Fragment Addition-Based\nDesign of Heteroaromatic-Biphenyl-DAPYs\nas Potent and Orally Available Non-nucleoside Reverse Transcriptase\nInhibitors Featuring Significantly Enhanced Safety

Our\npreviously disclosed biphenyl-DAPY <b>3</b> emerged as\na potent inhibitor against WT HIV-1 and various mutant strains. Yet,\nits journey toward clinical application was thwarted by pronounced\ncytotoxicity and low selectivity (CC<sub>50</sub> = 6 μM, SI\n= 3515). The safety improvement approach we employed in this work\nentailed the incorporation of diverse heteroaromatic substituents\nat the C5 position to exploit the tolerant regions of the NNRTIs’\nbinding pocket through fragment addition-based drug design strategy,\nultimately leading to the identification of a series of novel heteroaromatic-biphenyl-DAPYs.\nThe exemplary compound <b>10d</b> revealed a striking reduction\nin cytotoxicity (CC<sub>50</sub> > 272.81 μM), nearly 45.5\ntimes\nlower than <b>3</b>, while showcasing 15-fold increase in selectivity\n(SI > 52632). This analog sustained exceptional anti-HIV-1 activity\nagainst both WT HIV-1 (EC<sub>50</sub> = 5 nM) and various mutant\nstrains. Compared to <b>3</b>, a markedly slower rate of metabolism\nin human liver microsomes of <b>10d</b> was observed. Its pharmacokinetic\nprofile was equally captivating, featuring excellent oral bioavailability\n(<i>F</i> = 57.4%). Moreover, <b>10d</b> exhibited\na delicate sensitivity toward CYP, minimal inhibition of hERG, and\nno detectable acute toxicity in vivo. These enchanting findings illuminated\nthe potential of <b>10d</b> as a promising candidate for HIV-1\ntherapy.