A series of 13 acyclic nucleoside phosphonates (ANPs) as bisamidate prodrugs was prepared. Five compounds were found to be non-cytotoxic and selective inhibitors of Bordetella pertussis adenylate cyclase toxin (ACT) in J774A.1 macrophage cell-based assays. The 8-aza-7-deazapurine derivative of adefovir (PMEA) was found to be the most potent ACT inhibitor in the series (IC50 =16 nm) with substantial selectivity over mammalian adenylate cyclases (mACs). AC inhibitory properties of the most potent analogues were confirmed by direct evaluation of the corresponding phosphonodiphosphates in cell-free assays and were found to be potent inhibitors of both ACT and edema factor (EF) from Bacillus anthracis (IC50 values ranging from 0.5 to 21 nm). Moreover, 7-halo-7-deazapurine analogues of PMEA were discovered to be potent and selective mammalian AC1 inhibitors (no inhibition of AC2 and AC5) with IC50 values ranging from 4.1 to 5.6 μm in HEK293 cell-based assays.

• Keywords
• Bacillus anthracis, Bordetella pertussis, adefovir, adenylate cyclase, inhibitors,
• MeSH
• Adenine analogs & derivatives   chemical synthesis   chemistry   pharmacology   MeSH
• Adenylyl Cyclases metabolism   MeSH
• Bacillus anthracis enzymology   MeSH
• Bordetella pertussis enzymology   MeSH
• Enzyme Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Molecular Structure MeSH
• Organophosphonates chemical synthesis   chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• adefovir MeSH Browser
• Adenine MeSH
• Adenylyl Cyclases MeSH
• Enzyme Inhibitors MeSH
• Organophosphonates MeSH