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) 4, a series of novel biphenyl-DAPY derivatives were developed using
the fragment-hopping strategy. Most of the compounds 8a–v exhibited remarkably improved anti-HIV-1 potency. The most active
compound 8r 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 4. 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.