TY - JOUR
T1 - Structure–activity relationship studies on novel antiviral agents for norovirus infections
AU - Ferla, Salvatore
AU - Varricchio, Carmine
AU - Knight, William
AU - Ho, Pui Kei
AU - Saporito, Fabiana
AU - Tropea, Beatrice
AU - Fagan, Giulio
AU - Flude, Ben Matthew
AU - Bevilacqua, Federica
AU - Santos-Ferreira, Nanci
AU - Van Dycke, Jana
AU - Neyts, Johan
AU - Brancale, Andrea
AU - Rocha-Pereira, Joana
AU - Bassetto, Marcella
N1 - Funding Information:
Funding: This research received no external funding. S.F. is supported by the Sêr Cymru II programme, which is part-funded by Swansea University and the European Regional Development Fund through the Welsh Government. B.M.F. is supported by an EPSRC PhD studentship (PHFS4CT).
Publisher Copyright:
© 2021 by the authors. Li-censee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nu-cleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thio-phene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide por-tion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been re-placed by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thi-oamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cyto-toxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In ad-dition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.
AB - Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion USD per year. Despite this, no therapeutic options or vaccines are currently available to treat or prevent this infection. An antiviral therapy that can be used as treatment and as a prophylactic measure in the case of outbreaks is urgently needed. We previously described the computer-aided design and synthesis of novel small-molecule agents able to inhibit the replication of human norovirus in cell-based systems. These compounds are non-nu-cleoside inhibitors of the viral polymerase and are characterized by a terminal para-substituted phenyl group connected to a central phenyl ring by an amide-thioamide linker, and a terminal thio-phene ring. Here we describe new modifications of these scaffolds focused on exploring the role of the substituent at the para position of the terminal phenyl ring and on removing the thioamide por-tion of the amide-thioamide linker, to further explore structure-activity relationships (SARs) and improve antiviral properties. According to three to four-step synthetic routes, we prepared thirty novel compounds, which were then evaluated against the replication of both murine (MNV) and human (HuNoV) norovirus in cells. Derivatives in which the terminal phenyl group has been re-placed by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thi-oamide linker has been removed, showed promising results in inhibiting HuNoV replication at low micromolar concentrations. Particularly, compound 28 was found to have an EC50 against HuNoV of 0.9 µM. Although the most active novel derivatives were also associated with an increased cyto-toxicity in the human cell line, these compounds represent a very promising starting point for the development of new analogues with reduced cytotoxicity and improved selectivity indexes. In ad-dition, the experimental biological data have been used to create an initial 3D quantitative structure-activity relationship model, which could be used to guide the future design of novel potential anti-norovirus agents.
KW - Antiviral agents
KW - Computer-aided drug design
KW - Human norovirus
KW - SARs
UR - http://www.scopus.com/inward/record.url?scp=85113769043&partnerID=8YFLogxK
U2 - 10.3390/microorganisms9091795
DO - 10.3390/microorganisms9091795
M3 - Article
C2 - 34576691
AN - SCOPUS:85113769043
SN - 2076-2607
VL - 9
JO - Microorganisms
JF - Microorganisms
IS - 9
M1 - 1795
ER -
