Synthesis and Molecular Docking Studies of New Dispiropyrrolidines on West Nile Virus NS2B-NS3 Protease

https://doi.org/10.22146/ijc.66017

Nadia Mohamed Yusoff(1), Hasnah Osman(2), Mohd. Zaheen Hassan(3), Mohamed Ashraf Ali(4), Yeong Keng Yoon(5), Ezatul Ezleen Kamarulzaman(6), Muhammad Solehin Abd Ghani(7), Unang Supratman(8), Mohamad Nurul Azmi Mohamad Taib(9*)

(1) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia
(2) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia
(3) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia College of Pharmacy, King Khalid University, Abha, Saudi Arabia
(4) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia Department of Medicinal Chemistry, Sunrise University Alwar, Rajasthan-301030, India
(5) Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia School of Science, Monash University Malaysia Campus, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia
(6) School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia
(7) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia
(8) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang 45363, Indonesia
(9) School of Chemical Sciences, Universiti Sains Malaysia, Minden 11800 Penang, Malaysia
(*) Corresponding Author

Abstract


West Nile virus (WNV) is among the other four flavivirus genus, rapidly spreading worldwide. The number of cases increases globally as there are no clinically available approved drugs and vaccines against this disease. Based on our previous finding related to a flavivirus, a series of spiropyrrolidine derivatives were regioselectively synthesized via [3+2]-cycloaddition reaction of three components between isatins, sarcosine, and (E)-3,5-bis (arylidene)-4-piperidones. The yield of synthesized compounds was in a range between 81–95%. The structures of all the synthesized compounds were characterized using FT-IR, 1D- and 2D-NMR, and HRMS. Molecular docking studies of spiropyrrolidines on NS2B-NS3 protease were done to understand and explore the ligand-receptor interactions and hypothesize the drug's refinements. The inhibition of NS2B-NS3 protease has been considered a promising strategy because this enzyme is responsible for the viral replication process. Among them, compound 5c shows an excellent binding affinity with ‒7.71 kcal/mol free binding energy and an inhibition constant of 1.73 μM. It also showed the binding orientation into the active site of WNV NS2B-NS3 protease on Asn84, Tyr1161, Gly1151, and Gly1153.

Keywords


spiropyrrolidine; [3+2]-cycloaddition; molecular docking; West Nile virus; WNV NS2B-NS3 protease

Full Text:

Full Text PDF


References

[1] Pierson, T.C., and Diamond, M.S., 2020, The continued treat of emerging flaviviruses, Nat. Microbiol., 5 (6), 796–812.

[2] Mackenzie, J.S., Gubler, D.J., and Petersen, L.R., 2004, Emerging flaviviruses: The spread and resurgence of Japanese encephalitis, West Nile and dengue viruses, Nat. Med., 10 (12), S98–S109.

[3] Lim, S.P., 2019, Dengue drug discovery: Progress, challenges and outlook, Antiviral Res., 163, 156–178.

[4] World Health Organization, 2017, West Nile virus, https://www.who.int/news-room/fact-sheets/detail/west-nile-virus, accessed on 25 August 2021.

[5] Peterson, L.R., Brault, A.C., and Nasci, R.S., 2013, West Nile virus: Review of the literature, JAMA, 310 (3), 308–315.

[6] Richner, J.M., Gmyrek, G.B., Govero, J., Tu, Y., van der Windt, G.J.W., Metcalf, T.U., Haddad, E.K., Textor, J., Miller, M.J., and Diamond, M.S., 2015, Age-dependent cell trafficking defects in draining lymph nodes impair adaptive immunity and control of West Nile virus infection, PLoS Pathog., 11 (7), e1005027.

[7] Yao, Y., and Montgomery, R.R., 2016, Role of immune aging in susceptibility to West Nile virus, Methods Mol. Biol., 1435, 235–247.

[8] Montgomery, R.R., 2017, Age-related alterations in immune responses to West Nile virus infection, Clin. Exp. Immunol., 187 (1), 26–34.

[9] da Silva-Júnior, E.F., and de Araújo-Júnior, J.X., 2019, Peptide derivatives as inhibitors of NS2B-NS3 protease from Dengue, West Nile, and Zika flaviviruses, Bioorg. Med. Chem., 27 (18), 3963–3978.

[10] Bakonyi, T., and Haussig, J.M., 2020, West Nile virus keeps on moving up in Europe, Eurosurveillance, 25 (46), 2001938.

[11] Luo, D., Vasudevan, S.G., and Lescar, J., 2015, The flavivirus NS2B–NS3 protease-helicase as a target for anti-viral drug development, Antiviral Res., 118, 148–158.

