Synthesis and biological evaluation of novel amprenavir-based P1-substituted bi-aryl derivatives as ultra-potent HIV-1 protease inhibitors.
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.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
Jianwei
J
Yan
Ning
N
Huang
Shukun
S
Li
Liu-Meng
LM
Yang
Weiqiang
W
Xing
Yong-Tang
YT
Zheng
Youhong
Y
Hu
D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D002460:Cell Line; D005663:Furans; D015658:HIV Infections / Q000188:drug therapy; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1