Synthesis and biological evaluation of novel amprenavir-based P1-substituted bi-aryl derivatives as ultra-potent HIV-1 protease inhibitors

Jianwei Yan; Ning Huang; Shukun Li; Liu-Meng Yang; Weiqiang Xing; Yong-Tang Zheng; Youhong Hu

doi:10.1016/j.bmcl.2012.01.037

Synthesis and biological evaluation of novel amprenavir-based P1-substituted bi-aryl derivatives as ultra-potent HIV-1 protease inhibitors

Bioorg Med Chem Lett. 2012 Mar 1;22(5):1976-9. doi: 10.1016/j.bmcl.2012.01.037. Epub 2012 Jan 21.

Authors

Jianwei Yan¹, Ning Huang, Shukun Li, Liu-Meng Yang, Weiqiang Xing, Yong-Tang Zheng, Youhong Hu

Affiliation

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.

PMID: 22306123
DOI: 10.1016/j.bmcl.2012.01.037

Abstract

A series of P1-substituted biaryl amprenavir derivatives was designed and synthesized. These compounds were evaluated for enzyme inhibition and antiviral activity in vitro. Several compounds showed highly efficient antiviral activity with EC(50) values down to 0.10nM, which are more potent than marketed HIV-1 protease inhibitors. Docking study indicated that 12c has similar binding mode to amprenavir with full occupancy in P1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carbamates / chemical synthesis
Carbamates / chemistry*
Carbamates / pharmacology*
Catalytic Domain
Cell Line
Furans
HIV Infections / drug therapy
HIV Protease / chemistry
HIV Protease / metabolism*
HIV Protease Inhibitors / chemical synthesis
HIV Protease Inhibitors / chemistry*
HIV Protease Inhibitors / pharmacology*
HIV-1 / drug effects*
HIV-1 / enzymology*
Humans
Models, Molecular
Sulfonamides / chemical synthesis
Sulfonamides / chemistry*
Sulfonamides / pharmacology*

Substances

Carbamates
Furans
HIV Protease Inhibitors
Sulfonamides
amprenavir
HIV Protease
p16 protease, Human immunodeficiency virus 1