Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus replication

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Virology

Background:

• Hepatitis C Virus (HCV) infection poses a significant global health challenge, necessitating the development of novel antiviral agents.
• Nucleoside analogs are a cornerstone in antiviral drug discovery, offering diverse mechanisms for inhibiting viral replication.

Purpose of the Study:

• To synthesize novel acyclic triazole nucleosides incorporating ethynyl moieties.
• To evaluate the antiviral activity of these compounds against HCV replication.
• To conduct a preliminary structure-activity relationship (SAR) study to identify key structural features for anti-HCV activity.

Main Methods:

• Efficient one-step Sonogashira cross-coupling reaction in aqueous solution under microwave irradiation for nucleoside synthesis.
• In vitro assessment of anti-HCV activity using a subgenomic HCV replication assay.
• Cell proliferation assays to determine host cell toxicity.

Main Results:

• Successful synthesis of novel acyclic triazole nucleosides bearing various ethynyl groups.
• Compound 1f demonstrated potent inhibition of HCV subgenomic replication with an EC(50) of 22 microg/ml.
• Compound 1f exhibited no significant cytotoxicity to host cells at 50 microg/ml.

Conclusions:

• The synthesized acyclic triazole nucleosides represent a promising class of compounds for anti-HCV drug development.
• The phenyl ring and the triple bond linker are crucial structural elements contributing to the observed anti-HCV efficacy.
• Further investigation into these nucleoside analogs could lead to the development of new therapeutic strategies against Hepatitis C.