Selective in vitro and in vivo activities of 5-(2-haloalkyl)pyrimidine nucleoside analogs, particularly 5-(2-chloroethyl)-2'-deoxyuridine, against herpes simplex virus.
5-(2-Chloroethyl)-2'-deoxyuridine (CEDU), 5-(3-chloropropyl)-2'-deoxyuridine (CPDU), and 5-(2-chloroethyl)-2'-deoxycytidine (CEDC) were evaluated for activity against herpes simplex virus type 1 (HSV-1) and HSV-2 in vitro. Their MICs for HSV-1 in primary rabbit kidney cell cultures were 0.15, 0.20, and 0.60 micrograms/ml, respectively; their MICs for HSV-2 were about 10-fold higher. When tested in parallel, the reference compounds 5-ethyl-2'-deoxyuridine, 5-iodo-2'-deoxyuridine, acyclovir, and (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) gave MICs of 0.20, 0.18, 0.04, and 0.015 micrograms/ml, respectively. The antiviral indexes of CEDU, CPDU, and CEDC, as determined by the ratio of the minimum toxic dose for the normal host cell to the minimum inhibitory dose for HSV-1, were about 2,000, 100, and greater than or equal to 400, respectively. The three 5-(2-haloalkyl)pyrimidine derivatives were further evaluated for their antiviral effects in vivo. In hairless mice, CEDU suppressed the development of cutaneous HSV-1 lesions, and associated mortality, when applied topically at a concentration as low as 0.1%. For the treatment of systemic HSV-1 infection in Naval Medical Research Institute mice, a single oral dose per day of 5 mg of CEDU per kg achieved a significant reduction in the mortality rate. Against HSV-1 encephalitis, CEDU exerted a significant protective effect at a dosage of 50 mg/kg per day when administered intraperitoneally. CEDU was effective against systemic HSV-1 infection and HSV-1 encephalitis in mice at a 5- to 15-fold-lower dose than either BVDU or acyclovir. When given orally, CPDU and CEDC were considerably less active than CEDU against systemic HSV-1 infection.
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003588:Cytopathogenic Effect, Viral; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy*; D066298:In Vitro Techniques; D051379:Mice; D008826:Microbial Sensitivity Tests; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009696:Nucleic Acids / Q000096:biosynthesis; D014176:Protein Biosynthesis; D011741:Pyrimidine Nucleosides / Q000494:pharmacology* / Q000627:therapeutic use; D018139:Simplexvirus / Q000187:drug effects*; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D009696:Nucleic Acids; D011741:Pyrimidine Nucleosides; C047370:5-(2-chloroethyl)-2'-deoxyuridine; D003857:Deoxyuridine