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 <b>20a</b>, 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 <b>20a-D</b>, the dipeptide prodrug of <b>20a</b>, 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.