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

Abstract

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-1_NL4–3 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.