300 ×g. The cell count was adjusted, using DMEM HG medium, such that 200 μl of suspension contained approximately 10,000 cells. To each well of the 96-well microtitre plate, 200 μl of the cell suspension was added and the plate was incubated at 37°C and 5% CO2 atmosphere for 24 h. After 24 h, the spent medium was aspirated. Two hundred microlitres of different test concentrations of test drugs was added to the respective wells. The plate was then incubated at 37°C and 5% CO2 atmosphere for 24 h.

The percentage growth inhibition was calculated, after subtracting the background and the blank, and the concentration of the test drug needed to inhibit ACE2 human cells growth by 50% (CC50 and EC50) was generated from the dose–response curve for the cell line.

Microwave method was found to be more simple, convenient and efficient method than conventional method.[11],[12],[13],[14],[15] Nano-TiO2 catalyst accelerated the reactions. We followed green synthesis under solvent-free conditions.[16],[17],[18]

[Table 1] shows that 4a compound afforded in 30 s of reaction time under microwave irradiation. However, the same compound completed its reaction in 4 min under conventional method. 4b completed the reaction in 60 s and yielded highest amongst all the compounds.
Table 1: Reaction of 4a-j under microwave and conventional methods

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Compounds 4e and 4f possessing electron-withdrawing groups (-NO2). Hence, these completed the reaction in 75 s and 1 min, respectively. However, the remaining compounds possessing electron releasing groups completed reactions at shorter time than 4e and 4f.

Antiviral assays

All synthesised compounds and standard inhibitors were evaluated by using the experimental protocol.[19],[20],[21],[22] Inhibition of ACE2 human cells from COVID-19 was determined by MTT method [Figure 2]. Some compounds acted as potent ACE2 human cell receptors against COVID-19.
Figure 2: MTT images of angiotensin-converting enzyme 2 human cells tested against COVID-19

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[Table 2] shows that 4b, 4c and 4j compounds exhibited excellent CC50 values against COVID-19. 4a, 4h and 4i compounds showed very low CC50 values. However, 4c showed an excellent EC50 value (>5.0). 4e, 4f, 4g, 4h and 4j showed moderate EC50 values. 4a, 4b, 4d and 4i do not show activity against COVID-19.
Table 2: In vitro antiviral activity of pyrazole derivatives 4a-j against COVID-19

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4b, 4c, 4e, 4f and 4j exhibited more potency (CC50) than the standard drug ribavirin. However, all compounds showed less potency (EC50) than ribavirin. Similarly, all compounds showed less potency (CC50) than 6-azuridine. 4c, 4e, 4f, 4g and 4h exhibited more potency (EC50) than 6-azuridine; the remaining compounds showed NA result.

Time of addition assay

Time-of-addition experiments were performed on ACE2 human cells against COVID-19. The effects of compound 4b (84 μM = 10 × EC50) and reference inhibitor 6-azuridine (90 μM = 2 × EC50) were evaluated by using the experimental protocol reported.


  Conclusion Top


Synthesis of pyrazole derivatives via simple and convenient method, i.e. microwave method, is proved to be an efficient method. The use of nano-TiO2 under solvent-free conditions maintained green synthesis. In vitro screening of some compounds showed excellent CC50 values, and some compounds exhibited excellent EC50 values as ACE2 human cell receptors against COVID-19.

Acknowledgements

I am grateful to my research guide and co-guide for their moral support and guidance. I express my sincere gratitude to the Convener of IISc., Kudapura and Chitradurga for FT-IR characterisation and for the assistance of fluorescence spectrometer (source – xenon lamp 450W, range 180–850 nm and resolution 0.2 nm) (maximum at specific wavelengths, Software DATA MAX/GRAMS/31) in IISc. Bangalore.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Trilleras J, Polo E, Quiroga J, Cobo J, Nogueras M. Ultrasonics Promoted Synthesis of 5-(Pyrazol-4-yl)-4, 5-Dihydropyrazoles Derivatives. Appl Sci 2013;3:457-68.  Back to cited text no. 1
    
2.
Schmidt A, Dreger A. Recent advances in the chemistry of pyrazoles, properties, biological activities and syntheses. Curr Org Chem 2011;15:1423-63.  Back to cited text no. 2
    
3.
Gilfillan L, Artschwager R, Harkiss AH, Liskamp RM, Sutherland A. Synthesis of pyrazole containing α-amino acids via a highly regioselective condensation/aza-Michael reaction of β-aryl α,β-unsaturated ketones. Org Biomol Chem 2015;13:4514-23.  Back to cited text no. 3
    
4.
Kim H, Kim M, Lee J, Yu H, Hah JM. New potential antitumor pyrazole derivatives: Synthesis and cytotoxic evaluation. Bio Org Med Chem 2011;22:6760-7.  Back to cited text no. 4
    
