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Nature Inspired Molecular Design: Stereoselective Synthesis of Bicyclic and Polycyclic Ethers for Potent HIV‐1 Protease Inhibitors
Author(s) -
Ghosh Arun K.,
Brindisi Margherita
Publication year - 2018
Publication title -
asian journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.846
H-Index - 44
eISSN - 2193-5815
pISSN - 2193-5807
DOI - 10.1002/ajoc.201800255
Subject(s) - darunavir , chemistry , hiv 1 protease , stereocenter , stereochemistry , protease , combinatorial chemistry , stereoselectivity , template , hydrogen bond , human immunodeficiency virus (hiv) , bicyclic molecule , ring (chemistry) , enantioselective synthesis , nanotechnology , enzyme , biochemistry , molecule , antiretroviral therapy , organic chemistry , virology , materials science , viral load , biology , catalysis
Abstract 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.