title: Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines.
abstract: Various 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine [adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (HX)] and pyrimidine [cytosine (C), uracil (U), thymine (T)] have been evaluated for their antiviral properties. PMEDAP, (S)-HPMPA [and the cyclic phosphonate thereof, (S)-cHPMPA)], (S)-HPMPC, PMEG, PMEA, HPMPG and HPMPDAP proved to be effective inhibitors of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). (S)-HPMPA and (S)-cHPMPA were the most effective inhibitors of varicella-zoster virus (VZV), and (S)-HPMPC was the most effective inhibitor of cytomegalovirus (CMV). Against adenovirus (types 2, 3 and 4) and vaccinia virus again (S)-HPMPA and (S)-cHPMPA showed the greatest inhibitory activity. As a rule, the PME derivates were much less inhibitory to VZV, CMV, vaccinia and adenovirus than the HPMP derivatives. However, PMEA, PMEDAP and PMEMAP showed marked and selective activity against the human immunodeficiency virus (HIV). (S)-HPMPA was selected for further evaluation in animal model infections. It proved efficacious in the topical treatment of HSV-1 keratitis in rabbits and cutaneous HSV-1 infection in hairless mice, and in the systemic treatment of both HSV-1 and vaccinia virus infections in mice.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: T
authors.initials: T
authors.lastname: Sakuma
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: I
authors.initials: I
authors.lastname: Rosenberg
authors.forename: A
authors.initials: A
authors.lastname: Holý
mesh_terms: D000818:Animals; D000998:Antiviral Agents; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004267:DNA Viruses / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D009943:Organophosphorus Compounds / Q000494:pharmacology* / Q000633:toxicity; D011687:Purines / Q000494:pharmacology* / Q000633:toxicity; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D011817:Rabbits; D013329:Structure-Activity Relationship; D014777:Virus Diseases / Q000188:drug therapy
chemical_list: D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D011687:Purines; D011743:Pyrimidines