Tricyclic Pyrrole-Based Compounds as Zika Virus Inhibitors.

Area of Science:

• Medicinal Chemistry
• Virology
• Organic Synthesis

Background:

• Zika virus (ZIKV) and SARS-CoV pose significant global health threats.
• Novel antiviral agents are urgently needed to combat emerging viral infections.
• Pyrrole-based tricyclic compounds represent a potential scaffold for antiviral drug discovery.

Purpose of the Study:

• To synthesize and evaluate a library of pyrrole-based tricyclic derivatives for antiviral activity.
• To identify potent inhibitors of ZIKV and SARS-CoV replication.
• To investigate the mechanism of action of active compounds against ZIKV.

Main Methods:

• Synthesis of 23 pyrrole-based tricyclic derivatives with bulky amine moieties.
• Antiviral screening against ZIKV and SARS-CoV using cell-based assays.
• Determination of EC50 (half-maximal effective concentration) and CC50 (half-maximal cytotoxic concentration) values.
• Mechanism of action studies focusing on viral protein impairment.

Main Results:

• Three compounds (2g, 2h, 2j) demonstrated notable activity against ZIKV.
• Compound 2g, featuring a bornylamine residue, exhibited the highest potency against ZIKV in Huh-7 cells (EC50 = 0.4 μM).
• Compound 2g displayed a high Selectivity Index (SI) of 501, indicating a favorable safety profile.
• The active compounds were found to reduce ZIKV yield by interfering with viral protein production.

Conclusions:

• Pyrrole-based tricyclic derivatives, particularly compound 2g, show promising antiviral potential against ZIKV.
• The identified compounds represent valuable leads for the development of new ZIKV therapeutics.
• Impairment of viral protein synthesis is a key mechanism for the observed antiviral activity.