Chalcogen OCF₃ Isosteres Modulate Drug Properties without Introducing Inherent Liabilities.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Trifluoromethoxy (OCF3) groups are common in pharmaceuticals.
• Exploring isosteric replacements is crucial for optimizing drug properties.
• Chalcogen-containing CF3 groups offer novel structural modifications.

Purpose of the Study:

• To synthesize SCF3 and SeCF3 isosteres of OCF3-containing drugs.
• To evaluate the impact of chalcogen replacement on physicochemical and ADME properties.
• To assess the potential of these novel groups in pharmaceutical development.

Main Methods:

• Visible light and copper-catalyzed synthesis of SCF3 and SeCF3 isosteres.
• Characterization of physicochemical properties (e.g., lipophilicity).
• Assessment of metabolic stability (microsomal stability).

Main Results:

• Successful synthesis of SCF3 and SeCF3 isosteres was achieved.
• Chalcogen replacement modulated lipophilicity, increasing it compared to OCF3.
• Microsomal stability remained comparable to OCF3 counterparts, suggesting no new liabilities.
• These modifications may enhance in vivo half-life.

Conclusions:

• SCF3 and SeCF3 groups are viable isosteres for OCF3 in drug design.
• Chalcogen replacement offers a strategy to fine-tune drug properties.
• These novel fluorinated groups hold promise for future pharmaceutical applications.