5.
Buriol L, Frizzo CP, Marzari MR, Moreira DN, Prola LD, Zanatta N, et al. Pyrazole synthesis under microwave irradiation and solvent-free conditions. J Braz Chem Soc 2010;21:1222-8.  Back to cited text no. 5
    
6.
Sharma KH, Sharma M. Microwave assisted one pot synthesis of pharmaceutical pyrazole derivatives. Asian J Biomed Pharm Sci 2012;2:20-4.  Back to cited text no. 6
    
7.
Md. Alam J, Alam O, Alam P, Naim MJ. A review on pyrazole chemical entity and biological activity. Int J Pharm Sci Res IJPSR 2015;6:1433-42.  Back to cited text no. 7
    
8.
Ray S, Charusmriti. A QSAR study at AM1 semi empirical level of 1, 3-Diaryl pyrazole derivatives as anti-tumor agents against human DU145 prostate cancer cell line. Asian J Pharmaceutical Clin Res 2012;5:160-3.  Back to cited text no. 8
    
9.
Gouhar RS, Fathalla OA, Abd El-Karim SS. Synthesis and anticancer screening of some novel substituted pyrazole derivatives. Der Pharma Chemica 2013;5:225-33.  Back to cited text no. 9
    
10.
Kalpana K, Kumar RK, Babu VA, Vanjivaka S, Vantikommu J, Palle S. Synthesis and biological evaluation of pyrazole amides fused combretastatin derivatives as anticancer agents. Curr Bioact Compd 2018;14:357-63.  Back to cited text no. 10
    
11.
Hend Hafez N. Microwave-assisted synthesis and cytotoxicity evaluation of some novel pyrazole containing imidiazoles, pyrazoles, oxazoles, thiadiazoles and benzochromene derivatives. Egypt J Chem 2017;60:1015-28.  Back to cited text no. 11
    
12.
López C, Zougagh M, Algarra M, Rodríguez-Castellón E, Campos BB, Esteves da Silva JC, et al. Microwave-assisted synthesis of carbon dots and its potential as analysis of four heterocyclic aromatic amines. Talanta 2015;132:845-50.  Back to cited text no. 12
    
13.
Agudelo Mesa LB, Padró JM, Reta M. Analysis of non-polar heterocyclic aromatic amines in beefburguers by using microwave-assisted extraction and dispersive liquid-ionic liquid microextraction. Food Chem 2013;141:1694-701.  Back to cited text no. 13
    
14.
Pawełczyk A, Zaprutko L. Microwave assisted synthesis of unsaturated jasmone heterocyclic analogues as new fragrant substances. Eur J Med Chem 2009;44:3032-9.  Back to cited text no. 14
    
15.
Jeselnik M, Varma RS, Polanc S, Kocevar M. Catalyst-free reactions under solvent-free conditions: Microwave-assisted synthesis of heterocyclic hydrazones below the melting points of neat reactants. Chem Commun (Camb) 2001;18:1716-7.  Back to cited text no. 15
    
16.
Ganesh Yallappa N, Nagaraja D, Chandrashekhar U. Nano-catalysed green synthesisof pyrazole derivatives and its biological activityas EAC receptor antagonists. Pharmacophore 2019;10:28-32.  Back to cited text no. 16
    
17.
Fioravanti R, Desideri N, Carta A, Atzori EM, Delogu I, Collu G, et al. Inhibitors of yellow fever virus replication based on 1,3,5-triphenyl-4,5-dihydropyrazole scaffold: Design, synthesis and antiviral evaluation. Eur J Med Chem 2017;141:15-25.  Back to cited text no. 17
    
18.
Pauwels R, Balzarini J, Baba M, Snoeck R, Schols D, Herdewijn P, et al. Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J Virol Methods 1988;20:309-21.  Back to cited text no. 18
    
19.
Johnston PA, Phillips J, Shun TY, Shinde S, Lazo JS, Huryn DM, et al. HTS identifies novel and specific uncompetitive inhibitors of the two-component NS2B-NS3 proteinase of West Nile virus. Assay Drug Dev Technol 2007;5:737-50.  Back to cited text no. 19
    
20.
Lebedev AV, Lebedeva AB, Sheludyakov VD, Kovaleva EA, Ustinova OL, Kozhevnikov IB. Synthesis of 3-substituted arylpyrazole-4-carboxylic acids. Russ J General Chem 2007;75:782-9.  Back to cited text no. 20
    
21.
Li G, De Clercq E. Current therapy for chronic hepatitis C: The role of direct-acting antivirals. Antiviral Res 2017;142:83-122.  Back to cited text no. 21
    
22.
Carta A, Briguglio I, Piras S, Corona P, Ibba R, Laurini E, et al. A combined in silico/in vitro approach unveils common molecular requirements for efficient BVDV RdRp binding of linear aromatic N-polycyclic systems. Eur J Med Chem 2016;117:321-34.  Back to cited text no. 22
    


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