The Utility of Sulfonylhydrazines in the Study and Potential Treatment of African Sleeping Sickness

Abstract

African sleeping sickness is an invariably fatal disease caused by Trypanosoma brucei group trypanosomes and transmitted by the bite of a Tsetse fly. In the human bloodstream, there are two main forms: long slender rapidly proliferating forms and biochemically distinct, non-proliferating short stumpy forms. These short stumpy forms are preadapted for life in the Tsetse fly gut and cannot sustain or initiate infection in the mammalian host. It was observed that exposure of long slender bloodstream trypomastigotes to a wide range of methylating agents could induce the entire population to differentiate into short stumpy forms. The methylators varied in their nucleophile preference from hard oxygen targets to soft thiol targets. Despite this wide variability, the methylators were all almost equivalently active. It was therefore assumed that the salient target was likely nitrogen of intermediate hardness/softness which would be equivalently targeted by both groups of methylators. A number of sulfonylhydrazine methylators including prodrug forms, with improved biological distribution in animals, were synthesized. In addition, some amidine moiety containing methylators were also synthesized to exploit the propensity of long slender trypanomastigotes to accumulate agents containing this chemical group, in an attempt to enhance their efficacy. These agents may be of utility in the study of differentiation in T. brucei group trypanosomes, and the production of large quantities of short stumpy forms for biochemical studies. Additionally, they could have therapeutic potential in the treatment of late-stage African sleeping sickness.