Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1′-P2′ ligands. Issue 21 (1st November 2017)

• Record Type: Journal Article
• Authors: Ghosh, Arun K.; Sean Fyvie, W.; Brindisi, Margherita; Steffey, Melinda; Agniswamy, Johnson; Wang, Yuan-Fang; Aoki, Manabu; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 21(2017)
• Page Start: 4925
• Page End: 4931
• Publication Date: 2017-11-01
• Subjects: HIV protease -- Drug resistance -- P1′-P2′ ligands -- Macrocyclic inhibitors -- Structure-based design; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.09.003
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1′-P2′ tethers are reported. Inhibitor5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity ( K i = 13.2 nM, IC50 = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors5m and5o . These compounds showed excellent HIV-1 protease inhibitory ( K i = 62 pM and 14 pM, respectively) and antiviral activity (IC50 = 5.3 nM and 2.0 nM, respectively). Inhibitor5o also remained highly potent against a DRV-resistant HIV-1 variant.