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Updated: Jun 21, 2025
05:34
Efficient Synthesis of Polyfunctionalized Benzenes in Water via Persulfate-promoted Benzannulation of α,β-Unsaturated Compounds and Alkynes
Published on: December 16, 2019
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Three-dimensional saturated C(sp3)-rich bioisosteres for benzene
Jet Tsien1, Chao Hu1, Rohan R Merchant2
1Department of Biochemistry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature Reviews. Chemistry
|July 9, 2024
Summary
Medicinal chemistry is developing 3D, saturated benzene bioisosteres to improve drug properties. These novel scaffolds offer better metabolic stability and solubility compared to traditional benzene rings.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Drug Discovery
Background:
- Benzene rings are common in drugs but often cause poor drug-like properties such as metabolic instability and low solubility.
- C(sp3)-rich bioisosteric scaffolds show improved physicochemical profiles over arenes.
- Synthetic methods for saturated benzene bioisosteres have advanced, but ortho- and meta-substituted analogs remain underexplored due to synthetic challenges.
Purpose of the Study:
- To review emerging synthetic methodologies for accessing 3D ortho-, meta-, and multi-substituted benzene bioisosteres.
- To discuss the impact of these saturated motifs on drug properties.
- To provide a perspective on next-generation bioisosteres in novel chemical space.
Main Methods:
- Literature review of synthetic methodologies.
- Analysis of physicochemical properties of bioisosteric scaffolds.
- Discussion of applications in medicinal chemistry.
Main Results:
- Significant progress in synthesizing saturated bioisosteres for various substitution patterns.
- Demonstrated potential of these scaffolds to overcome limitations of benzene rings in drug design.
- Identification of underexplored areas and future directions for bioisostere development.
Conclusions:
- Emerging synthetic methods enable access to challenging 3D benzene bioisosteres.
- These saturated scaffolds offer a promising strategy to enhance drug-like properties.
- Further exploration of novel bioisosteres is crucial for advancing drug discovery.
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