Hydrophobic Pocket Occupation Design of Difluoro-Biphenyl-Diarylpyrimidines as Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: from <i>N</i>-Alkylation to Methyl Hopping on the Pyrimidine Ring

Considering the nonideal metabolic stability of difluoro-biphenyl-diarylpyrimidine lead compound 4, a series novel alkylated difluoro-biphenyl-diarylpyrimidines were designed and synthesized based on their structure. Introducing alkyl or substituted groups linker region to block potential sensitive sites generated 22 derivatives. Among them, 12a with an N-methyl group displayed excellent anti-HIV-1 activity selectivity. The methyl was hopped central pyrimidine occupy small maintain water-mediated hydrogen bond observed in binding 4 RT. resulting 16y exhibited improved activity, much lower cytotoxicity, nanomolar toward multiple mutants. In addition, has better human liver microsomes than 4. Moreover, no apparent vivo acute toxicity 16y-treated female, especially pregnant mice. This compounds highly potency safety represent promising template for future discovery.