Reshaping an Acyclic Nucleoside Phosphonate into a Selective Anti-hepatitis B Virus Compound.

Minor structural modifications of acyclic nucleoside phosphonates can dramatically affect their antiviral properties. This work discloses a shift in the selectivity spectrum of 3-hydroxy-2-(phosphonomethoxy)propyl (HPMP) nucleotides from herpesviruses toward hepatitis B virus (HBV) induced by their acyclic chain 2-substitution with a nonpolar group. Two series of racemic ( R , S )-2-methyl-3-hydroxy-2-(phosphonomethoxy)propyl (MHPMP) and ( R , S )-2-ethynyl-3-hydroxy-2-(phosphonomethoxy)propyl (EHPMP) nucleotides were initially synthesized. Among these, guanine-containing derivatives exhibited significant anti-HBV activities in the submicromolar range. Enantioenriched MHPMPG and EHPMPG analogues were subsequently obtained by Sharpless asymmetric epoxidation. The ( S )-enantiomers possessed an 8- to 26-fold higher potency than the relative ( R )-forms. A further comparison of the EC 90 values indicated that ( S )-EHPMPG inhibited HBV replication more effectively than its 2-methyl analogue. A phosphonodiamidate prodrug of ( S )-EHPMPG was thus prepared and found to exert a remarkably high anti-HBV activity (EC 50 = 9.27 nM) with excellent selectivity (SI 50 > 10,787), proving to be a promising candidate for anti-HBV drug development.