Synthesis, Antiviral Activity, and Biological Properties of Vinylacetylene Analogs of Enviroxime

Abstract

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.

Potential Use of Antiviral Agents in Polio Eradication

“…However, a further exploration of the potential of enviroxime analogs could be worthwhile, in an attempt to improve the activity, selectivity, and in particular, the pharmacokinetic profi le (25,26).…”

“…Previous in vivo studies with enviroxime, however, have shown toxicity and only weak to moderate activity, due to poor solubility and pharmacokinetics (21)(22)(23)(24). Structural derivatives of enviroxime such as the C 2 -and vinylacetylene analogs were reported to have a better oral bioavailability and pharmacologic profi le (25,26) and may therefore be considered as leading candidates for further development.…”

Novel synthesis of benzimidazole by Ring Contraction Rearrangement of benzodiazepine

“…Many reports have revealed that the influence of the substitution at the 1,2 and 5-positions of the benzimidazole ring was very important for their pharmacological effects (Ashnagar et al, 2009;Patel and Singh, 2009). It is well known that several 1,2-disubstituted benzimidazoles 1 (DeLong, 1984;Miller et al, 1985), 2 (Porcari et al, 1998), 3 (Victor et al, 1997), 4 (Garuti et al, 1998), 5 (Swayze et al, 1993), 6 (Gardiner et al, 1995) were potent inhibitors of RNA viruses. Thus, this let us to prepare and evaluate other derivatives (Figure 1).…”

Antiviral and Antiproliferative Activity in vitro of some New Benzimidazole Derivatives

“…The pyridine portion in position 2 of the heterocyclic ring also contributes to the antiviral activity, as has been demonstrated in the case of a series of 2-(4-pyridylaminomethyl)-benzimidazoles (Nobukatsu et al 1985). Finally, regarding the position N-1, the sulphonyl group plays an important role in improving the compounds' activity against Rhinovirus, Poliovirus and Coxsackievirus (Wikel et al 1980;Victor et al 1997).…”