Chiral resolution, absolute configuration assignment and biological activity of racemic diarylpyrimidine CH(OH)-DAPY as potent nonnucleoside HIV-1 reverse transcriptase inhibitors

(+)-3a and (−)-3a were successfully separated from racemate (±)-3a by the chiral technique of supercritical fluid chromatography (SCF) with enantiomeric excess (ee%) >99% and purity >99%, and assigned for their absolute configuration as R and S, respectively, by the experimental electronic circular dichroism (ECD) spectrum and simulated ECD spectra calculated by time-dependent density functional theory (TDDFT) calculations. (+)-(R)-3a displayed excellent activity with an EC50 of 5.3 nM against wild-type HIV-1, which was 12-fold more potent than (−)-(S)-3a. However, (−)-(S)-3a showed higher potency than (+)-(R)-3a against the double HIV-1 RT mutant (K103N + Y181C) as well as HIV-2 strain ROD. The possible reason for the difference of (R)- and (S)-3a in anti-HIV-1 activity was interpreted by molecular docking.

Graphical AbstractDiarylpyrimidines (+)-3a and (−)-3a were separated from racemate (±)-3a, assigned for their absolute configurations, and evaluated for their anti-HIV activity.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Diarylpyrimidines (+)- and (−)-3a were separated from (±)-3a. ► The absolute configurations of (+)- and (−)-3a were confirmed by ECD spectroscopy. ► (+)-(R)-3a and (−)-(S)-3a were evaluated for their anti-HIV activity.