enviradene and viroxime

A series of vinylacetylene analogs of Enviroxime (1) was synthesized. The new compounds are potent inhibitors of poliovirus in tissue culture. Cross-sensitivity with Enviroxime-derived mutants shows that the new compounds have the same mechanism of action as Enviroxime, which involves the viral 3A protein. In studies with Rhesus monkeys, the p-fluoro derivative 12 was found to be unique in providing oral bioavailability. Metabolism studies using hepatic microsomes suggest that this procedure would be a useful in vitro method for selecting the appropriate animal model for testing oral absorption. Compound 12 was found to be efficacious by oral administration in treating a Coxsackie A21 infection in CD-1 mice.

Topics: Animals; Antiviral Agents; Benzimidazoles; Biological Availability; Enterovirus; Humans; Macaca mulatta; Magnetic Resonance Spectroscopy; Male; Mice; Microsomes, Liver; Oximes; Poliovirus; Rats; Rats, Inbred F344; Sulfonamides

Enviradone (EvirD, (E)-1-[(1-methylethyl) sulfonyl]-6-(1-phenyl-1-propenyl)-1 H- benzimidazole-2-amine) and Enviroxime (EvirX, 2-amino-1-(isopropyl-sulfonyl)-6-benzimidazole phenyl ketone oxime) inhibited enterovirus 70 (EV70) and coxsackievirus A24 variant (CA24v) infection of conjunctival and laryngeal cells. On average, the continuous presence of 1-3 micrograms of EvirD or EvirX/ml in cell cultures acutely infected with EV70 or CA24v inhibited virus production (> 2 log10 reduction) and 100% of the viral cytopathogenic effect (CPE). The 50% CPE inhibitory dose (ID50) for EvirD and EvirX against 11 EV70 and 15 CA24v isolates ranged from 0.01 to 0.3 microgram and 0.01-0.65 microgram/ml, respectively. The mean ID50 for EvirD and EvirX against the 26 AHC viruses was 0.17 +/- 0.12 microgram and 0.13 +/- 0.14 microgram/ml, respectively. Pretreatment for 15 min with 3 micrograms EvirX/ml or for 1-2 h with 3 micrograms EvirD/ml protected conjunctival cells against viral CPE. The cells were resistant to infection for 1-2 h at 33 and 37 degrees C after removal of EvirD and EvirX. The addition of 10 micrograms EvirD/ml up to 6 h or 10 micrograms EvirX/ml 1-2 h after low multiplicity infection inhibited viral CPE. Ten-fold less EvirD inhibited EV70 when added to glioma cells 2 h before infection than when added 2 h after infection. Our results indicate that EvirX and EvirD inhibit AHC viruses in vitro at concentrations that are not cytotoxic and suggest that EvirX or EvirD may be prove useful against AHC.

Topics: Antiviral Agents; Benzimidazoles; Cell Line; Conjunctivitis, Acute Hemorrhagic; Cytopathogenic Effect, Viral; Enterovirus; Humans; Oximes; Sulfonamides; Time Factors; Tumor Cells, Cultured; Virus Replication

A significant reduction in the death rate of infant mice infected with ten 50% lethal doses (LD50) of coxsackievirus A16 was observed when they were treated 58 h after infection with two injections of guanidine at 145 mg/kg per injection. Tremors occurred at this level but disappeared after treatment was discontinued. Tremors were apparent, but less severe at 97 mg/kg per injection and did not occur at 48 mg/kg per injection. No antiviral effect could be detected at either of these levels of guanidine. When an inactive level of guanidine (97 mg/kg per injection) was combined with 1.7 mg/kg per injection of LY122771-72, LY127123, or 2-(alpha-hydroxybenzyl)benzimidazole (HBB) and 17 mg/kg per injection of 2-guanidino-benzimidazole (GB), significant activity resulted with 2-8 treatments begun 58 h after infection. The same treatment schedule using 136 mg/kg per injection of LY122771-72, 90 mg/kg per injection of LY127123, 136 mg/kg per injection of HBB and 68 mg/kg per injection of GB produced no effect. Guanidine-associated tremors were also enhanced by the addition of the substituted benzimidazoles. When guanidine was reduced to 48 mg/kg per injection, 34 mg/kg per injection of LY122771-72 was required to produce a significant reduction in the death rate and no tremors were observed.

Topics: Animals; Antiviral Agents; Benzimidazoles; Coxsackievirus Infections; Drug Combinations; Drug Synergism; Enterovirus; Guanidine; Guanidines; Mice; Oximes; Structure-Activity Relationship; Sulfonamides