Rational Design of Potent Non-Nucleoside Inhibitors of HIV‑1 Reverse Transcriptase

A new series of non-nucleoside reverse transcriptase inhibitors based on an imidazole-amide biarylether scaffold has been identified and shown to possess potent antiviral activity against HIV-1, including the NNRTI-resistant Y188L mutated virus. X-ray crystallography of inhibitors bound to reverse transcriptase, including a structure of the Y188L RT protein, was used extensively to help identify and optimize the key hydrogen-bonding motif. This led directly to the design of compound <b>43</b> that exhibits remarkable antiviral activity (EC<sub>50</sub> < 1 nM) against a wide range of NNRTI-resistant viruses and a favorable pharmacokinetic profile across multiple species.