HCV NS5A replication complex inhibitors. Part 4. Optimization for genotype 1a replicon inhibitory activity

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• Hepatitis C virus (HCV) infection remains a significant global health concern.
• Development of effective antiviral therapies targeting HCV replication is crucial.
• HCV NS5A is a key non-structural protein essential for viral RNA replication and assembly.

Purpose of the Study:

• To synthesize and evaluate a series of symmetrical E-stilbene prolinamides as potential inhibitors of HCV replication.
• To identify selective inhibitors targeting HCV genotypes 1a and 1b.
• To explore structure-activity relationships (SAR) within the prolinamide scaffold for improved potency and selectivity.

Main Methods:

• Library synthesis of E-stilbene prolinamide derivatives.
• Antiviral screening against HCV genotype 1a and 1b replicons.
• Selectivity profiling against Bovine viral diarrhea virus (BVDV).
• Cytotoxicity assays to assess safety profiles.

Main Results:

• Compound 11 demonstrated selective inhibition of HCV NS5A with submicromolar potency against both genotype 1a and 1b replicons.
• Further structural modifications led to the identification of compound 30.
• Compound 30 exhibited potent dual inhibition against both HCV genotype 1a and 1b NS5A replicons.

Conclusions:

• Symmetrical E-stilbene prolinamides represent a promising scaffold for developing novel HCV NS5A inhibitors.
• Compound 30 is a potent dual inhibitor of HCV genotypes 1a and 1b NS5A, warranting further investigation for therapeutic potential.