Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2

Muhammed Trawally; Fatıma Nur Yılmaz; Berna Özbek Çelik; Atilla Akdemir; Özlen Güzel Akdemir

Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2

Abstract

Human parainfluenza viruses (HPIVs) are responsible for a wide range of respiratory infections in humans, particularly in children, the elderly, and immunocompromised individuals. This paper presents a study regarding the antiviral activity of a series of 3-phenyl-5-sulfamoyl-N-(7/8/9-(non)substituted-3-oxo-1-thia-4- azaspiro[4.4]non/[4.5]dec-4-yl)-1H-indole-2-carboxamide derivatives against HPIV-2. Our findings suggest the compounds displayed low potency against HPIV-2. Compounds 4 and 8 exhibited the most potent antiviral effects with inhibition of 95.46 and 90.90 % at 10 mg/mL, respectively. Molecular modeling studies were conducted on hemagglutinin-neuraminidase, a crucial druggable target for HPIV, to predict the binding modes of the compounds.

Keywords

References

[1] Nair H, Nokes DJ, Gessner BD, Dherani M, Madhi SA, Singleton RJ, O'Brien KL, Roca A, Wright PF, Bruce N, Chandran A, Theodoratou E, Sutanto A, Sedyaningsih ER, Ngama M, Munywoki PK, Kartasasmita C, Simões EAF, Rudan I, Weber MW, Campbell H. Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis. Lancet Lond Engl. 2010; 375: 1545–55. https://doi.org/10.1016/S0140-6736(10)60206-1
[2] DeGroote NP, Haynes AK, Taylor C, Killerby ME, Dahl RM, Mustaquim D, Gerber SI, Watson JT. Human parainfluenza virus circulation, United States, 2011-2019. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2020; 124: 104261. https://doi.org/10.1016/j.jcv.2020.104261
[3] Wang X, Li Y, Deloria-Knoll M, Madhi SA, Cohen C, Arguelles VL, Basnet S, Bassat Q, Brooks WA, Echavarria M, Fasce RA, Gentile A, Goswami D, Homaira N, Howie SRC, Kotloff KL, Khuri-Bulos N, Krishnan A, Lucero MG, Lupisan S, Mathisen M, McLean KA, Mira-Iglesias A, Moraleda C, Okamoto M, Oshitani H, O'Brien KL, Owor BE, Rasmussen ZA, Rath BA, Salimi V, Sawatwong P, Scott JA, Simões EAF, Sotomayor V, Thea DM, Treurnicht FK, Yoshida LM, Zar HJ, Campbell H, Nair H. Global burden of acute lower respiratory infection associated with human parainfluenza virus in children younger than 5 years for 2018: a systematic review and meta-analysis. Lancet Glob Health. 2021; 9: e1077–87. https://doi.org/10.1016/S2214-109X(21)00218-7
[4] Bhasin S, Nadar M, Hasija Y. Epicatechin analogues may hinder human parainfluenza virus infection by inhibition of hemagglutinin-neuraminidase protein and prevention of cellular entry. J Mol Model. 2022; 28: 319. https://doi.org/10.1007/s00894-022-05310-9
[5] Alsaleh AN, Aziz IM, Alkubaisi NA, Almajhdi FN. Genetic analysis of human parainfluenza type 2 virus in Riyadh, Saudi Arabia. Virus Genes. 2023: 1–8. https://doi.org/10.1007/s11262-023-02035-6.
[6] Lee K, Lee J, Perry K. Abstract 1256: The surface-specific antigenic peptide designs of HPIV-type 2 hemagglutinin-neuraminidase and fusion protein for anti-viral immunotherapy drug development. J Biol Chem. 2023; 299: 103991. https://doi.org/10.1016/j.jbc.2023.103991
[7] Bailly B, Dirr L, El-Deeb IM, Altmeyer R, Guillon P, von Itzstein M. A dual drug regimen synergistically blocks human parainfluenza virus infection. Sci Rep. 2016; 6: 24138. https://doi.org/10.1038/srep24138
[8] Rota P, La Rocca P, Bonfante F, Pagliari M, Piccoli M, Cirillo F, Ghiroldi A, Franco V, Pappone C, Allevi P, Anastasia L. Design, synthesis, and antiviral evaluation of sialic acid derivatives as ınhibitors of Newcastle Disease Virus hemagglutinin-neuraminidase: A translational study on Human Parainfluenza Viruses. ACS Infect Dis. 2023; 9: 617–630. https://doi.org/10.1021/acsinfecdis.2c00576

