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Here we report that three newly designed CNS-targeting HIV-1 protease inhibitors (PIs), GRL-083-13, GRL-084-13, and GRL-087-13, which contain a P1-3,5-\n            <jats:italic>bis<\/jats:italic>\n            -fluorophenyl or P1-\n            <jats:italic>para<\/jats:italic>\n            -monofluorophenyl ring, and P2-\n            <jats:italic>bis<\/jats:italic>\n            -tetrahydrofuran (\n            <jats:italic>bis<\/jats:italic>\n            -THF) or P2-tetrahydropyrano-tetrahydrofuran (\n            <jats:italic>Tp<\/jats:italic>\n            -THF), with a sulfonamide isostere, are highly active against wild-type HIV-1 strains and primary clinical isolates (50% effective concentration [EC\n            <jats:sub>50<\/jats:sub>\n            ], 0.0002 to \u223c0.003\u2009\u03bcM), with minimal cytotoxicity.\n          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