Abstract
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-nucleoside 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 thiophene 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 portion 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 Derivatives in which the terminal phenyl group has been replaced by an unsubstituted benzoxazole or indole, and the thioamide component of the amide-thioamide linker has been removed, showed promising results in inhibiting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 cytotoxicity 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 addition, 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.
Highlights
Known as the Norwalk Virus [1], human norovirus (HuNoV) is the main responsible for acute gastroenteritis outbreaks worldwide [2]
With the aim to further explore structure-activity relationships and improve the antiviral properties of our previous hits 3 and 4, a first series of novel analogues 5–26 was designed, to insert different substituents at the para position of the terminal phenyl ring (Ar group) of the hit scaffolds (5–14), as the presence of a methyl substituent in this position had previously been found associated with activity retention [15]
Two heteroaromatic rings were explored as replacements of the phenyl group in this position, a 2-furan and 2-thiophene ring (15–18)
Summary
Known as the Norwalk Virus [1], human norovirus (HuNoV) is the main responsible for acute gastroenteritis outbreaks worldwide [2]. Norovirus infections represent a serious health concern especially in the developing countries, and they cause. Sent a serious health concern especially in the developing countries, and they cause every. 2 of year ~ 214,000 deaths, in immunocompromised patients, the elderly and chil‐. 4.2 billion in direct health system costs and $ 60.3 billion in societal costs annually [4]. Every year ~214,000 deaths, in immunocompromised patients, the elderly and Currently, there are no vaccines or antiviral agents approved for this viral infection, with children under the age of five [3]. Norovirus represents a major financial burden, with an$4.2 urgent need for the development of therapeutic measures to be used for the treatment billion in direct health system costs and $60.3 billion in societal costs annually [4].
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