Potential transition state phosphoramidate inhibitors of beta-tubulin as antifilarial agents

Transition state phosphoramidate inhibitors of beta -tubulin were designed as potential antifilarial agents. The reaction of 2-aminobenzimidazole with diisopropyl phosphite and carbon tetrachloride at a low temperature gave the unexpected 1-diisopropoxyphosph oryl-2-aminobenzimidazole which on heating gave the novel benzimidazole der ivative, 2-(diisopropoxyphosphoryl)aminobenzimidazole. Both products were f ully characterized and the synthetic procedure to both compounds was optimi zed. The procedure was used to prepare the related 5-benzoyl-2-(diisopropox yphosphoryl)aminobenzimidazole and 5-benzoyl-2-(diethoxyphosphoryl)aminoben zimidazole (1d). In a preliminary trial against Brugia pahangi compound Id was found to have no antifilarial activity. This lack of activity may be at tributed to its extreme insolubility and thus low bioavailability. The synt hesis of analogous, more soluble, phosphorothioate-substituted benzimidazol es using the same methods may yield compounds with greater antifilarial act ivity.