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 tsetse 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 Trypanosoma species, which cause human sleeping sickness.


METHODS
Chalcone and acyl hydrazide derivatives are known to retard the growth of Plasmodium falciparum in vitro and inhibit the malarial 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 trypanopain-Tb, the major cysteine proteinase of T. b. brucei.


RESULTS
Several related chalcones, acyl hydrazides, and amides killed cultured bloodstream forms of T. b. brucei, with the most effective compound reducing parasite numbers by 50% relative to control populations at a concentration of 240 nM. The most effective inhibitors protected mice from an otherwise lethal T. b. brucei infection in an in vivo model of acute parasite infection. Many of the compounds also inhibited trypanopain-Tb, with the most effective inhibitor having a Ki value of 27 nM. Ki values for trypanopain-Tb inhibition were up to 50- to 100-fold lower than for inhibition of mammalian cathepsin L, suggesting the possibility of selective inhibition of the parasite enzyme.


CONCLUSIONS
Chalcones, acyl hydrazides, and amides show promise as antitrypanosomal chemotherapeutic agents, with trypanopain-Tb possibly being one of their in vivo targets.
Troeberg
L
L
School of Molecular and Cellular Biosciences, University of Natal Pietermaritzburg, Scottsville, South Africa.
Chen
X
X
Flaherty
T M
TM
Morty
R E
RE
Cheng
M
M
Hua
H
H
Springer
C
C
McKerrow
J H
JH
Kenyon
G L
GL
Lonsdale-Eccles
J D
JD
Coetzer
T H
TH
Cohen
F E
FE
D000577:Amides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D010450:Endopeptidases; D006801:Humans; D006834:Hydrazines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D012756:Sheep; D014344:Trypanocidal Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D014352:Trypanosomiasis / Q000188:drug therapy / Q000469:parasitology
D000577:Amides; D015853:Cysteine Proteinase Inhibitors; D006834:Hydrazines; D014344:Trypanocidal Agents; D002599:Chalcone; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C100684:trypanopain Tb; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse