Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl design

Authors:
  • PFPaula M. D. Fitzgerald
    Paula M. D. Fitzgerald
  • MHM. Katharine Holloway
    M. Katharine Holloway
  • EEEmilio A. Emini
    Emilio A. Emini
  • PDPaul L. Darke
    Paul L. Darke
  • BMBrian M. McKeever
    Brian M. McKeever
  • WSWilliam A. Schleif
    William A. Schleif
  • JQJulio C. Quintero
    Julio C. Quintero
  • JZJoan A. Zugay
    Joan A. Zugay
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Abstract
By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.