Evaluation of human PDE4 inhibitors cilomilast and piclamilast as lead compounds for the treatment of human African trypanosomiasis (HAT).

Abstract

1Northeastern University, Department of Chemistry and Chemical Biology, Hurtig 102, 360 Huntington Avenue, Boston, MA 02115. 2Marine Biological Laboratory, Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, 7 MBL Street, Woods Hole, MA 02543

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In the present work we illustrate our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT).

We have previously shown that the human PDE4 inhibitor piclamilast and some of its analogues show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei. Here we describe our recent progress in understanding the SAR of the human PDE4 inhibitors piclamilast and cilomilast, tested against the parasitic enzyme TbrPDEB1. Inhibitor design strategies and compound syntheses will be reported.