Enhancing thiazolide efficacy: C-4 aryl modifications drive selective SARS-CoV-2 inhibition

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• COVID-19 necessitates broad-spectrum antiviral agents.
• Nitazoxanide (NTZ) shows promise against SARS-CoV-2 but has limitations.
• Development of improved NTZ analogues is crucial.

Purpose of the Study:

• Synthesize and evaluate novel thiazolide analogues for SARS-CoV-2 antiviral activity.
• Identify analogues with enhanced potency and selectivity compared to NTZ.
• Assess drug-like properties and safety profiles of promising candidates.

Main Methods:

• Synthesized 24 thiazolide analogues with diverse substitutions.
• Evaluated in vitro antiviral efficacy against SARS-CoV-2 using Vero E6 cells.
• Determined antiviral potency (IC50), cytotoxicity (CC50), and selectivity indices (SI).
• Performed in silico ADMET profiling for drug-likeness and toxicity prediction.

Main Results:

• Several 4'-aryl and dual-substituted thiazolides demonstrated SI > 30, outperforming NTZ (SI ≈ 14).
• Analogue 6e exhibited the highest SI (≈ 51) with potent antiviral activity (IC50 ≈ 0.21 µM).
• Benzothiazole analogue 8a showed a favorable SI (≈ 11).
• In silico analysis predicted acceptable oral bioavailability, low CYP450 inhibition, and minimal cardiotoxicity risk.

Conclusions:

• Lipophilic, electron-withdrawing substituents at the thiazole C-4 position enhance antiviral potency.
• 4'-(PhOCF3) substitutions represent promising scaffolds for further preclinical development.
• Optimized thiazolides offer a potential therapeutic strategy against SARS-CoV-2 and other emerging viruses.