Novel HIV‑1 Non-nucleoside Reverse Transcriptase Inhibitor Agents: Optimization of Diarylanilines with High Potency against Wild-Type and Rilpivirine-Resistant E138K Mutant Virus

Three series (<b>6</b>, <b>13</b>, and <b>14</b>) of new diarylaniline (DAAN) analogues were designed, synthesized, and evaluated for anti-HIV potency, especially against the E138K viral strain with a major mutation conferring resistance to the new-generation non-nucleoside reverse transcriptase inhibitor drug rilpivirine (<b>1b</b>). Promising new compounds were then assessed for physicochemical and associated pharmaceutical properties, including aqueous solubility, log P value, and metabolic stability, as well as predicted lipophilic parameters of ligand efficiency, ligand lipophilic efficiency, and ligand efficiency-dependent lipophilicity indices, which are associated with ADME property profiles. Compounds <b>6a</b>, <b>14c</b>, and <b>14d</b> showed high potency against the <b>1b</b>-resistant E138K mutated viral strain as well as good balance between anti-HIV-1 activity and desirable druglike properties. From the perspective of optimizing future NNRTI compounds as clinical trial candidates, computational modeling results provided valuable information about how the R¹ group might provide greater efficacy against the E138K mutant