Abstract
Treatment of animal African trypanosomiasis (AAT) requires urgent need for safe, potent and affordable drugs and this has necessitated this study. We investigated the trypanocidal activities and mode of action of selected 3-aminosteroids against Trypanosoma brucei brucei. The in vitro activity of selected compounds of this series against T. congolense (Savannah-type, IL3000), T. b. brucei (bloodstream trypomastigote, Lister strain 427 wild-type (427WT)) and various multi-drug resistant cell lines was assessed using a resazurin-based cell viability assay. Studies on mode of antitrypanosomal activity of some selected 3-aminosteroids against Tbb 427WT were also carried out. The tested compounds mostly showed moderate-to-low in vitro activities and low selectivity to mammalian cells. Interestingly, a certain aminosteroid, holarrhetine (10, IC50 = 0.045 ± 0.03 µM), was 2 times more potent against T. congolense than the standard veterinary drug, diminazene aceturate, and 10 times more potent than the control trypanocide, pentamidine, and displayed an excellent in vitro selectivity index of 2130 over L6 myoblasts. All multi-drug resistant strains of T. b. brucei tested were not significantly cross-resistant with the purified compounds. The growth pattern of Tbb 427WT on long and limited exposure time revealed gradual but irrecoverable growth arrest at ≥ IC50 concentrations of 3-aminosteroids. Trypanocidal action was not associated with membrane permeabilization of trypanosome cells but instead with mitochondrial membrane depolarization, reduced adenosine triphosphate (ATP) levels and G2/M cell cycle arrest which appear to be the result of mitochondrial accumulation of the aminosteroids. These findings provided insights for further development of this new and promising class of trypanocide against African trypanosomes.
Highlights
Animal African trypanosomiasis (AAT), a severe wasting disease of domestic livestock, is caused predominantly by T. congolense, T. vivax and T. b. brucei [1]
Against the backdrop of our continued effort towards the development of 3-aminosteroid lead compounds, we report the trypanocidal activities of some 3-aminosteroids against Trypanosoma congolense (Tc-IL3000, Savannah type strain), wild-type strain of Trypanosoma brucei brucei (Tbb 427WT) and some resistant strains derived from the wild type and further present observations on the mode of action of two selected 3-aminosteroids against T. brucei species
50 = 1.62 μ M) being the most active compounds against T. b. brucei under our much higher levels of activity previously determined are against the human pathogen, b
Summary
Animal African trypanosomiasis (AAT), a severe wasting disease of domestic livestock, is caused predominantly by T. congolense, T. vivax and T. b. brucei [1]. With a high mortality rate of 20–50% within months of infecting cattle compounded by the lack of vaccine, and the steady increase in reported cases of drug resistance, AAT has remained a threat to food security in the affected regions [4,5] It is endemic in 37 sub-Saharan countries where about 50 million cattle are at risk of contracting the disease, while deterring the importation of horses, high-yield dairy cattle and other non-indigenous domestic animals that are vulnerable to AAT, to the further detriment of agricultural production [6]. Against the backdrop of our continued effort towards the development of 3-aminosteroid lead compounds, we report the trypanocidal activities of some 3-aminosteroids against Trypanosoma congolense (Tc-IL3000, Savannah type strain), wild-type strain of Trypanosoma brucei brucei (Tbb 427WT) and some resistant strains derived from the wild type and further present observations on the mode of action of two selected 3-aminosteroids against T. brucei species
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