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.