Bisamidate Prodrugs of 2-Substituted 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA, adefovir) as Selective Inhibitors of Adenylate Cyclase Toxin from Bordetella pertussis

ChemMedChem. 2015 Aug;10(8):1351-64. doi: 10.1002/cmdc.201500183. Epub 2015 Jul 1.


Novel small-molecule agents to treat Bordetella pertussis infections are highly desirable, as pertussis (whooping cough) remains a serious health threat worldwide. In this study, a series of 2-substituted derivatives of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir), in their isopropyl ester bis(L-phenylalanine) prodrug form, were designed and synthesized as potent inhibitors of adenylate cyclase toxin (ACT) isolated from B. pertussis. The series consists of PMEA analogues bearing either a linear or branched aliphatic chain or a heteroatom at the C2 position of the purine moiety. Compounds with a small C2 substituent showed high potency against ACT without cytotoxic effects as well as good selectivity over human adenylate cyclase isoforms AC1, AC2, and AC5. The most potent ACT inhibitor was found to be the bisamidate prodrug of the 2-fluoro PMEA derivative (IC50 =0.145 μM). Although the bisamidate prodrugs reported herein exhibit overall lower activity than the bis(pivaloyloxymethyl) prodrug (adefovir dipivoxil), their toxicity and plasma stability profiles are superior. Furthermore, the bisamidate prodrug was shown to be more stable in plasma than in macrophage homogenate, indicating that the free phosphonate can be effectively distributed to target tissues, such as the lungs. Thus, ACT inhibitors based on acyclic nucleoside phosphonates may represent a new strategy to treat whooping cough.

Keywords: Bordetella pertussis; PMEA; adenylate cyclase toxin; bisamidates; nucleosides; phosphonates; prodrugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / toxicity
  • Adenylate Cyclase Toxin / antagonists & inhibitors*
  • Adenylate Cyclase Toxin / metabolism
  • Animals
  • Binding Sites
  • Bordetella pertussis / metabolism*
  • Cell Line
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Half-Life
  • Humans
  • Male
  • Mice
  • Molecular Docking Simulation
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry*
  • Organophosphonates / toxicity
  • Prodrugs / chemistry*
  • Prodrugs / pharmacokinetics
  • Prodrugs / toxicity
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Protein Structure, Tertiary
  • Rats
  • Rats, Wistar


  • Adenylate Cyclase Toxin
  • Organophosphonates
  • Prodrugs
  • Protein Isoforms
  • Adenine
  • adefovir dipivoxil