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 Abstract Graphical Abstract Highlights Diarylpyrimidines (+)-3a and (－)-3a were separated from racemate (±)-3a, assigned for their absolute configurations, and evaluated for their anti-HIV activity.

► 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.

Authors:		Shuang-Xi Gu, Zhi-Ming Li, Xiao-Dong Ma, Shi-Qiong Yang, Qiu-Qin He, Fen-Er Chen, Erik De Clercq, Jan Balzarini, Christophe Pannecouque
Journal:		European Journal of Medicinal Chemistry
Year:		2012
DOI:		10.1016/j.ejmech.2012.04.004
Publication date:		23-04-2012

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