Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV-1 Protease Inhibitors

作者：Ghosh Arun K^*; Brindisi Margherita

来源：Asian Journal of Organic Chemistry, 2018, 7(8): 1448-1466.

DOI：10.1002/ajoc.201800255

• cyclic ethers
• drug discovery
• HIV-1 protease inhibitors
• Natural products
• synthesis

We have developed a conceptually new generation of non-peptidic HIV-1 protease inhibitors incorporating novel structural templates inspired by nature. This has resulted in protease inhibitors with exceptional potency and excellent pharmacological and drug-resistance profiles. The design of a stereochemically defined bis-tetrahydrofuran (bis-THF) scaffold followed by modifications to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease led to darunavir, the first clinically approved drug for treatment of drug resistant HIV. Subsequent X-ray crystal structure-based design efforts led us to create a range of exceptionally potent inhibitors incorporating other intriguing molecular templates possessing fused ring polycyclic ethers with multiple stereocenters. These structural templates are critical to inhibitors' exceptional potency and drug-like properties. Herein, we will highlight the synthetic strategies that provided access to these complex scaffolds in a stereoselective and optically active form, enabling our medicinal chemistry and drug development efforts.

• 出版日期2018-8