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

• Published in: Journal of medicinal chemistry Vol. 65; no. 13; pp. 9396 - 9417
• Main Authors: Tan, Shuai, Groaz, Elisabetta, Kalkeri, Raj, Ptak, Roger, Korba, Brent E., Herdewijn, Piet
• Format: Journal Article
• Language: English
• Published: American Chemical Society 14.07.2022
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c00667

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 EC90 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 (EC50 = 9.27 nM) with excellent selectivity (SI50 > 10,787), proving to be a promising candidate for anti-HBV drug development.