[9] Chibanga VP, Dirr L, Guillon P, El-Deeb IM, Bailly B, Thomson RJ, von Itzstein M. New antiviral approaches for human parainfluenza: Inhibiting the haemagglutinin-neuraminidase. Antiviral Res. 2019; 167: 89–97. https://doi.org/10.1016/j.antiviral.2019.04.001
[10] Smielewska A, Emmott E, Goodfellow I, Jalal H. In vitro sensitivity of human parainfluenza 3 clinical isolates to ribavirin, favipiravir and zanamivir. J Clin Virol Off Publ Pan Am Soc Clin Virol. 2018; 102: 19–26. https://doi.org/10.1016/j.jcv.2018.02.009
[11] Marcink TC, Englund JA, Moscona A. Paramyxoviruses: Parainfluenza Viruses. Viral Infect. Hum., Springer, New York, NY; 2022, p. 1–50. https://doi.org/10.1007/978-1-4939-9544-8‗ 25-1
[12] Marcink TC, Yariv E, Rybkina K, Más V, Bovier FT, des Georges A, Greninger AL, Alabi CA, Porotto M, Ben-Tal N, Moscona A. Hijacking the fusion complex of human parainfluenza virus as an antiviral strategy. mBio. 2020; 11. https://doi.org/10.1128/mBio.03203-19
[13] Marcink TC, Wang T, Des Georges A, Porotto M, Moscona A. Human parainfluenza virus fusion complex glycoproteins imaged in action on authentic viral surfaces. PLoS Pathog. 2020; 16: e1008883. https://doi.org/10.1371/journal.ppat.1008883
[14] Farzan SF, Palermo LM, Yokoyama CC, Orefice G, Fornabaio M, Sarkar A, Kellogg GE, Greengard O, Porotto M, Moscona A. Premature activation of the paramyxovirus fusion protein before target cell attachment with corruption of the viral fusion machinery. J Biol Chem. 2011; 286: 37945–37954. https://doi.org/10.1074/jbc.M111.256248
[15] Guillon P, Dirr L, El-Deeb IM, Winger M, Bailly B, Haselhorst T, Dyason JC, von Itzstein M. Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin-neuraminidase inhibitors. Nat Commun. 2014; 5: 5268. https://doi.org/10.1038/ncomms6268
[16] Eveno T, Dirr L, El-Deeb IM, Guillon P, von Itzstein M. Targeting Human Parainfluenza Virus Type-1 haemagglutinin-neuraminidase with mechanism-based ınhibitors. Viruses 2019; 11(5):417. https://doi.org/10.3390/v11050417
[17] Porotto M, Fornabaio M, Kellogg GE, Moscona A. A second receptor binding site on human parainfluenza virus type 3 hemagglutinin-neuraminidase contributes to activation of the fusion mechanism. J Virol. 2007; 81: 3216–3228. https://doi.org/10.1128/JVI.02617-06
[18] Barreca ML, Chimirri A, De Luca L, Monforte AM, Monforte P, Rao A, Zappalà M, Balzarini J, De Clercq E, Pannecouque C, Witvrouw M. Discovery of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV-1 agents. Bioorg Med Chem Lett. 2001; 11: 1793–1796. https://doi.org/10.1016/S0960-894X(01)00304-3
[19] Küçükgüzel G, Kocatepe A, de Clercq E, Sahin F, Güllüce M. Synthesis and biological activity of 4-thiazolidinones, thiosemicarbazides derived from diflunisal hydrazide. Eur J Med Chem. 2006; 41: 353–359. https://doi.org/10.1016/j.ejmech.2005.11.005
[20] Balzarini J, Orzeszko B, Maurin JK, Orzeszko A. Synthesis and anti-HIV studies of 2-adamantyl-substituted thiazolidin-4-ones. Eur J Med Chem. 2007; 42: 993–1003. https://doi.org/10.1016/j.ejmech.2007.01.003
[21] Cihan-Üstündağ G, Gürsoy E, Naesens L, Ulusoy-Güzeldemirci N, Çapan G. Synthesis and antiviral properties of novel indole-based thiosemicarbazides and 4-thiazolidinones. Bioorg Med Chem. 2016; 24: 240–246. https://doi.org/10.1016/j.bmc.2015.12.008
[22] Zhang GN, Li Q, Zhao J, Zhang X, Xu Z, Wang Y, Fu Y, Shan Q, Zheng Y, Wang J, Zhu M, Li Z, Cen S, He J, Wang Y. Design and synthesis of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides as novel dual inhibitors of respiratory syncytial virus and influenza virus A. Eur J Med Chem. 2020;186:111861. https://doi.org/10.1016/j.ejmech.2019.111861
[23] Dhadda S, Sharma S, Jakhar P, Sharma H. Contemporary progress in the green synthesis of spiro-thiazolidines and their medicinal significance: a review. RSC Adv. 2023; 13: 3723–3742. https://doi.org/10.1039/d2ra07474e
[24] Demir-Yazıcı K, Bua S, Akgüneş NM, Akdemir A, Supuran CT, Güzel-Akdemir Ö. Indole-based hydrazones containing a sulfonamide moiety as selective ınhibitors of tumor-associated human carbonic anhydrase ısoforms IX and XII. Int J Mol Sci. 2019; 20(9):2354. https://doi.org/10.3390/ijms20092354.
