Macrocycles: lessons from the distant past, recent developments, and future directions.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Increasing molecular complexity of drug targets necessitates larger therapeutic agents beyond traditional small molecules.
• Macrocycles (cyclic compounds ≥12 atoms) are suitable for interrogating extended protein interfaces.
• Achieving cellular permeability and bioavailability for macrocycles, especially peptides, remains a significant challenge.

Purpose of the Study:

• To provide an overview of mechanistic and structural aspects of macrocycles as a unique molecular class.
• To explore historical studies contributing to the current resurgence of macrocycles in drug discovery.
• To present recent developments that highlight the therapeutic potential of macrocycles.

Main Methods:

• Review of mechanistic and structural issues relevant to macrocycle synthesis and modification.
• Historical analysis of key studies in macrocycle development.
• Survey of recent synthetic advancements and their implications for therapeutic applications.

Main Results:

• Macrocycles are increasingly recognized for their ability to interact with complex biological targets.
• Creative synthetic strategies are being developed to overcome challenges in macrocycle synthesis and modification.
• Recent progress indicates that macrocycles may become a viable therapeutic modality.

Conclusions:

• Macrocycles represent a promising class of molecules for addressing challenging drug targets.
• Ongoing synthetic innovation is crucial for realizing the therapeutic potential of macrocycles.
• Further research into macrocycle properties and synthesis will likely enhance their role in medicine.