Newly designed HIV-1 protease inhibitors that maximize interactions with the protein backbone, especially in the form of hydrogen bonds, may enhance the antiviral potency of these compounds and minimize acquisition of drug-resistant mutations. Herein, we described a series of new HIV-1 PIs containing phenols as the P2 ligands and chiral isopropanol as the P1′ ligands, in combination with 4-trifluoromethylphenylsulfonamide or 4-nitrophenylsulfonamide as the P2′ ligands. And most of these compounds exhibited nanomolar inhibitory potency. In particular, inhibitors 13c and 13e with 4-trifluoromethylphenylsulfonamide as the P2′ ligand and (R) – isopropanol as the P1′ ligand, exhibited antiviral IC50 values of 1.64 nM and 2.33 nM, respectively. Furthermore, they also showed remarkable activity against wild-type and DRV-resistant HIV-1 variants that raised the prospect of designing more effective PIs further.