Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants

Abstract

We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2′-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2′ ligands, respectively. GRL-001-15 and GRL-003-15 have meta -monofluorophenyl and para -monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (EC 50 s) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CC 50 s) of 38 and 11 μM, respectively.