To date, there are no specific treatment regimens for the HIV-1-related central nervous system (CNS) complications, such as HIV-1-associated neurocognitive disorders (HAND). In the present study, we report that two newly generated CNS-targeting HIV-1 protease inhibitors (PIs), GRL-08513 and GRL-08613, which have P1-3,5-
bis
-fluorophenyl- or P1-
para
-monofluorophenyl-ring, and P2-tetrahydropyrano-tetrahydrofuran (
Tp
-THF) with a sulfonamide isostere, are potent against wild-type HIV-1s and multiple clinically isolated HIV-1s (EC
50
: 0.0001∼0.0032 μM). As assessed with HIV-1 variants that had been selected
in vitro
to propagate at 5 μM concentration of each HIV-1 PI (atazanavir, lopinavir, or amprenavir), GRL-08513 and GRL-08613 efficiently inhibited the replication of these highly-PI-resistant variants (EC
50
: 0.003∼0.006 μM). GRL-08513 and GRL-08613 also maintained their antiviral activity against HIV-2
ROD
as well as severe multi-drug-resistant clinical HIV-1 variants. Additionally, when we assessed with the
in vitro
blood-brain barrier (BBB) reconstruction system, GRL-08513 and GRL-08613 showed the most promising properties of CNS-penetration among the evaluated compounds including the majority of FDA-approved cART drugs. In the crystallographic analysis of compound-protease (PR) complexes, it was demonstrated that the
Tp
-THF rings at the P2 moiety of GRL-08513 and GRL-08613 form robust hydrogen-bond interactions with the active-site of HIV-1 PR. Furthermore, both the P1-3,5-
bis
-fluorophenyl- and P1-
para
-monofluorophenyl-rings sustain greater contact surfaces and form stronger van der Waals interactions with PR compared to the case of darunavir-PR complex. Taken together, these results strongly suggest that GRL-08513 and GRL-08613 have favorable features for the patients infected with wild-type/multi-drug-resistant HIV-1s, and might serve as candidates of preventive and/or therapeutic for HAND and other CNS complications.