Reagent based DOS: a "Click, Click, Cyclize" strategy to probe chemical space

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Synthetic Organic Chemistry

Background:

• The discovery of novel therapeutic agents relies on synthesizing small organic molecules.
• Exploring chemical and biological space is crucial for identifying new drug candidates.

Purpose of the Study:

• To develop a diversity-oriented synthetic (DOS) strategy for generating structurally diverse small molecules.
• To utilize a "Click, Click, Cyclize" protocol for efficient synthesis of S-heterocycles.
• To evaluate the chemical diversity of the synthesized compounds using in silico methods.

Main Methods:

• Employed a reagent-based diversity-oriented synthetic (DOS) strategy.
• Utilized a "Click, Click, Cyclize" protocol involving sulfonamide linchpins.
• Performed in silico analysis including Principal Component (PC) analysis, Principal Moment of Inertia (PMI), and Polar Surface Area (PSA) calculations.

Main Results:

• Successfully synthesized a collection of structurally diverse S-heterocycles.
• Demonstrated the utility of the "Click, Click, Cyclize" protocol in DOS.
• Quantified the chemical space, shape space, and polar surface area diversity of the compound library.

Conclusions:

• The developed "Click, Click, Cyclize" DOS strategy is effective for generating diverse S-heterocycles.
• This approach provides a valuable platform for probing chemical and biological space in drug discovery.
• In silico analysis confirmed the significant diversity of the synthesized compound collection.