Development of Novel Dihydrofuro[3,4-d]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C

Here, we report the design, synthesis, structure–activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-d]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds 14b(EC50= 5.79–28.3 nM) and 16c(EC50= 2.85–18.0 nM) exhibited superior potency against a panel of HIV-1-resistant strains. Especially, for the changeling mutations F227L/V106A and K103N/Y181C, both compounds exhibited remarkably improved activity compared to those of etravirine and rilpivirine. Moreover, 14band 16cshowed moderate RT enzyme inhibition (IC50= 0.14–0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14band 16cexhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.