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Design and Synthesis of Fsp3-Enriched Spirocyclic-Based Biological Screening Compound Arrays via DOS Strategies and
Ildar R Iusupov1, Evgeny R Lukyanenko1, Andrea Altieri1,2
1Department of Chemistry, Lomonosov Moscow State University, 1/3 Leninsky Gory, Moscow, 119991, Russia.
Chemmedchem
|October 4, 2022
Summary
Medicinal chemists can now create novel 3D spiro-scaffolds using a new synthetic cascade. This technology enhances drug discovery by generating diverse, rigid molecules with high Fsp3 values for better biological target interactions.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Computational Chemistry
Background:
- The majority of existing drugs are flat, unlike natural products which are more three-dimensional (3D) and serve as a rich source of bioactive compounds.
- Three-dimensional (3D) metrics and computational descriptors, such as the fraction of sp3 hybridized carbon atoms (Fsp3), are crucial for evaluating and prioritizing compounds based on their 3D geometry.
- There is a need for advanced synthetic methodologies to create novel chemotypes with high Fsp3 values.
Purpose of the Study:
- To develop a diversity-oriented synthesis (DOS) approach for generating novel, three-dimensional (3D) spiro-scaffolds.
- To create compounds with high Fsp3 values and inherent structural rigidity for improved biological target interactions.
- To explore the drug-like properties and potential NNMT enzyme modulatory activity of the synthesized compounds.
Main Methods:
- A novel synthetic cascade technology was employed, starting from two simple reagents.
- The methodology focused on diversity-oriented synthesis (DOS) to generate a library of spiro-scaffolds.
- Synthesized compounds were evaluated for their drug-like properties and potential as NNMT enzyme modulators.
Main Results:
- A highly enriched Fsp3 novel and diverse spiro-scaffold was successfully generated using the developed synthetic cascade.
- The spiro nature of the scaffolds contributes to high Fsp3 values and increased rigidity, facilitating precise stereo-interactions with biological targets.
- Initial profiling indicated favorable drug-like properties and potential for modulating the NNMT enzyme.
Conclusions:
- The described DOS synthetic cascade technology provides a valuable tool for medicinal chemists to access novel 3D chemotypes with high Fsp3 values.
- The generated spiro-scaffolds possess inherent rigidity and diversity, making them promising candidates for drug discovery and development.
- The synthesized compounds show potential as NNMT enzyme modulators, warranting further investigation.
