Design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing pyrrolidine-derived P2 ligands to combat drug-resistant variant

The design, synthesis, and biological evaluation of a novel series of HIV-1 Protease Inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2' ligands were described. A number of inhibitors demonstrated potent efficacy in both Enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2' ligand displayed exceptional Enzyme inhibitory activity with an IC₅₀ value of 0.32 nM. Furthermore, 34b also exhibited robust Antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC₅₀ values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 Protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 Protease Inhibitors.

Antiviral activity; Drug-resistant variant; Enzyme inhibitory activity; HIV-1 protease inhibitors; Molecular modelling; Pyrrolidine.