Here, we report the design, synthesis, structure-activity relationship studies, antiviral activity, enzyme inhibition, and druggability evaluation of dihydrofuro[3,4-]pyrimidine derivatives as a potent class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Compounds (EC = 5.79-28.3 nM) and (EC = 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, and showed moderate RT enzyme inhibition (IC = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, and exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.
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Development of Novel Dihydrofuro[3,4-]pyrimidine Derivatives as HIV-1 NNRTIs to Overcome the Highly Resistant Mutant Strains F227L/V106A and K103N/Y181C.
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