Rational design, synthesis, and evaluating primary biological activities of novel HIV-1 protease inhibitors containing heteraryl acetamides as the P2 ligands.

A series of novel potent HIV-1 protease inhibitors featuring diverse hydroxyaromatic acetanilide derivatives as P2 ligands and 4-substituted phenyl sulfonamides as P2' ligands were designed, synthesized, and biologically evaluated. The majority of the target compounds demonstrated potent enzyme inhibitory activity with IC50 values below100 nM. Notably, compound 18h, incorporating a 2-(4-hydroxypyrimidin-5-yl) acetamide P2 ligand and a 4-methoxybenzenesulfonamide as the P2' ligand, exhibited exceptional potency with an enzyme IC50 of 0.46 nM and antiviral EC50 of 0.26 μM against HIV-1NL4-3 strain. In addition, 18h displayed activity with EC50 value of 0.25 μM against the subtype C HIV-1 Indie strain. The extensive hydrogen-bonding interactions with the protease active site revealed in the molecular docking analysis of 18h-bound HIV-1 protease provided valuable structural insights for the rational design of next-generation HIV-1 protease inhibitors.