Considering the undesirable metabolic stability of our recently identified NNRTI <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min) in human liver microsomes, we directed our efforts to improve its metabolic stability by introducing a new favorable hydroxymethyl side chain to the C-5 position of pyrimidine. This strategy provided a series of novel methylol-biphenyl-diarylpyrimidines with excellent anti-HIV-1 activity. The best compound <b>9g</b> was endowed with remarkably improved metabolic stability in human liver microsomes (<i>t</i><sub>1/2</sub> = 2754 min), which was about 29-fold longer than that of <b>5</b> (<i>t</i><sub>1/2</sub> = 96 min). This compound conferred picomolar inhibition of WT HIV-1 (EC<sub>50</sub> = 0.9 nmol/L) and low nanomolar activity against five clinically drug-resistant mutant strains. It maintained particularly low cytotoxicity (CC<sub>50</sub> = 264 μmol/L) and good selectivity (SI = 256,438). Molecular docking studies revealed that compound <b>9g</b> exhibited a more stable conformation than <b>5</b> due to the newly constructed hydrogen bond of the hydroxymethyl group with E138. Also, compound <b>9g</b> was characterized by good safety profiles. It displayed no apparent inhibition of CYP enzymes and hERG. The acute toxicity assay did not cause death and pathological damage in mice at a single dose of 2 g/kg. These findings paved the way for the discovery and development of new-generation anti-HIV-1 drugs.
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