9-(2-(phosphonomethoxy)ethyl)adenine-diphosphate and Neuralgia

A series of novel acyclic nucleoside phosphonates (ANPs) was synthesized as potential adenylate cyclase inhibitors, where the adenine nucleobase of adefovir (PMEA) was replaced with a 5-substituted 2-aminothiazole moiety. The design was based on the structure of MB05032, a potent and selective inhibitor of fructose 1,6-bisphosphatase and a good mimic of adenosine monophosphate (AMP). From the series of eighteen novel ANPs, which were prepared as phosphoroamidate prodrugs, fourteen compounds were potent (single digit micromolar or submicromolar) inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT), mostly without observed cytotoxicity in J774A.1 macrophage cells. Selected phosphono diphosphates (nucleoside triphosphate analogues) were potent inhibitors of ACT (IC

Topics: Adenylate Cyclase Toxin; Adenylyl Cyclase Inhibitors; Animals; Anti-Bacterial Agents; Bacillus anthracis; Bordetella pertussis; Cell Line; Dose-Response Relationship, Drug; Humans; Mice; Microbial Sensitivity Tests; Molecular Structure; Neuralgia; Organophosphonates; Structure-Activity Relationship; Thiazoles