Bioisosterism-driven design of orally active, safe, and broad-spectrum biphenyl-DAPY derivatives as highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors.

This study aimed to identify ideal pharmaceutical candidates featuring strong anti-HIV-1 activity and desirable drug-like characteristics. Our endeavor involved the implementation of a bioisosterism strategy, leading to the discovery of an assemblage of halogen-containing biphenyl-diarylpyrimidines as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Notably, compound demonstrated exceptional efficacy against both WT HIV-1 (EC = 1.9 nmol/L) and seven mutant strains (EC = 1.7-157 nmol/L), surpassing that of the lead compound and comparable to etravirine. Furthermore, this analog exhibited minimal adverse effects with significantly reduced cytotoxicity (CC = 195 μmol/L) and a high selectivity index (SI = 102,608), superior to those of etravirine (CC > 4.6 μmol/L, SI > 1436) and rilpivirine (CC = 3.98 μmol/L, SI = 3989). It displayed low inhibition of CYP (IC = 6.99-25 μmol/L) and hERG (IC > 40 μmol/L), indicating a safer profile compared to etravirine and rilpivirine. No acute toxicity or organ pathological damage was observed at a single dose of 2 g/kg. Additionally, exhibited favorable oral bioavailability ( = 29.2%) and an extended elimination half-life ( = 13.56 h), enabling convenient oral administration at minimal doses. These findings indicated that could serve as a promising drug candidate for HIV treatment.