[12] Bastos Lima, A., Behnam, M.A.M., El Sherif, Y., Nitsche, C., Vechi, S.M., and Klein, C.D., 2015, Dual inhibitors of the dengue and West Nile virus NS2B–NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids, Bioorg. Med. Chem., 23 (17), 5748–5755.

[13] Chappell, K., Stoermer, M., Fairlie, D., Young, P., 2008, West Nile virus NS2B/NS3 protease as anti-viral target, Curr. Med. Chem., 15 (27), 2771–2784.

[14] Li, Z., Sakamuru, S., Huang, R., Brecher, M., Koetzner, C.A., Zhang, J., Chen, H., Qin, C.F., Zhang, Q.Y., Zhou, J., Kramer, L.D., Xia, M., and Li, H., 2018, Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease, Antiviral Res., 150, 217–225.

[15] Skoreński, M., Milewska, A., Pyrć, K., Sieńczyk, M., and Oleksyszyn, J., 2019, Phosphonate inhibitors of West Nile virus NS2B/NS3 protease, J. Enzyme Inhib. Med. Chem., 34 (1), 8–14.

[16] Kang, C., Gayen, S., Wang, W., Severin, R., Chen, A.S., Lim, H.A., Chia, C.S.B., Schϋller, A., Doan, D.N.P., Poulsen, A., Hill, J., Vasudevan, S.G., and Keller, T.H., 2013, Exploring the binding of peptidic West Nile virus NS2B–NS3 protease inhibitors by NMR, Antiviral Res., 97 (2), 137–144.

[17] Wei, A.C., Ali, M.A., Yoon, K.Y., Ismail, R., Choon, T.S., Kumar, R.S., Arumugam, N., Almansour, A.I., and Osman, H., 2012, Antimycobacterial activity: A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines, Bioorg. Med. Chem. Lett., 22 (15), 4930–4933.

[18] Wei, A.C., Ali, MA, Yoon, K.Y., Ismail, R., Choon, T.S., and Kumar, R.S., 2013, A facile three-component [3+2]-cycloaddition for the regioselective synthesis of highly functionalised dispiropyrrolidines acting as antimycobacterial agents, Bioorg. Med. Chem. Lett., 23 (5), 1383–1386.

[19] Wei, A.C., Ali, M.A., Yoon, K.Y., Ismail, R., Choon, T.S., Khaw, K.Y., Murugaiyah, V., and Lakshmipathi, V.S., 2014, Synthesis of highly functionalised dispiropyrrolidine derivatives as novel acetylcholinesterase inhibitors, Lett. Drug Des. Discovery, 11 (2), 156–161.

[20] Kumar, R.S., Rajesh, S.M., Perumal, S., Banerjee, D., Yogeeswari, P., and Sriram, D., 2010, Novel three-component domino reactions of ketones, isatin and amino acids: Synthesis and discovery of antimycobacterial activity of highly functionalised novel dispiropyrrolidines, Eur. J. Med. Chem., 45 (1), 411–422.

[21] Lawson, S., Arumugam, N., Almansour, A.I., Kumar, R.S., and Thangamani, S., 2020, Dispiropyrrolidine tethered piperidone heterocyclic hybrids with broad-spectrum antifungal activity against Candida albicans and Cryptococcus neoformans, Bioorg. Chem., 100, 103865.

[22] Karthikeyan, K., Sivakumar, P.M., Doble, M., and Perumal, P.T., 2010, Synthesis, antibacterial activity evaluation and QSAR studies of novel dispiropyrrolidines, Eur. J. Med. Chem., 45 (8), 3446–3452.

[23] Hassaneen, H.M., Eid, E.M., Eid, H.A., Farghaly, T.A., and Mabkhot, Y.N., 2017, Facial regioselective synthesis of novel bioactive spiropyrrolidine/pyrrolizine-oxindole derivatives via a three components reaction as potential antimicrobial agents, Molecules, 22 (3), 357.

[24] Bhaskar, G., Arun, Y., Balachandran, C., Saikumar, C., and Perumal, P.T., 2012, Synthesis of novel spirooxindole derivatives by one pot multicomponent reaction and their antimicrobial activity, Eur. J. Med. Chem., 51, 79–91.

[25] Almansour, A.I., Arumugam, N., Kumar, R.S., Al-thamili, D.M., Periyasami, G., Ponmurugan, K., Al-Dhabi, N.A., Perumal, K., and Premnath, D., 2019, Domino multicomponent approach for the synthesis of functionalized spiro-Indeno[1,2-b]quinoxaline heterocyclic hybrids and their antimicrobial activity, synergistic effect and molecular docking simulation, Molecules, 24 (10), 1962–1976.

