In vitro and in vivo evaluation of 28DAP010, a novel diamidine for treatment of second-stage African sleeping sickness

Tanja Wenzler; Sihyung Yang; Donald A Patrick; Olivier Braissant; Mohamed A Ismail; Richard R Tidwell; David W Boykin; Michael Zhuo Wang; Reto Brun

doi:10.1128/AAC.02309-13

In vitro and in vivo evaluation of 28DAP010, a novel diamidine for treatment of second-stage African sleeping sickness

Antimicrob Agents Chemother. 2014 Aug;58(8):4452-63. doi: 10.1128/AAC.02309-13. Epub 2014 May 27.

Authors

Tanja Wenzler¹, Sihyung Yang², Donald A Patrick³, Olivier Braissant⁴, Mohamed A Ismail⁵, Richard R Tidwell³, David W Boykin⁵, Michael Zhuo Wang², Reto Brun⁶

Affiliations

¹ Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland Tanja.Wenzler@unibas.ch.
² Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, USA.
³ Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
⁴ University of Basel, Basel, Switzerland Department of Urology, University Hospital of Basel, Basel, Switzerland.
⁵ Department of Chemistry, Georgia State University, Atlanta, Georgia, USA.
⁶ Medical Parasitology & Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland University of Basel, Basel, Switzerland.

Abstract

African sleeping sickness is a neglected tropical disease transmitted by tsetse flies. New and better drugs are still needed especially for its second stage, which is fatal if untreated. 28DAP010, a dipyridylbenzene analogue of DB829, is the second simple diamidine found to cure mice with central nervous system infections by a parenteral route of administration. 28DAP010 showed efficacy similar to that of DB829 in dose-response studies in mouse models of first- and second-stage African sleeping sickness. The in vitro time to kill, determined by microcalorimetry, and the parasite clearance time in mice were shorter for 28DAP010 than for DB829. No cross-resistance was observed between 28DAP010 and pentamidine on the tested Trypanosoma brucei gambiense isolates from melarsoprol-refractory patients. 28DAP010 is the second promising preclinical candidate among the diamidines for the treatment of second-stage African sleeping sickness.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amidines / chemical synthesis
Amidines / pharmacokinetics
Amidines / pharmacology*
Animals
Dose-Response Relationship, Drug
Female
Humans
Melarsoprol / pharmacokinetics
Melarsoprol / pharmacology
Mice
Pentamidine / pharmacokinetics
Pentamidine / pharmacology
Pyridines / chemical synthesis
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Structure-Activity Relationship
Trypanocidal Agents / chemical synthesis
Trypanocidal Agents / pharmacokinetics
Trypanocidal Agents / pharmacology*
Trypanosoma brucei gambiense / drug effects*
Trypanosoma brucei gambiense / growth & development
Trypanosoma brucei gambiense / pathogenicity
Trypanosoma brucei rhodesiense / drug effects*
Trypanosoma brucei rhodesiense / growth & development
Trypanosoma brucei rhodesiense / pathogenicity
Trypanosomiasis, African / drug therapy*
Trypanosomiasis, African / parasitology

Substances

Amidines
CPD 0801
CPD0905
Pyridines
Trypanocidal Agents
Pentamidine
Melarsoprol