[25] Garg V, Maurya RK, Thanikachalam PV, Bansal G, Monga V. An insight into the medicinal perspective of synthetic analogs of indole: A review. Eur J Med Chem. 2019; 180: 562–612. https://doi.org/10.1016/j.ejmech.2019.07.019
[26] Güzel-Akdemir Ö, Trawally M, Özbek-Babuç M, Özbek-Çelik B, Ermut G, Özdemir H. Synthesis and antibacterial activity of new hybrid derivatives of 5-sulfamoyl-1H-indole and 4-thiazolidinone groups. Monatshefte Für Chem - Chem Mon. 2020; 151: 1443–1452. https://doi.org/10.1007/s00706-020-02664-9
[27] Güzel-Akdemir Ö, Demir-Yazıcı K, Vullo D, Supuran C, Akdemir A. New Pyridinium salt derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide as selective ınhibitors of tumour-related human carbonic anhydrase ısoforms IX and XII. Anticancer Agents Med Chem. 2022; 22(14):2637-2646. https://doi.org/10.2174/1871520622666220207092123
[28] Zhang M-Z, Chen Q, Yang G-F. A review on recent developments of indole-containing antiviral agents. Eur J Med Chem. 2015; 89: 421–441. https://doi.org/10.1016/j.ejmech.2014.10.065.
[29] Dorababu A. Indole - a promising pharmacophore in recent antiviral drug discovery. RSC Med Chem. 2020; 11: 1335–1353. https://doi.org/10.1039/D0MD00288G
[30] Trawally M, Demir-Yazıcı K, Dingiş Birgül SI, Kaya K, Akdemir A, Güzel Ö. Mandelic acid-based spirothiazolidinones targeting M. tuberculosis: Synthesis, in vitro and in silico investigations. Bioorganic Chem. 2022; 121:105688. https://doi.org/10.1016/j.bioorg.2022.105688
[31] Vanderlinden E, Göktas F, Cesur Z, Froeyen M, Reed ML, Russell CJ, Cesur N, Naesens L. Novel inhibitors of influenza virus fusion: structure-activity relationship and interaction with the viral hemagglutinin. J Virol. 2010; 84: 4277–4288. https://doi.org/10.1128/JVI.02325-09
[32] Göktaş F, Vanderlinden E, Naesens L, Cesur N, Cesur Z. Microwave assisted synthesis and anti-influenza virus activity of 1-adamantyl substituted N-(1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide derivatives. Bioorg Med Chem. 2012; 20: 7155–7159. https://doi.org/10.1016/j.bmc.2012.09.064
[33] Göktaş F, Vanderlinden E, Naesens L, Cesur Z, Cesur N, Taş P. Synthesis and structure-activity relationship of n-(3-oxo-1-thia-4-azaspiro[4.5]decan-4-yl)carboxamide ınhibitors of ınfluenza virus hemagglutinin mediated fusion. Phosphorus Sulfur Silicon Relat Elem. 2015; 190: 1075–1087. https://doi.org/10.1080/10426507.2014.965819
[34] Cihan-Üstündağ G, Naesens L, Şatana D, Erköse-Genç G, Mataracı-Kara E, Çapan G. Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives. Monatshefte Für Chem - Chem Mon. 2019; 150: 1533–1544. https://doi.org/10.1007/s00706-019-02457-9
[35] Apaydın ÇB, Tansuyu M, Cesur Z, Naesens L, Göktaş F. Design, synthesis and anti-influenza virus activity of furan-substituted spirothiazolidinones. Bioorg Chem. 2021; 112: 104958. https://doi.org/10.1016/j.bioorg.2021.104958
[36] Soylu-Eter Ö, Duran GN, Özbil M, Göktaş F, Cihan-Üstündağ G, Karalı N. Antiviral activity and molecular modeling studies on 1H-indole-2,3-diones carrying a naphthalene moiety. J Mol Struct. 2023; 1281: 135100. https://doi.org/10.1016/j.molstruc.2023.135100
[37] Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997; 25: 3389–3402. https://doi.org/10.1093/nar/25.17.3389
[38] Chiang LC, Chiang W, Chang MY, Ng LT, Lin CC. Antiviral activity of Plantago major extracts and related compounds in vitro. Antiviral Res. 2002; 55: 53–62. https://doi.org/10.1016/s0166-3542(02)00007-4
[39] Trawally M, Demir-Yazıcı K, Dingiş-Birgül SI, Kaya K, Akdemir A, Güzel-Akdemir Ö. Dithiocarbamates and dithiocarbonates containing 6-nitrosaccharin scaffold: Synthesis, antimycobacterial activity and in silico target prediction using ensemble docking-based reverse virtual screening. J Mol Struct. 2023; 1277: 134818. https://doi.org/10.1016/j.molstruc.2022.134818
[40] Pattar SV, Adhoni SA, Kamanavalli CM, Kumbar SS. In silico molecular docking studies and MM/GBSA analysis of coumarin-carbonodithioate hybrid derivatives divulge the anticancer potential against breast cancer. Beni-Suef Univ J Basic Appl Sci. 2020; 9:36. https://doi.org/10.1186/s43088-020-00059-7

