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

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.

Automated summary

In this study, darunavir derived HIV-1 protease inhibitors were synthesized and evaluated for their biological activity. Modification of the P2' 4-amino functionality led to the development of amide derivatives that interacted with residues in the S2' subsite of the protease active site. Some compounds exhibited potent enzyme inhibitory and antiviral activity. X-ray crystallography revealed the binding mode of a chloroacetate derivative to the protease, showing enhanced hydrogen bonding interactions with the backbone atoms in the S2'-subsite.