Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 610 Medicine and health
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2017
• Mô tả vật lý: Size: p. 4925-4931 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260410
• Chủ đề: 1. 60 applied life sciences; 2. Drug resistance; 3. Hiv protease; 4. Macrocyclic inhibitors; 5. P1?-p2? ligands; 6. Structure-based design

Tóm tắt

 Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (K<
 sub>
 i<
 /sub>
  = 13.2 nM, IC<
 sub>
 50<
 /sub>
  = 22 nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. Lastly, these compounds showed excellent HIV-1 protease inhibitory (K<
 sub>
 i<
 /sub>
  = 62 pM and 14 pM, respectively) and antiviral activity (IC<
 sub>
 50<
 /sub>
  = 5.3 nM and 2.0 nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.