Structure-based design, synthesis, X-ray studies, and biological evaluation of novel HIV-1 protease inhibitors containing isophthalamide-derived P2-ligands

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4903-4909. doi: 10.1016/j.bmcl.2015.05.052. Epub 2015 May 30.


We describe the design, synthesis and biological evaluation of a series of novel HIV-1 protease inhibitors bearing isophthalamide derivatives as the P2-P3 ligands. We have investigated a range of acyclic and heterocyclic amides as the extended P2-P3 ligands. These inhibitors displayed good to excellent HIV-1 protease inhibitory activity. Also, a number of inhibitors showed very good antiviral activity in MT cells. Compound 5n has shown an enzyme Ki of 0.17 nM and antiviral IC50 of 14 nM. An X-ray crystal structure of inhibitor 5o-bound to HIV-1 protease was determined at 1.11Å resolution. This structure revealed important molecular insight into the inhibitor-HIV-1 protease interactions in the active site.

Keywords: Antiviral; Design; HIV-1 protease; Inhibitors; Isophthalamide; Synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Catalytic Domain / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • Ligands
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Phthalic Acids / chemical synthesis
  • Phthalic Acids / chemistry
  • Phthalic Acids / pharmacology*
  • Structure-Activity Relationship


  • HIV Protease Inhibitors
  • Ligands
  • Phthalic Acids
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1