Design and evaluation of novel piperidine HIV-1 protease inhibitors with potency against DRV-resistant variants

A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme K_i value of 29 pM and antiviral IC₅₀ value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1_NL4-3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC₅₀ values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.