Chalcone, acyl hydrazide, and related amides kill cultured Trypanosoma brucei brucei

Background: Protozoan parasites of the genus Trypanosoma cause disease in a wide range of mammalian hosts. Trypanosoma brucei brucei, transmitted by t setse fly to cattle, causes a disease (Nagana) of great economic importance in parts of Africa. T. b. brucei also serves as a model for related Trypan asoma species, which cause human sleeping sickness. Materials and Methods: Chalcone and acyl hydrazide derivatives are known to retard the growth of Plasmodium falciparum in vitro and inhibit the malari al cysteine proteinase, falcipain. We tested the effects of these compounds on the growth of bloodstream forms of T. b. brucei in cell culture and in a murine trypanosomiasis model, and investigated their ability to inhibit t rypanopain-Tb, the major cysteine proteinase of T. b. brucei. Results: Several related chalcones, acyl hydrazides, and amides killed cult ured bloodstream forms of T. b. brucei, with the most effective compound re ducing parasite numbers by 50% relative to control populations at a concent ration of 240 nM. The most effective inhibitors protected mice from an othe rwise lethal T. b. brucei infection in an in vivo model of acute parasite i nfection. Many of the compounds also inhibited trypanopain-Tb, with the mos t effective inhibitor having a K-i value of 27 nM. K-i values for trypanopa in-Tb inhibition were up to 50- to 100-fold lower than for inhibition of ma mmalian cathepsin L, suggesting the possibility of selective inhibition of the parasite enzyme. Conclusions: Chalcones, acyl hydrazides, and amides show promise as antitry panosomal chemotherapeutic agents, with trypanopain-Tb possibly being one o f their in vivo targets.