Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach

• Novel DAPY derivatives were designed by a structure-guided core refining approach.
• 16 compounds inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM.
• 7a has EC50 values of 2.5 nM and 0.33 μM against wt and double mutant HIV-1 strains.
• Compound 8c demonstrated moderate anti-HIV-2 potency (EC50 = 5.57 μM).
• SARs and molecular modeling studies were discussed in detail.

Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 μM (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 μM). Preliminary structure–activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail.

A novel series of non-nucleoside reverse transcriptase inhibitors with DAPY scaffold was rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells. Figure optionsDownload as PowerPoint slide