Author:

Keywords:

ASSAY, Chemistry, Medicinal, DESIGN, DRUG-RESISTANCE, Life Sciences & Biomedicine, Pharmacology & Pharmacy, REVERSE-TRANSCRIPTASE INHIBITORS, Science & Technology, Animals, Anti-HIV Agents, Drug Design, Female, Furans, HIV Reverse Transcriptase, HIV-1, Male, Mice, Molecular Docking Simulation, Molecular Structure, Mutation, Protein Binding, Pyrimidines, Rats, Sprague-Dawley, Reverse Transcriptase Inhibitors, Structure-Activity Relationship, Rats, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry, 1115 Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry, 3214 Pharmacology and pharmaceutical sciences, 3404 Medicinal and biomolecular chemistry, 3405 Organic chemistry

Abstract:

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, 14b and 16c showed moderate RT enzyme inhibition (IC50 = 0.14-0.15 μM), which demonstrated that they acted as HIV-1 NNRTIs. Furthermore, 14b and 16c exhibited favorable pharmacokinetic and safety properties, making them excellent leads for further development.