Evaluation of darunavir-derived HIV-1 protease inhibitors incorporating P2' amide-derivatives: Synthesis, biological evaluation and structural studies

Bioorg Med Chem Lett. 2023 Mar 1:83:129168. doi: 10.1016/j.bmcl.2023.129168. Epub 2023 Feb 3.

Abstract

We report here the synthesis and biological evaluation of darunavir derived HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. The P2' 4-amino functionality was modified to make a number of amide derivatives to interact with residues in the S2' subsite of the HIV-1 protease active site. Several compounds exhibited picomolar enzyme inhibitory and low nanomolar antiviral activity. The X-ray crystal structure of the chloroacetate derivative bound to HIV-1 protease was determined. Interestingly, the active chloroacetate group converted to the acetate functionality during X-ray exposure. The structure revealed that the P2' carboxamide functionality makes enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.

Keywords: Darunavir; HIV-1 protease; Inhibitor; Synthesis; X-ray structure.

Publication types

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

MeSH terms

  • Amides / pharmacology
  • Chloroacetates / pharmacology
  • Crystallography, X-Ray
  • Darunavir / pharmacology
  • Drug Design
  • HIV Protease / metabolism
  • HIV Protease Inhibitors*
  • HIV-1*
  • Structure-Activity Relationship

Substances

  • Darunavir
  • HIV Protease Inhibitors
  • p16 protease, Human immunodeficiency virus 1
  • Amides
  • HIV Protease
  • Chloroacetates