Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies

J Med Chem. 1998 Apr 23;41(9):1446-55. doi: 10.1021/jm970524i.


Comparison of the high-resolution X-ray structures of the native HIV-1 protease and its complexes with the inhibitors suggested that the enzyme flaps are flexible. The movement at the tip of the flaps could be as large as 7 A. On the basis of this observation, cyclic cyanoguanidines have been designed, synthesized, and evaluated as HIV-1 protease (PR) inhibitors. Cyclic cyanoguanidines were found to be very potent inhibitors of HIV-1 protease. The choice of cyclic cyanoguanidines over cyclic guanidines was based on the reduced basicity of the former. X-ray structure studies of the HIV PR complex with cyclic cyanoguanidine demonstrated that in analogy to cyclic urea, cyclic cyanoguanidines also displace the unique structural water molecule. The structure-activity relationship of the cyclic cyanoguanidines is compared with that of the corresponding cyclic urea analogues. The differences in binding constants of the two series of compounds have been rationalized using high-resolution X-ray structure information.

Publication types

  • Comparative Study

MeSH terms

  • Anti-HIV Agents* / chemical synthesis
  • Anti-HIV Agents* / chemistry
  • Anti-HIV Agents* / metabolism
  • Anti-HIV Agents* / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • Guanidines* / chemical synthesis
  • Guanidines* / chemistry
  • Guanidines* / metabolism
  • Guanidines* / pharmacology
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors* / chemical synthesis
  • HIV Protease Inhibitors* / chemistry
  • HIV Protease Inhibitors* / metabolism
  • HIV Protease Inhibitors* / pharmacology
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Hydrogen Bonding
  • Models, Molecular
  • Structure-Activity Relationship
  • Urea / analogs & derivatives
  • Urea / chemistry


  • Anti-HIV Agents
  • Guanidines
  • HIV Protease Inhibitors
  • Urea
  • HIV Protease