%0 Journal Article
%T Design, synthesis, and biological evaluation of novel HIV-1 protease inhibitors containing pyrrolidine-derived P2 ligands to combat drug-resistant variant.
%A Zhou H
%A Ma L
%A Dong B
%A Wang J
%A Zhang G
%A Wang M
%A Cen S
%A Zhu M
%A Shan Q
%A Wang Y
%J Eur J Med Chem
%V 255
%N 0
%D 2023 Jul 5
%M 37120996
%F 7.088
%R 10.1016/j.ejmech.2023.115389
%X 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.