Design, Synthesis, and Biological Evaluation of Novel Core Scaffold-Modified HIV-1 Protease Inhibitors for Overcoming Drug Resistance

Given the urgent need to combat HIV-1 drug resistance, we designed and synthesized a novel series of HIV-1 protease inhibitors with modified core scaffolds, including amino acid-linked hydroxyethyl sulfonamide, hydroxyethyl sulfonimidamide, and hydroxyethyl phosphonamidite. Most of these compounds exhibited potent activities in both enzymatic and cellular assays. Notably, compound 20a, featuring an extended l-asparagine linker, displayed an enzymatic IC₅₀ of 10 pM and an antiviral EC₅₀ of 10.4 nM. Furthermore, it maintained excellent potency against the multidrug-resistant variants (EC₅₀ = 30 ∼ 34.3 nM), demonstrating a superior resistance profile relative to Darunavir. Molecular modeling revealed that the introduction of the l-asparagine fragment promoted extensive interactions with various residues throughout the protease active site. Subsequent investigations indicated that compound 20a-D, the dipeptide prodrug of 20a, exhibited improved ADME properties. Consequently, this study highlighted the potential of core scaffold modification in generating candidates to overcome multidrug resistance and provided valuable information for further optimization.