title: In vitro and in vivo anti-picornavirus activity of some p-benzoylphenoxypyridines.
abstract: Fifteen p-benzoylphenoxypyridines were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2 and 64 and coxsackie virus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice lethally challenged with Cox A21. One compound, (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone, was selected for additional evaluation. These studies showed the compound to possess MIC50 values of less than or equal to 5 micrograms/ml against only 6 of 20 (30.0%) RV serotypes tested. In contrast, the compound was active at concentrations of less than or equal to 5.0 micrograms/ml against 10 of 12 (83.3%) enteroviruses evaluated. In vivo studies showed the compound to significantly protect mice lethally infected with Cox A21 after a single oral dose of 37.5 mg/kg (P less than 0.02) and during a regimen of continuous oral doses of at least 4.7 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibits picornavirus uncoating or some earlier virus-host cell-associated event. Isotopic studies show that (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone perturbs HeLa cell macromolecular synthesis at concentrations of as low as 3.12 micrograms/ml. This concentration is only 4-fold higher than the concentration of compound necessary to inhibit Cox A21 RNA synthesis by 90%. This narrow therapeutic ratio limits the potential clinical utility of this compound to all but the most serious picornavirus infections.
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004458:Echovirus 6, Human / Q000187:drug effects; D004770:Enterovirus / Q000187:drug effects; D029822:Enterovirus B, Human / Q000187:drug effects; D006367:HeLa Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D051379:Mice; D010849:Picornaviridae / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D011725:Pyridines