Design and synthesis of highly potent HIV-1 protease inhibitors with novel isosorbide-derived P2 ligands.
The design, synthesis, and biological evaluation of a series of six HIV-1 protease inhibitors incorporating isosorbide moiety as novel P2 ligands are described. All the compounds are very potent HIV-1 protease inhibitors with IC50 values in the nanomolar or picomolar ranges (0.05-0.43 nM). Molecular docking studies revealed the formation of an extensive hydrogen-bonding network between the inhibitor and the active site. Particularly, the isosorbide-derived P2 ligand is involved in strong hydrogen bonding interactions with the backbone atoms.
Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China.
Xin
X
Qiu
Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China.
Guo-Dong
GD
Zhao
Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China.
Long-Qiang
LQ
Tang
Institute of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong Province, PR China. Electronic address: liuzhaop@sdu.edu.cn.
Zhao-Peng
ZP
Liu
D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007547:Isosorbide / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; D007547:Isosorbide
Design; Drug-resistant; HIV-1 protease inhibitors; Isosorbides; P2 ligand; Synthesis