Fragment Hopping-Based Design of Novel Biphenyl-DAPY Derivatives as Potent Non-Nucleoside Reverse Transcriptase Inhibitors Featuring Significantly Improved Anti-Resistance Efficacy

To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) <b>4</b>, a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds <b>8a-v</b> exhibited remarkably improved anti-HIV-1 potency. The most active compound <b>8r</b> proved to be exceptionally potent against the wild-type HIV-1 (EC₅₀ = 2.3 nM) and five mutant strains, such as K103N (EC₅₀ = 8 nM) and E138K (EC₅₀ = 6 nM), significantly better than <b>4</b>. The new DAPY analogue was 8-fold less cytotoxic and had a 17-fold higher selectivity index (CC₅₀ = 40.77 μM, SI > 17391) than etravirine and rilpivirine. Also, it displayed favorable pharmacokinetic properties with an oral bioavailability of 31.19% and weak sensitivity toward both CYP and hERG. No apparent acute toxicity (2 g/kg) and tissue damage occurred. These findings will further expand the possibility of successfully identifying biphenyl-DAPY analogues as highly potent, safe, and orally active NNRTIs for HIV treatment.