Synthesis of privileged scaffolds by using diversity-oriented synthesis

Area of Science:

• Organic Synthesis
• Medicinal Chemistry
• Drug Discovery

Background:

• Chiral bicyclic lactams are versatile starting materials for synthesizing complex molecular architectures.
• Developing efficient synthetic routes to biologically active scaffolds is crucial for drug discovery.

Purpose of the Study:

• To develop a novel reagent-controlled strategy for generating diverse, biologically active scaffolds from a chiral bicyclic lactam.
• To evaluate the drug-like properties and biological activities, including anticancer and antibacterial properties, of the synthesized compounds.

Main Methods:

• A chiral bicyclic lactam was subjected to reduction with lithium aluminum hydride (LAH) or alkylation with lithium bis(trimethylsilyl)amide (LHMDS) to initiate distinct cyclization pathways.
• Generated scaffolds, including pyrrolidines, indolines, and cyclotryptamines, were derivatized to create compound libraries.
• In silico studies were performed to assess drug-like properties.
• Selected compounds underwent in vitro anticancer screening against three cell lines and antibacterial screening.

Main Results:

• The developed strategy efficiently generated privileged scaffolds like pyrrolidines, indolines, and cyclotryptamines.
• Compound libraries with diverse substitution patterns were successfully synthesized.
• In silico analysis indicated favorable drug-like properties for the synthesized compounds.
• Directly generated compounds exhibited potent anticancer activity at low nanomolar concentrations, exemplified by spiroindoline 14, with no further optimization needed.

Conclusions:

• The developed reagent-controlled strategy provides a facile route to diverse, biologically active scaffolds from chiral lactams.
• The methodology enables the rapid generation of potent anticancer agents.
• This approach holds promise for accelerating drug discovery efforts by directly yielding promising drug candidates.