Design, asymmetric synthesis, and evaluation of pseudosymmetric sulfoximine inhibitors against HIV-1 protease

作者：Lu Ding; Sham Yuk Yin; Vince Robert^*

来源：Bioorganic & Medicinal Chemistry, 2010, 18(5): 2037-2048.

DOI：10.1016/j.bmc.2010.01.020

• HIV
• HIV protease
• Sulfoximine inhibitors
• Transition state mimetic
• Peptidomimetic
• Asymmetric synthesis

The HIV-1 protease is a validated drug target for the design of antiretroviral drugs to combat AIDS. We previously established the sulfoximine functionality as a valid transition state mimetic (TSM) in the HIV-1 protease inhibitors ( PI) design and have identified a lead pseudosymmetric compound with nano-molar enzymatic inhibitory activity. Here, we report the asymmetric synthesis of this compound and its application in the synthesis of sulfoximine-based peptidomimetic HIV-1 protease inhibitors. Molecular modeling revealed the potential mode of binding of the sulfoximine inhibitor as a TSM. The predicted absolute binding free energies suggested similar inhibitory effect as observed in our enzymatic inhibitory studies.

• 出版日期2010-3-1