Details

Primary Language

English

Subjects

Pharmaceutical Chemistry

Journal Section

Research Article

Authors

Muhammed Trawally This is me
Türkiye

Fatıma Nur Yılmaz
0000-0001-8442-8538
Türkiye

Berna Özbek Çelik This is me
0000-0001-8909-8398
Türkiye

Atilla Akdemir This is me
0000-0001-8416-0471
Türkiye

Özlen Güzel Akdemir ^*
0000-0003-3680-1945
Türkiye

Publication Date

June 28, 2025

Submission Date

November 25, 2023

Acceptance Date

December 27, 2023

Published in Issue

Year 2024 Volume: 28 Number: 1

IZ

https://izlik.org/JA62ND55UL

Cite

RIS / Bibtex

APA

Trawally, M., Yılmaz, F. N., Özbek Çelik, B., Akdemir, A., & Güzel Akdemir, Ö. (2025). Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2. Journal of Research in Pharmacy, 28(1), 213-224. https://izlik.org/JA62ND55UL

AMA

1.Trawally M, Yılmaz FN, Özbek Çelik B, Akdemir A, Güzel Akdemir Ö. Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2. J. Res. Pharm. 2025;28(1):213-224. https://izlik.org/JA62ND55UL

Chicago

Trawally, Muhammed, Fatıma Nur Yılmaz, Berna Özbek Çelik, Atilla Akdemir, and Özlen Güzel Akdemir. 2025. “Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2”. Journal of Research in Pharmacy 28 (1): 213-24. https://izlik.org/JA62ND55UL.

EndNote

Trawally M, Yılmaz FN, Özbek Çelik B, Akdemir A, Güzel Akdemir Ö (June 1, 2025) Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2. Journal of Research in Pharmacy 28 1 213–224.

IEEE

[1]M. Trawally, F. N. Yılmaz, B. Özbek Çelik, A. Akdemir, and Ö. Güzel Akdemir, “Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2”, J. Res. Pharm., vol. 28, no. 1, pp. 213–224, June 2025, [Online]. Available: https://izlik.org/JA62ND55UL

ISNAD

Trawally, Muhammed - Yılmaz, Fatıma Nur - Özbek Çelik, Berna - Akdemir, Atilla - Güzel Akdemir, Özlen. “Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2”. Journal of Research in Pharmacy 28/1 (June 1, 2025): 213-224. https://izlik.org/JA62ND55UL.

JAMA

1.Trawally M, Yılmaz FN, Özbek Çelik B, Akdemir A, Güzel Akdemir Ö. Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2. J. Res. Pharm. 2025;28:213–224.

MLA

Trawally, Muhammed, et al. “Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2”. Journal of Research in Pharmacy, vol. 28, no. 1, June 2025, pp. 213-24, https://izlik.org/JA62ND55UL.

Vancouver

1.Muhammed Trawally, Fatıma Nur Yılmaz, Berna Özbek Çelik, Atilla Akdemir, Özlen Güzel Akdemir. Antiviral Properties of 5‑Sulfamoyl‑1H‑Indole-Linked Spirothiazolidinone Derivatives: A Study on Human Parainfluenza Virus-2. J. Res. Pharm. [Internet]. 2025 Jun. 1;28(1):213-24. Available from: https://izlik.org/JA62ND55UL