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Volume 15
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10.3390/cryst15090772
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Thienyl-Based Amides of M2 and Neuraminidase Inhibitors: Synthesis, Structural Characterization, and In Vitro Antiviral Activity Against Influenza A Viruses

by
Maya Chochkova
1,*,
Boyka Stoykova
1,
Magdalena Angelova
2,
Hristina Sbirkova-Dimitrova
2,
Rusi Rusew
2,
Yuhuan Li
3,
Andrey Popatanasov
4,
Nejc Petek
5,
Martin Štícha
6 and
Boris Shivachev
2
1
Faculty of Mathematics and Natural Sciences, South-West University ‘‘Neofit Rilski’’, Ivan Mihailov Str. 66, 2700 Blagoevgrad, Bulgaria
2
Institute of Mineralogy and Crystallography “Acad. Ivan Kostov”, Bulgarian Academy of Sciences, Acad. G. Bonchev Bl. 107, 1113 Sofia, Bulgaria
3
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Tiantan Xili, Beijing 100050, China
4
Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev Bl. 23, 1113 Sofia, Bulgaria
5
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna Pot 113, 1000 Ljubljana, Slovenia
6
Section of Chemistry, Faculty of Science, Charles University, Hlavova 2030/8, 12843 Prague, Czech Republic
*
Author to whom correspondence should be addressed.
Crystals 2025, 15(9), 772; https://doi.org/10.3390/cryst15090772
Submission received: 31 July 2025 / Revised: 23 August 2025 / Accepted: 24 August 2025 / Published: 29 August 2025
(This article belongs to the Special Issue Celebrating the 10th Anniversary of International Crystallography)
Versions Notes

Abstract

Influenza A viruses that cause pandemics, as well as other harmful pathogens (e.g., SARS-CoV-2 variants), are known as the ‘silent bioterrorists’ of the 21st century. Due to high mutability, anti-influenza chemotherapeutic treatment is a vital defense strategy to combat both seasonal and pandemic influenza strains, especially when vaccines fail. Consequently, the development of novel therapies to combat this serious threat is of great concern. Hence, in this study, 3-(2-thienyl) acrylic acid (TA) was converted into amides of anti-influenza drugs (aminoadamantanes and oseltamivir) through TBTU-mediated coupling. The crystal structures of the thienyl-based amide hybrids (TA-Am (1), TA-Rim (2), TA-Os-OEt (3), and TA-OsC (4)) were also investigated using single-crystal X-ray diffraction, powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Moreover, the antiviral activities of the hybrids against influenza virus A/Fort Monmouth/1/1947 (H1N1), clinically isolated influenza strain A/Wuhan/359/1995 (H3N2), and oseltamivir-resistant A/Jinnan/15/2009 (H1N1) were evaluated in vitro. Amongst the tested thienyl-based amides, bisamide 8 (Boc-Os-Hda-TA) exhibited the most potent activity against influenza virus A (A/Wuhan/359/1995) with an IC50 value of 18.52 μg/mL and a selectivity index (SI) = 13.0.
Keywords: amantadine; rimantadine; oseltamivir; anti-influenza drugs; thienyl propenoic acid; 3-(2-thienyl) acrylic acid; thiophene-based amide; crystal structure amantadine; rimantadine; oseltamivir; anti-influenza drugs; thienyl propenoic acid; 3-(2-thienyl) acrylic acid; thiophene-based amide; crystal structure

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MDPI and ACS Style

Chochkova, M.; Stoykova, B.; Angelova, M.; Sbirkova-Dimitrova, H.; Rusew, R.; Li, Y.; Popatanasov, A.; Petek, N.; Štícha, M.; Shivachev, B. Thienyl-Based Amides of M2 and Neuraminidase Inhibitors: Synthesis, Structural Characterization, and In Vitro Antiviral Activity Against Influenza A Viruses. Crystals 2025, 15, 772. https://doi.org/10.3390/cryst15090772

AMA Style

Chochkova M, Stoykova B, Angelova M, Sbirkova-Dimitrova H, Rusew R, Li Y, Popatanasov A, Petek N, Štícha M, Shivachev B. Thienyl-Based Amides of M2 and Neuraminidase Inhibitors: Synthesis, Structural Characterization, and In Vitro Antiviral Activity Against Influenza A Viruses. Crystals. 2025; 15(9):772. https://doi.org/10.3390/cryst15090772

Chicago/Turabian Style

Chochkova, Maya, Boyka Stoykova, Magdalena Angelova, Hristina Sbirkova-Dimitrova, Rusi Rusew, Yuhuan Li, Andrey Popatanasov, Nejc Petek, Martin Štícha, and Boris Shivachev. 2025. "Thienyl-Based Amides of M2 and Neuraminidase Inhibitors: Synthesis, Structural Characterization, and In Vitro Antiviral Activity Against Influenza A Viruses" Crystals 15, no. 9: 772. https://doi.org/10.3390/cryst15090772

APA Style

Chochkova, M., Stoykova, B., Angelova, M., Sbirkova-Dimitrova, H., Rusew, R., Li, Y., Popatanasov, A., Petek, N., Štícha, M., & Shivachev, B. (2025). Thienyl-Based Amides of M2 and Neuraminidase Inhibitors: Synthesis, Structural Characterization, and In Vitro Antiviral Activity Against Influenza A Viruses. Crystals, 15(9), 772. https://doi.org/10.3390/cryst15090772

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