New prodrugs of the antiprotozoal drug pentamidine

ChemMedChem. 2011 Dec 9;6(12):2233-42. doi: 10.1002/cmdc.201100422. Epub 2011 Oct 7.


Pentamidine is an effective antimicrobial agent that is approved for the treatment of African trypanosomiasis but suffers from poor oral bioavailability and central nervous system (CNS) penetration. This work deals with the development and systematic characterisation of new prodrugs of pentamidine. For this reason, numerous prodrugs that use different prodrug principles were synthesised and examined in vitro and in vivo. Another objective of the study was the determination of permeability of the different pentamidine prodrugs. While some of the prodrug principles applied in this study are known, such as the conversion of the amidine functions into amidoximes or the O-alkylation of amidoximes with a carboxymethyl residue, others were developed more recently and are described here for the first time. These newly developed methods aim to increase the affinity of the prodrug for the transporters and mediate an active uptake via carrier systems by conjugation of amidoximes with compounds that improve the overall solubility of the prodrug. The different principles chosen resulted in several pentamidine prodrugs with various advantages. The objective of this investigation was the systematic characterisation and evaluation of eight pentamidine prodrugs in order to identify the most appropriate strategy to improve the properties of the parent drug. For this reason, all prodrugs were examined with respect to their solubility, stability, enzymatic activation, distribution, CNS delivery, and oral bioavailability. The results of this work have allowed reliable conclusions to be drawn regarding the best prodrug principle for the antiprotozoal drug pentamidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antiprotozoal Agents / chemical synthesis
  • Antiprotozoal Agents / chemistry*
  • Antiprotozoal Agents / pharmacokinetics
  • Cell Line
  • Cell Membrane Permeability
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Stability
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Microsomes, Liver / metabolism
  • Pentamidine / chemical synthesis
  • Pentamidine / chemistry*
  • Pentamidine / pharmacokinetics
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacokinetics
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Swine
  • Tissue Distribution


  • Antiprotozoal Agents
  • Prodrugs
  • Pentamidine
  • Cytochrome P-450 Enzyme System