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-diisopropoxyphosphoryl-2-aminobenzimidazole, which on heating gave the novel benzimidazole derivative, 2-(diisopropoxyphosphoryl)aminobenzimidazole. Both products were fully characterized and the synthetic procedure to both compounds was optimized. The procedure was used to prepare the related 5-benzoyl-2-(diisopropoxyphosphoryl)aminobenzimidazole and 5-benzoyl-2-(diethoxyphosphoryl)aminobenzimidazole (1d). In a preliminary trial against Brugia pahangi compound 1d was found to have no antifilarial activity. This lack of activity may be attributed to its extreme insolubility and thus low bioavailability. The synthesis of analogous, more soluble, phosphorothioate-substituted benzimidazoles using the same methods may yield compounds with greater antifilarial activity.
Anderson
R J
RJ
Institute of Pharmacy and Chemistry, University of Sunderland, UK.
Bendell
D J
DJ
Hooper
M
M
Cairns
D
D
Mackay
S P
SP
Hiremath
S P
SP
Jivanagi
A S
AS
Badami
S
S
Biradar
J S
JS
Townson
S
S
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017179:Brugia pahangi / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000737:chemistry; D005369:Filaricides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010756:Phosphoric Acids / Q000494:pharmacology*; D013696:Temperature; D050257:Tubulin Modulators
D000577:Amides; D001562:Benzimidazoles; D005369:Filaricides; D010756:Phosphoric Acids; D050257:Tubulin Modulators; C011067:phosphoramidic acid; D002251:Carbon Tetrachloride; C027391:2-aminobenzimidazole