title: Amidate Prodrugs of Deoxythreosyl Nucleoside Phosphonates as Dual Inhibitors of HIV and HBV Replication.
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 EC50of 4.69 μM against HIV-1 and an EC50value 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.
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Shrinivas G
authors.initials: SG
authors.lastname: Dumbre
authors.affiliation: Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pannecouque
authors.affiliation: Infectious Disease Research, Southern Research , 431 Aviation Way, Frederick, Maryland 21701, United States.
authors.forename: Chunsheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Infectious Disease Research, Southern Research , 431 Aviation Way, Frederick, Maryland 21701, United States.
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.affiliation: Infectious Disease Research, Southern Research , 431 Aviation Way, Frederick, Maryland 21701, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Murray
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: De Jonghe
authors.affiliation: Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven , Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Piet
authors.initials: P
authors.lastname: Herdewijn
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000577:Amides; D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; D000241:Adenosine