Considering the exceptional anti-HIV-1 potency of rilpivirine (RPV) against diverse mutant strains and its remarkable human ether-a-go-go related gene (hERG) potassium channel inhibition (IC₅₀ = 0.50 μmol/L) as well as low selectivity (SI = 3989), a series of novel furo-[3,2-d]pyrimidine derivatives were rationally designed through a scaffold hopping strategy. Encouragingly, compound 10 revealed a striking reduction in hERG channel inhibition (IC₅₀ > 30 μmol/L) and significant increase in selectivity (SI = 161580). Notably, 10 exhibited excellent antiviral activity against various HIV-1 strains (EC₅₀ = 1.9-46.3 nmol/L). In particular, 10 displayed prominent inhibitory potency against Y188L (EC₅₀ = 15.5 nmol/L) and F227L + V106A strain (EC₅₀ = 8.7 nmol/L), which was superior to those of RPV (EC₅₀ ₍Y₁₈₈L₎ = 79.4 nmol/L, EC₅₀ ₍F₂₂₇L ₊ V₁₀₆A₎ = 81.6 nmol/L). Besides, no apparent cytotoxicity (CC₅₀ = 314.8 μmol/L) and negligible suppression of CYP isoenzymes were detected. Overall, these findings illustrated that 10 was a potentially promising NNRTI for HIV-1 therapy.

HIV-1  /  Reverse transcriptase (RT)  /  Non-nucleoside RT inhibitors (NNRTIs)  /  Diarylpyrimidine (DAPY)  /  Human ether-a-go-go related gene (hERG)