Amidate Prodrugs of Deoxythreosyl Nucleoside Phosphonates as Dual Inhibitors of HIV and HBV Replication

The
synthesis of four l-2′-deoxy-threose nucleoside
phosphonates with the natural nucleobases adenine, thymine, cytosine,
and guanosine has been performed. Especially the adenine containing
analogue (PMDTA) was endowed with potent antiviral activity displaying
an EC50 of 4.69 μM against HIV-1 and an EC50 value of 0.5 μM against HBV, whereas completely lacking cytotoxicity.
The synthesis of a number of phosphonomonoamidate and phosphonobisamidate
prodrugs of PMDTA led to a boost in antiviral potency. The most potent
congeners were a l-aspartic acid diisoamyl ester phenoxy
prodrug and a l-phenylalanine propyl ester phosphonobisamidate
prodrug that both display anti-HIV and anti-HBV activities in the
low nanomolar range and selectivity indexes of more than 300.