2. Academic Validation
  3. Amidate Prodrugs of Deoxythreosyl Nucleoside Phosphonates as Dual Inhibitors of HIV and HBV Replication

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

  • J Med Chem. 2016 Oct 27;59(20):9513-9531. doi: 10.1021/acs.jmedchem.6b01260.
Chao Liu 1,  Shrinivas G Dumbre 1,  Christophe Pannecouque 2,  Chunsheng Huang 3,  Roger G Ptak 3,  Michael G Murray 3,  Steven De Jonghe 1,  Piet Herdewijn 1
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
  • 2 Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 3 Infectious Disease Research, Southern Research , 431 Aviation Way, Frederick, Maryland 21701, United States.
PMID: 27748590 DOI: 10.1021/acs.jmedchem.6b01260
Abstract

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.

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