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

Abstract

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 A12 demonstrated exceptional efficacy against both WT HIV-1 (EC50 = 1.9 nmol/L) and seven mutant strains (EC50 = 1.7–157 nmol/L), surpassing that of the lead compound 6 and comparable to etravirine. Furthermore, this analog exhibited minimal adverse effects with significantly reduced cytotoxicity (CC50 = 195 μmol/L) and a high selectivity index (SI = 102,608), superior to those of etravirine (CC50 > 4.6 μmol/L, SI > 1436) and rilpivirine (CC50 = 3.98 μmol/L, SI = 3989). It displayed low inhibition of CYP (IC50 = 6.99–25 μmol/L) and hERG (IC50 > 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, A12 exhibited favorable oral bioavailability (F = 29.2%) and an extended elimination half-life (T1/2 = 13.56 h), enabling convenient oral administration at minimal doses. These findings indicated that A12 could serve as a promising drug candidate for HIV treatment.

Keywords

• AIDS
• HIV-1
• NNRTIs
• Diarylpyrimidines
• Bioisosterism
• Anti-resistance potency