[26] Almansour, A.I., Kumar, R.S., Beevi, F., Shirazi, A.N., Osman, H., Ismail, R., Choon, T.S., Sullivan, B., McCaffrey, K., Nahhas, A., and Parang, K., 2014, Facile, regio-and diastereoselective synthesis of spiro-pyrrolidine and pyrrolizine derivatives and evaluation of their antiproliferative activities, Molecules, 19 (7), 10033–10055.

[27] Girgis, A.S., Panda, S.S., Ahmed Farag, I.S., El-Shabiny, A.M., Moustafa, A.M., Ismail, N.S.M., Pillai, G.G., Panda, C.S., Hall, C.D., and Katritzky, A.R., 2015, Synthesis, and QSAR analysis of anti-oncological active spiro-alkaloids, Org. Biomol. Chem., 13 (6), 1741–1754.

[28] Girgis, A.S., Panda, S.S., Aziz, M.N., Steel, P.J., Hall, C.D., and Katritzky, A.R., 2015, Rational design, synthesis, and 2D-QSAR study of anti-oncological alkaloids against hepatoma and cervical carcinoma, RSC Adv., 5 (36), 28554–28569.

[29] Girgis, A.S., Panda, S.S., Shalaby, E.M., Mabied, A.F., Steel, P.J., Hall, C.D., and Katritzky, A.R., 2015, Regioselective synthesis and theoretical studies of an anti-neoplastic fluoro-substituted dispirooxindole, RSC Adv., 5 (19), 14780–14787.

[30] Murugan, R., Anbazhagan, S., and Narayanan, S.S., 2009, Synthesis and in vivo antidiabetic activity of novel dispiropyrrolidines through [3+2] cycloaddition reactions with thiazolidinedione and rhodanine derivatives, Eur. J. Med. Chem., 44 (8), 3272–3279.

[31] Toumi, A., Boudriga, S., Hamden, K., Sobeh, M., Cheurfa, M., Askri, M., Knorr, M., Strohmann, C., and Brieger, L., 2021, Synthesis, antidiabetic activity and molecular docking study of rhodanine-substitued spirooxindole pyrrolidine derivatives as novel α-amylase inhibitors, Bioorg. Chem., 106, 104507.

[32] Ali, M.A., Lakshmipathi, V.S., Beevi, F., Kumar, R.S., Ismail, R., Choon, T.S., Wei, A.C., Yoon, Y.K., and Basiri, A., 2013, Antimycobacterial activity: Synthesis and biological evaluation of novel substituted (3E,5E)-3,5-diarylidene-1-phenethylpiperidine-4-one Derivatives, Lett. Drug Des. Discovery, 10 (5), 471–476.

[33] Shalaby, E.M., Girgis, A.S., Moustafa, A.M., ElShaabiny, A.M., El-Gendy, B.E.M., Mabied, A.F., and Farag, I.S.A., 2014, Regioselective synthesis, stereochemical structure, spectroscopic characterization and geometry optimization of dispiro[3H-indole-3,2′-pyrrolidine-3′,3″-piperidines], J. Mol. Struct., 1075, 327–334.

[34] Kumar, R.S., and Perumal, S., 2007, Novel three-component tandem reactions of cyclic mono ketones, isatin and sarcosine: Formation of dispiropyrrolidines, Tetrahedron Lett., 48 (40), 7164–7168.

[35] Osman, H., Idris, N.H., Kamarulzaman, E.E., Wahab, H.A., and Hassan, M.Z., 2017, 3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors, Acta Pharm. Sin. B, 7 (4), 479–484.

[36] Skoreński, M., Milewska, A., Pyrć, K., Sieńczyk, M., and Oleksyszyn, J., 2019, Phosphonate inhibitors of West Nile virus NS2B/NS3 protease, J. Enzyme Inhib. Med. Chem., 34(1), 8–14.

[37] de Oliveira, A.S., Gazolla, P.A.R., Oliveira, A.F.C.S., Pereira, W.L., de S Viol, L.C., Maia, A.F.S., Santos, E.G., da Silva, Í.E.P., Mendes, T.A.O., da Silva, A.M., Dias, R.S., da Silva, C.C., Polêto, M.D., Teixeira, R.R., and de Paula, S.O., 2019, Discovery of novel West Nile Virus protease inhibitor based on isobenzonafuranone and triazolic derivatives of eugenol and indan-1,3-dione scaffolds, PLoS One, 14 (9), e0223017.



DOI: https://doi.org/10.22146/ijc.66017

Article Metrics

Abstract views : 1569 | views : 1450


Copyright (c) 2021 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 


Indonesian Journal of Chemistry (ISSN 1411-9420 / 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web
Analytics View The Statistics of Indones. J. Chem.