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.PMID:36738797 | DOI:10.1016/j.bmcl.2023.129168

Source: Bioorganic and Medicinal Chemistry Letters - February 4, 2023 Category: Chemistry Authors: Arun K Ghosh Dana Shahabi Maya Kipfmiller Ajay K Ghosh Megan Johnson Yuan-Fang Wang Johnson Agniswamy Masayuki Amano Irene T Weber Hiroaki Mitsuya Source Type: research